Vol.:(0123456789)
Topics in Current Chemistry (2019) 377:19https://doi.org/10.1007/s41061-019-0243-6
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REVIEW
In the Search of Glycoside‑Based Molecules as Antidiabetic Agents
Aleksandra Pałasz, et al. [full author details at the end of the article]
Received: 20 December 2018 / Accepted: 14 May 2019 / Published online: 5 June 2019 © The Author(s) 2019
AbstractThis review is an effort to summarize recent developments in synthesis of O-glyco-sides and N-, C-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the O-glycosides used in the treatment of diabetes are presented, followed by the N-glycosides and finally the C-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing poten-tial drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order. C-Glycosyl compounds mim-icking O-glycosides structure, exhibit the best features in terms of pharmacody-namics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various C-glycosides. Also N-glycosides such as N-(β-d-glucopyranosyl)-amides, N-(β-d-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidia-betic agents. In order to indicate which of the compounds presented in the given sec-tions have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect. 5. In Sect. 6, biological mechanisms of action of the glycosides and patents of marketed drugs are described.
Keywords O-Glycosides · N-Glycosides · C-Glycosides · Diabetes type 2 · Glycogen phosphorylase inhibitor · Sodium-dependent glucose cotransporter inhibitor
AbbreviationsAc AcetylAr Aryl
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Asn AsparagineAsp Aspartic acidBn BenzylBoc tert-ButyloxycarbonyliBu Isobutyln-Bu n-Butylt-Bu tert-ButylBz BenzoylCAN Cerium ammonium nitrateCuAAC Copper-catalyzed azide–alkyne cycloadditionDBU 1,8-Diazabicyclo[5.4.0]undec-7-eneDCC N,N’-DicyclohexylcarbodiimideDCM DichloromethaneDIAD Diisopropyl azodicarboxylateDMAP N,N-Dimethyl-4-aminopyridineDME DimethoxyethaneDMF DimethylformamideDMSO Dimethyl sulfoxideEDCI N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimideEt EthylGP Glycogen phosphorylaseGS Glycogen synthaseHetaryl Heteroaromatic ringHMPA HexamethylphosphoramideHOBt HydroxybenzotriazoleHPLC High-performance liquid chromatographyIC50 Half maximal inhibitory concentrationKi Inhibition constantLDA Lithium diisopropylamideMe MethylMOM MethoxymethylMOMCl Methoxymethyl chlorideMs MesylNBS N-bromosuccinimideNCS N-chlorosuccinimideNMM N-MethylmorpholineNMO N-Methylmorpholine N-oxidePh PhenyliPr IsopropylPTP1B Protein tyrosine phosphatase 1BQSAR Quantitative structure–activity relationshipRMGP Rat muscle glycogen phosphorylaseSAR Structure–activity relationshipSGLT Sodium-dependent glucose cotransporterTBA tert-Butyl alcoholTBAF Tetrabutylammonium fluoride
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TBDMS tert-ButyldimethylsilylTBDMSCl tert-Butyldimethylsilyl chlorideTBS tert-ButyldimethylsilylTBSCl tert-Butyldimethylsilyl chlorideT2DM Type 2 diabetes mellitusTEA TriethylamineTFA Trifluoroacetic acidTHF TetrahydrofuranTIPS TriisopropylsilylTMS TrimethylsilylTMSI Trimethylsilyl iodideTMSOTf Trimethylsilyl trifluoromethanesulfonateTs TosylTyr Tyrosine
1 Introduction
Diabetes mellitus is a disease closely associated with the metabolic syndrome and in developed countries it is a major public health problem [1–3]. There are three main types of diabetes mellitus: type 1 (insulin-dependent), type 2 (insulin resistance), and gestational diabetes. Type 2 diabetes mellitus (T2DM) accounts for 90–95% of the diabetic cases. In T2DM, insulin resistance is the major problem. Chronic hyper-glycemia is associated with long-term damage, dysfunction and failure of various organs such as eyes, kidneys, nerves, heart and blood vessels. While type 1 diabetics can be treated by the administration of exogenous insulin, for type 2 patients gen-erally diet, exercise, and oral hypoglycemic agents are prescribed. A large number of oral antidiabetic drugs aimed to eliminate three major metabolic disorders lead-ing to hyperglycemia-dysfunction of β-cells, peripheral insulin resistance, excessive hepatic glucose production [4, 5]. Current pharmacological treatments are sympto-matic and aim at maintaining the blood glucose levels close to the fasting normo-glycemic range of 3.5–6 mM/l. This can be achieved by an array of small molecule drugs (e.g., biguanides, sulfonylureas, thiazolidinediones, glycosidase inhibitors) and ultimately by administration of insulin.
Metformin is a biguanide, which is now the most widely prescribed antidia-betic drug (Fig. 1). Metformin is the first-line medication for the treatment of type 2 diabetes particularly in people who are overweight and is believed to be
Fig. 1 Metformin—the most widely prescribed antidiabetic drug
NH
N NH3C
CH3 H
NH
NH2
Metformin
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the most widely used medication for diabetes, which is taken by mouth. However, for 30–40% of T2DM patients, combination therapy is frequently applied as phar-macological treatments.
Glycogen is a polymer of α-1,4- and α-1,6-linked glucose units that provides a readily available source of energy in living organisms. Glycogen synthase (GS) and glycogen phosphorylase (GP) are the two enzymes that control the synthe-sis and degradation of this polysaccharide. A key role in glycogen metabolism plays GP [6, 7]. With the rapid increase of type 2 diabetic patients recently, it is becoming an interesting field to discover GP inhibitors for potential antidiabetic drugs. As GP is a typical allosteric protein with several key inhibitor-binding sites including the inhibitor, the catalytic, the allosteric, and the new allosteric sites, the research works were mainly focused on compounds that can bind these sites and show selective inhibitory effect [6–10]. So, GP transfers a glucose unit from the non-reducing end of the storage polysaccharide glycogen to an inorganic phosphate. Three isoforms of GP exist in the brain, muscle, and liver tissue. The liver is capable of storing glucose as glycogen and producing and releasing glu-cose to the bloodstream [6, 7]. GP is an allosteric enzyme, which exists in two interconvertible forms GPa (phosphorylated, active, high substrate affinity) and GPb (unphosphorylated, inactive, low substrate affinity). Design of GP inhibi-tors is a target for a better control of hyperglycemia. The inhibitors targeting the seven binding sites of GP show a large molecular diversity. Among them, vari-ous glucose derivatives bind mostly to the catalytic site of the enzyme. N-Acyl-β-d-glucopyranosylamines, N-acyl-N′-β-d-glucopyranosyl ureas, glucopyra-nosylidene-spiro-heterocycles, as well as N- and C-glucosylated heterocycles belong to the most potent classes of this inhibitor family [6, 7]. In 2001, So and Karplus designed a number of potential GP inhibitors with a variety of computa-tional approaches [11]. 2D and 3D similarity-based QSAR models were used to identify novel molecules that may bind to the glucose-binding site. The designed ligands were evaluated by a multiple screening method [12]. In this way, a total of 301 candidate ligands for GP have been designed using an array of computational approaches.
Several kinds of mimics of O-glycosides, first of all S-, N-, and C-glycosyl deriv-atives, may display similar biological activities; however, due to their significantly distinct chemical properties, such molecules can be valuable tools in deciphering the biological roles of natural sugars, and may also serve as leads for new drugs. Among glycomimetics, C-glycosides have attracted much attention due to the existence of a number of naturally occurring representatives. Comparing to O-glycosides, the C-glycosides are structurally more stable against acidic and enzymatic cleavage due to the existence of their C–C glycosidic bond. Bristol-Myers Squibb [13] and Koto-buki [14] disclosed C-aryl glucosides in 2001, which appear to have potent inhibi-tion and good stability in vivo.
Many efforts devoted to develop carbohydrate-based therapeutics aim at finding inhibitors of glycoprocessing enzymes and discovering their structure–activity rela-tionships (SAR). In therapies of diabetes, sugar derived or glycomimetic structures, such as acarbose, miglitol, or voglibose, have been applied (Fig. 2) [15].
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In 2017, Bokor et al. presented a review [16] where they described the syntheses and diverse bioactivities of C-glycopyranosyl arenes and heteroarenes. They pro-vided a classification of the preparative routes to these synthetic targets according to methodologies and compound categories. Several of these compounds display anti-diabetic properties due to enzyme inhibition and are used in the pharmacological treatment of type 2 diabetes. Figure 3 shows the glycoside structures that are dis-cussed in this article. O-Glycosides, N-glycosides, and C-glycosides as antidiabetic drugs have been described in the following sections.
2 O‑Glycosides as Antidiabetic Agents
It is known that an O-glycoside—natural product phlorizin (Fig. 4) can lower plasma glucose levels and improve insulin resistance by increasing renal glucose excretion [17]. However, its sensitivity toward hydrolysis by glucosidases, unselective inhi-bition of both SGLTs (sodium glucose transporters), and unfavorable effects of its aglycon phloretin on other glucose transporters prevented this compound from use as an antidiabetic drug.
More recently, guava leaves have gained attention in the control of T2DM [18, 19]. In 2013, Eidenberger and coworkers investigated in vitro the effect of extracts from Psidium guajava L. leaves containing the flavonol-glycoside components [20]. An ethanolic extract was prepared from dried, powdered leaves of guava and was found to contain seven main flavonol-glycosides, which were isolated by semi-pre-parative HPLC and tested individually. All isolated flavonol-glycosides were tested for their antidiabetic potential. Peltatoside 1, hyperoside 2, isoquercitrin 3, and guai-javerin 4 (Fig. 5) show an inhibitory effect 5–10 times higher than that obtained for the three other partially characterized flavonol-glycosides. It seems therefore that most of the inhibitory action of the guava extract is due to the four identified fla-vonol constituents 1–4 [20].
In 2015, Diaz-Lobo et al. [21] reported on the synthesis and biological evalu-ation of O-glycoside—a selective inhibitor that consists of an azobenzene moiety
NHO
HO
OHHO
OH3C
HO OH
OO
OO
HOHO OHOH
OH
HHO HO
Acarbose
Miglitol Voglibose
N
HO
HO
HO
OH
OH
N
OHHO
HOHO
OH
H
OH
OH
Fig. 2 Carbohydrate derivatives and glycomimetic compounds in therapies of T2DM
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glycosidically linked to the anomeric carbon of a glucose molecule. The molecule incorporates an azobenzene photoswitch whose conformation can be significantly altered by irradiation with UV light. Synthesis of compound 9 (Scheme 1) started with the quantitative peracetylation of d-glucose 5 with acetic anhydride in pyri-dine. Next, the anomeric acetyl group of 1,2,3,4,6-penta-O-acetyl-d-glucopyra-noside 6 was selectively cleaved using benzylamine in THF to furnish 7 that was employed for the glycosylation of 4-hydroxyazobenzene by the Mitsunobu reaction. The resulting 4-(phenylazo)phenyl-2,3,4,6-tetra-O-acetyl-d-glucopyranoside 8 was deacetylated with MeONa/MeOH to give 4-(phenylazo)phenyl-d-glucopyranoside 9. The azoglucoside 9 was obtained as a mixture of the α and β anomers. UV light
N-glycosides
O
OR1
R1ON
NN
R3OR1R2
R1O
O
OR1
R1ON
OR1
R1O
R2
R3O
OR1
R1O
OR1
R1O N N
O
R2
C-glycosides
O
OR
RO
OR
RO
O
O
O
OR
RO
OR
RO Aryl
O
OR1
R1O
OR1
R1O
O
R2 S
OR
RO
OR
RO Aryl
ONR1
R2
OCR1
R2
R3
O
OH
HOHO
OHO
HO OH
O
OH
O
OH
HOHO
OHO
N N
O
O
O
OH
OH
OH
HO
sugar
OO R
O-glycosides
O
OR1
R1OR1O
OR1NH
O
R2
O
OR
RO
OR
RO Hetaryl
O
OH
HOHO
OHO
HO
OH
OH
cis, trans
O
OR1
R1OR1O
OR1NH
O
NHR2
O
OR
RO
OR
ROHetaryl
Fig. 3 O-Glycosides and N-, C-glycosyl antidiabetic molecules that are discussed in this review
Fig. 4 Structure of the natural product phlorizin
O
OH
HOHO
OHO
HO OH
O
OH
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induced E→Z photoisomerization of the azobenzene glucoside 9 was observed. In the ground state, the more stable (E)-isomer of the azobenzene glucoside 9 had a slight inhibitory effect on rat muscle GP (RMGP, IC50 = 4.9 mM) and Escheri-chia coli GS (EcGS, IC50 = 1.6 mM). After irradiation and subsequent conversion to the (Z)-form, the inhibitory potency of the azobenzene O-glucoside did not sig-nificantly change for RMGP (IC50 = 2.4 mM), while its effect on EcGS increased 50-fold (IC50 = 32 μM). Although compound 9 was synthesized as a 1:4 mixture of the α- and β-anomers, analysis suggested that the more abundant β-anomer is the one responsible for the observed inhibition. So, Diaz-Lobo et al. showed that the ability to selectively photocontrol the catalytic activity of key enzymes of glycogen
O
O
O
OH
OH
OH
HO
O
HO OH
OH
O
O
OH
OH
OH
O
O
O
OH
OH
OH
HO
O
HO OH
OH
OH
O
O
O
OH
OH
OH
HO
O
HO OH
OH
OH
O
O
O
OH
OH
OH
HO
O
HO OH
OH
1 2
3 4
Fig. 5 Structures of the flavonol-glycosides: peltatoside 1, hyperoside 2, isoquercitrin 3, guaijaverin 4 [20]
O
OH
HOHO
OHOH
Ac2Opyridine, rt
BnNH2THF, rt
HO NN
DIPAD, PPh3THF, rt
MeONaMeOH, rt
5 6 7
89
O
OAc
AcOAcO
OAcOAc
O
OAc
AcOAcO
OAcOH
O
OAc
AcOAcO
OAcO
N N
O
OH
HOHO
OHO
N N
99 % 60 %
57 %
99 %
Scheme 1 Synthesis of 4-(phenylazo)phenyl-d-glucopyranoside 9 [21]
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metabolism might represent a new approach for the treatment of glycogen metabo-lism disorders [21].
Functional foods can be used alone or in combination with existing therapies in preventing and treating type 2 diabetes. Trans-2,3,5,4′-tetrahydroxystilbene 2-O-β-glucopyranoside (trans-THSG) 10 (Fig. 6), a dominant bioactive compound from Polygonum multiflorum (PM), has attracted increasing research interests due to its strong antioxidant activity. The content of naturally occurring cis-THSG (cis-2,3,5,4′-tetrahydroxystilbene 2-O-β-glucopyranoside) 11 (Fig. 6) is very low in PM root, therefore W. Tang et al. prepared in 2017 cis-THSG by mimicking the tradi-tional process of PM [22]. The anti-diabetic effects of trans- and cis-THSG were evaluated in type 2 diabetes. Cis-THSG 11 was found to be more effective than trans-THSG 10 in hypoglycemic effect [22].
Figure 7 presents information on the antidiabetic activity of O-glycosides dis-cussed in Sect. 2. Below the structural formula of each inhibitor, the number of the compound and the scheme number on which it is located and the corresponding reference are provided. The most important information on the action of a given compound as a specific inhibitor is also included. Analyzing the structure of the compounds shown in Fig. 7, it can be seen that the phenyl groups are a structural element that is repeated in each compound. In the case of three compounds, they are phenolic derivatives. An interesting approach to the issue of active inhibitor struc-ture is the idea presented by Diaz-Lobo and coworkers [21], in which they turned their attention to the ability to selectively photocontrol the catalytic activity of key enzymes of glycogen metabolism.
3 N‑Glycosides as Antidiabetic Agents
3.1 N‑(β‑d‑Glucopyranosyl) Amides and N‑(β‑d‑Glucopyranosyl)‑Urea Derivatives
Since O-glycosides are usually hydrolytically unstable, many carbohydrate ana-logues such as N- or C-glycosides have been synthesized as therapeutic agents. Inhibition of GP is one of several intensively investigated approaches to find novel treatments for type 2 diabetes mellitus. Some N-glycosides such as N-(β-d-glucopyranosyl) amides 12–14 (Fig. 8) were examined as inhibitors of GP [23].
O
OH
HOHO
OHO
HO
OH
OH
10 11
O
OH
HOHO
OH
O
HO
OH
OH
Fig. 6 Structures of trans-THSG 10 and cis-THSG 11 [22]
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N-(β-d-glucopyranosyl)-N’-acyl urea derivatives 15 and 16 are also inhibitors of GP. Compound 17 represents the most efficient glucose analogue inhibitor [24].
In 2004, Gyorgydeak et al. transformed 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl- and 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-d-glucopyranosyl azides 18 into the corresponding per-O-acetylated N-(β-d-glycopyranosyl) amides 19 by Staudinger protocol (Scheme 2) [25]. Removal of the protecting groups car-ried out by Zemplén deacetylation furnished compounds 20. Compounds 19 and 20 were tested against rabbit muscle glycogen phosphorylase. The best inhibitor of this series was N-(β-d-glucopyranosyl) 3-(2-naphthyl)-propenoic amide (Ki = 3.5 μM). It was shown that the acyl urea moiety is essential for the strong inhibition. A prop-erly positioned and large enough hydrophobic group attached to the amide moiety makes the inhibition one order of magnitude stronger than that of the best amide inhibitor known earlier [N-(β-d-glucopyranosyl) acetamide 12, Fig. 8]. However,
O
OH
HOHO
OHO
HO OH
O
OH
Phlorizin, Fig. 4, [17]hSGLT1 IC50 400 nMhSGLT2 IC50 65 nM
O
OH
HOHO
OHO
HO
OH
OH
cis, trans
10, 11, Fig. 6, [22]
cis-THSG is more effectivethan trans-THSG in suppressing transcriptionof phosphoenopyruvate carboxykinase (PEPCK)
O
OH
OHHO O
N N
HO
RMGPa IC50 (Z) 2.4 ± 0.1 mMIC50 (E) 4.9 ± 0.2 mM
9, Scheme 1, [21]
O
OO
OHOH
OH
HO
sugar
1-4, Fig. 5, [20]Dipeptidyl-peptidase IV (DP-IV)IC50 380 µg/mL guava extract
Fig. 7 Antidiabetic activity of O-glycosides described in Sect. 2
O
OH
HOHO
OHNH
O
R
12 R = CH3, Ki = 32 µM13 R = C6H5, Ki = 81 µM14 R = NH2, Ki = 140 µM
15 R = CH3, Ki = 370 µM16 R = C6H5, Ki = 4,6 µM17 R = 2-naphthyl, Ki = 0.4 µM
NH
O
NH
O
RO
OH
HOHO
OH
Fig. 8 N-(β-d-glucopyranosyl) amides 12–14 and N-(β-d-glucopyranosyl)-N’-acyl urea derivatives 15–17 as inhibitors of GP [23]
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N-(β-d-glucopyranosyl) 3-(2-naphthyl)-propenoic amide is still much less efficient than the best-known inhibitor urea derivative 17 (Ki = 0.4 μM) [25].
In 2006, Czifrak et al. used extension of the modified Staudinger methodology to the synthesis of N-(β-d-glucopyranosyl) monoamides of various dicarboxylic acids [26]. Such compounds offer the possibility to place a strongly polar group (COOH) at different distances from the sugar moiety while the ability to form the important H-bond from the amide can be maintained. O-Peracetylated N-(β-d-glucopyranosyl)imino trimethylphosphorane obtained in situ from 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosyl azide 21 and PMe3 (Scheme 3) was reacted with satu-rated and unsaturated aliphatic and aromatic dicarboxylic acids, or their anhydrides, or monoesters to give the corresponding N-(β-d-glucopyranosyl) monoamides of dicarboxylic acids or derivatives (e.g., derivative 23, Scheme 3). The acetyl protect-ing groups were removed according to the Zemplén protocol to give a series of com-pounds, which were moderate inhibitors against rabbit muscle glycogen phosphory-lase b. The best inhibitor was 3-(N-β-d-glucopyranosyl-carbamoyl) propanoic acid 23 (n = 2) with Ki = 20 μM [26].
In 2008, Somsak et al. showed that the synthesis of the highly efficient glyco-gen phosphorylase inhibitors N-(β-d-glucopyranosyl)-N′-substituted ureas has been significantly improved by using of glucopyranosylammonium carbamate [27]. This compound allowed the preparation of N-(β-D-glucopyranosyl)-N′-substituted ureas, -thioureas and selenourea 27 in two steps from d-glucose 24 (Scheme 4).
In 2012, Nagy et al. synthesized N-(4-substituted-benzoyl)-N′-(β-d-glucopyranosyl) urea derivatives 32 by addition of O-peracetylated
O
OAc
AcOAcO N3
R1
R1 = OAc, NHAc
18 19, 20
19 R1 = OAc, NHAc, R3 = Ac
20 R1 = OH, NHAc, R3 = H
NaOMeMeOH
O
OR3
R3OR3O NHCOR2
R1
1. Me3P, Me-C6H5, DCM2. R2COX
21-88 %
X = OH, Cl, OCOCH3
R2 = Me, CF3, C6H5, NH2, NHCOMe, NHCOPh,NHCOC10H7 (2-naphthyl), n-C5H11, n-C11H23, Me3C,1-adamantyl, C6H5CH2, (C6H5)2CH, C6H5CH2CH2C6H5CH=CH, 4-Me-C6H4, 4-C6H5-C6H4, 1-naphthyl,2-naphthyl, C10H7CH=CH (2-naphthyl),3,4,5-(MeO)3-C6H2, 4-Cl-C6H4-OCH2
C6H5C C Me
BocNHH
BnO2C CH2
NHBoc
17-99 %
Scheme 2 Synthesis of N-(β-d-glucopyranosyl)- and N-(2-acetamido-2-deoxy-β-d-glucopyranosyl) amides 20 [25]
AcOAcO
O
OAc
OAc
N3
1. Me3PO
O
O
(CH2)n2.
NaOMeMeOH
O
N
O
(CH2)nAcO
AcOO
OAc
OAc
HOHO
O
OH
OH
NH
O
(CH2)n CO2H21 22 23
n = 2, 3, 4
Scheme 3 Synthesis of N-(β-d-glucopyranosyl) monoamides 23 of various dicarboxylic acids [26]
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β-d-glucopyranosylamine 28 to acyl-isocyanates 29 and subsequent deprotec-tion (Scheme 5) [28]. Some compounds 32 were obtained by reactions of β-d-glucopyranosylammonium carbamate 31 with acyl-isocyanates 29. Most of the new compounds 32 were low micromolar inhibitors of rabbit muscle glycogen phos-phorylase b. There was no significant improvement of the inhibitory efficiency for N-(4-substituted-benzoyl)-urea 32 in comparison to N-benzoyl-urea. These results indicated the lack of a specific and crucial interaction from four position in phenyl ring within the catalytic site. The best inhibitors were compounds 32 with substitu-ents R=4-CH3–C6H4 (Ki = 2.3 μM) and R=4-NO2–C6H4 (Ki = 3.3 μM) [28].
In 2012, Konya et al. synthesized new glucose derivatives for the inhibi-tion of GP [29]. They have reported on the synthesis and enzymatic evaluation of a series O-peracetylated N-(β-d-glucopyranosyl)-carboxamides with isoxa-zole or 1,2,3-triazole rings. In a DCC-mediated coupling 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamine 34 and propiolic acid gave N-propynoyl-2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylamine 35, which was transformed by 1,3-dipolar cycloadditions with aromatic azides and nitrile-oxides to the corresponding O-per-acetylated N-(β-d-glucopyranosyl)-1-substituted-1,2,3-triazole-4-carboxamides 36
O
OH
HOHO
OHOH C
O
NH2NH4O MeOH, 37oC, 1 day
R NCXpyridinertX = O, S, Se
R = Ph, 2-Cl-C6H4, 3-Cl-C6H4, 4-Cl-C6H4, 2-F-C6H4, 4-F-C6H4,4-Br-C6H4, 4-NO2-C6H4, 4-MeO-C6H4, 3-CF3-C6H4, 4-CF3-C6H4,3-CN-C6H4, 1-naphthyl, 2-naphthyl, 4-tBu-C6H4CO
24 25
O
OH
HOHO
OHNH2 C
O
NH2HO
26
27
NHCX
NHR
O
OH
HOHO
OH
91 %
19-98 %
Scheme 4 Synthesis of GP inhibitors N-(β-d-glucopyranosyl)-N’-substituted ureas 27 with using of glu-copyranosylammonium carbamate 26 [27]
20-67 %
54-99 %NaOMeMeOHrt
R = H, Me, Ph, Cl, OH, NO2,NH2, OCH3, COOMe, COOBn, COOH
28 29 30
32
R CO
NCOMeCN, Ar, rt
R CO
NCO Pyridine, rt
31 29
O
OAc
AcOAcO
OAcNH2
O
OAc
AcOAcO
OAcNH
O
NH
O
R
O
OH
HOHO
OHNH
O
NH
O
RO
OH
HOHO
OHNH2
CO
NH2HO39-73 %
Scheme 5 Synthesis of N-(4-substituted-benzoyl)-N′-(β-d-glucopyranosyl) urea derivatives 32 [28]
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and N-(β-d-glucopyranosyl)-3-substitutedisoxazole-5-carboxamides 38, respectively (Scheme 6). These compounds were O-deacetylated by Zemplén protocol to com-pounds 37 and 39, which were tested as inhibitors of rabbit muscle glycogen phos-phorylase b. Deacylated compounds 37 and 39 inhibited rabbit muscle glycogen phosphorylase b in the low micromolar range. The best inhibitors of the two series were N-(β-d-glucopyranosyl)-1-(3,5-dimethyl-phenyl)-1,2,3-triazole-4-carboxamide 37 (Ar=3,5-di-Me-C6H3, Ki = 34 μM) and N-(β-d-glucopyranosyl)-3-(indol-2-yl)-isoxazole-5-carboxamide 39 (Ar=indol-2-yl, Ki = 164 μM).
In 2014, Parmenopoulou and coworkers reported the in silico screening in the Zinc database of 1888 N-acyl-β-d-glucopyranosylamines as potential GP inhibi-tors [30]. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. The direct acyla-tion of 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylamine 41, easily prepared from the per-O-acetylated β-d-glucopyranosyl azide 40 upon catalytic hydrogenation, with a diverse set of commercially available acyl chlorides RCOCl, furnished the pro-tected N-acyl-β-d-glucopyranosylamines 42. Removal of the acetyl groups of the derivatives 42, performed either by saturated methanolic ammonia or by the Zem-plén method yielded analogues 43 (Scheme 7). Their inhibition constants’ values Ki in vitro ranged from 5 to 377 μM while two of them were effective at causing inacti-vation of GP in rat hepatocytes at low μM concentrations [30].
Figure 9 presents the best GPb inhibitors from the N-(β-copper-catalyzed azide–alkyne cycloaddition-glucopyranosyl) amides and N-(β-d-glucopyranosyl)-urea derivatives described in Sect. 3.1. The structural formula of each inhibitor, the number of the compound, the scheme number and the corresponding reference are provided. In the figure, the inhibitors are arranged in order from the strongest char-acterized by the lowest inhibitory constant Ki value to the weaker one with the high-est Ki value. It can be seen that all inhibitors accumulated in Fig. 8 are derivatives of glucose and compound 17 represents the most efficient glucose analogue inhibitor.
O
OAc
AcOAcO
OAcN3
H2/Ra-Ni O
OAc
AcOAcO
OAcNH2
HC C COOHDCC O
OAc
AcOAcO
OAcN
O
H
ArN3
CuSO4.5H2O (5 mol%)
L-ascorbic acid (15 mol%)CH2Cl2/H2O 1:1, 50oC
O
OR
RORO
ORN
O
NN
N ArH
Ar = Ph, 2-Naphthyl, 3,5-di-Me-C6H34-CF3-C6H4, 4-tBu-C6H4
33 34 35
36 R = Ac37 R = H
NaOMeMeOH
ArCH=NOH,NaOCl, THF/H2O
O
OR
RORO
ORN
O
NO ArH
38 R = Ac39 R = H
NaOMeMeOH
Ar = Ph, 2-Naphthyl, Benzo-[b]-furan-2-ylBenzo-[b]-thiophen-2-yl, Benzothiazol-2-ylIndol-2-yl, Indol-3-yl
88 %
Scheme 6 Synthesis of N-(β-d-glucopyranosyl)-1-substituted-1,2,3-triazole-4-carboxamides 37 and N-(β-d-glucopyranosyl)-3-substituted-isoxazole-5-carboxamides 39 [29]
1 3
Topics in Current Chemistry (2019) 377:19 Page 13 of 84 19
3.2 1,2,3‑Triazolyl N‑Glycosides
The medicinal importance of triazoles is due to their bioisosterism with peptide bonds as they can actively participate in hydrogen bonding, and due to their strong dipole moments, the triazoles are extremely stable to hydrolysis and oxidative/reductive conditions. In 2011, Anand and coworkers described an efficient synthe-sis of 1,2,3-1H-triazolyl glycohybrids with two sugar units via copper-catalyzed azide-alkyne cycloaddition (CuAAC) [31]. Potential inhibitors were prepared by a 1,3-dipolar cycloaddition of glycosyl azides 47 and 49 to 2,3-unsaturated alkynyl glycosides 46 (Scheme 8). The synthesized glycohybrids were screened for their α-glucosidase, glycogen phosphorylase, and glucose-6-phosphatase inhibitory
H2, 10% Pd/C, EtOH20oC, 24h
DMF, RCOClEt3N, rt, 1h
NH3/MeOH orNaOMe/MeOH
O
OH
HOHO NH
O
R
43
O
OAc
AcOAcO N3
40
O
OAc
AcOAcO NH2
41
O
OAc
AcOAcO NH
O
R
42
R =
O
Me
Me
62-83 %
66-81 %
Scheme 7 Synthesis of N-acyl-β-d-glucopyranosylamines 43 [30]
17, Fig 8, [23]
GPb Ki 0.4 µM
O
OH
OHNH
O
NH
O
HOHO
32, Scheme 5, [28]GPb Ki 2.3 µM
NH
O
NH
O
CH3O
OH
OHHO
HO
20, Scheme 2, [25]or 43, Scheme 7, [30]
GPb Ki 3.5 µM
NH
O
O
OH
OHHO
HO
37, Scheme 6, [29]
GPb Ki 34 µM
NNH
O
NN
CH3
CH3
O
OH
OHHO
HO
39, Scheme 6, [29]GPb Ki 164 µM
O
OH
OHHO
HO NH
O
NON
H
NH
O
COOH
23, Scheme 3, [26]GPb Ki 20 µM
O
OH
OHHO
HO
Fig. 9 Values of inhibitory constants Ki of the best GPb inhibitors from the N-glycosides described in Sect. 3.1
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 14 of 84
activities. A few of the glycohybrids showed promising inhibitory activities against these enzymes [31].
In 2014, Goyard et al. examined CuAAC between acetylated β-d-glucosyl azide 51 and alkyl or phenyl acetylenes 52, which led to the corresponding 4-substituted 1-glucosyl-1,2,3-triazoles 54 (Scheme 9) [32]. 5-Halogeno analogues 56 were pre-pared in similar conditions but with 2 equiv CuI or CuBr. In reactions with two equiv CuCl and either propargyl acetate or phenyl acetylene, the major products 59 dis-played two 5,5′-linked triazole rings resulting from homocoupling of the 1-glucosyl-4-substituted 1,2,3-triazoles (Scheme 10). The cycloaddition of 51 and 52 afforded four different products 53, 55, 57, and 59 with only minor amounts of the expected chlorinated derivatives 55 and with the dimeric products 59 being isolated as the major component. The two 4-phenyl substituted structures of compound 59 were unambiguously identified as atropisomers with aR stereochemistry. All O-unpro-tected derivatives (Schemes 9, 10) were tested as inhibitors of GP. The modest inhi-bition activities measured showed that 4,5-disubstituted 1-glucosyl-1,2,3-triazoles
81-87 %
OAcO
OAc
AcOR1X
HO
X = CH2, R1 = HX = (CH2)2, R1 = HX = _CH(CH2)4CH3, R1 = HX = (CH2)2, R1= (CH2)2CH3
X = CH2, R1 = CH2OH
Lewis acid (Montmorilonite)CH2Cl2, rt
44 45 X = CH2, R1 = HX = (CH2)2, R1 = HX = _CH(CH2)4CH3, R1 = HX = (CH2)2, R1 = (CH2)2CH3
X = CH2, R1 =
O
OAc
AcO
O CH2
O
O
O
HO
N3
CuSO4 (2 mol%)sodium ascorbate (5 mol%)1:1 tert-BuOH/H2O, 30oC
CuSO4 (2 mol%)sodium ascorbate (5 mol%)1:1 tert-BuOH/H2O, 30oC
O
OR2
R2O OX
NN
N
O
O
O
HO
47
48 76-85 %
49
50 76-84 %
46
OX
R1
46
O
OR2
R2O OX
NN
N
O
OR2
OR2
OR2
R2O
O
OAc
AcOOX
R1O
OAc
AcOAcO
OAc
N3R1 = H
NaOMeMeOHrt
R2 = AcR2 = H
NaOMeMeOHrt
R2 = AcR2 = H
O
OAc
AcO
Scheme 8 Synthesis of 1,2,3-1H-triazolyl glycohybrids 48 and 50 by 1,3-dipolar cycloaddition of glyco-syl azides 47 and 49 to 2,3-unsaturated alkynyl glycosides 46 [31]
1 3
Topics in Current Chemistry (2019) 377:19 Page 15 of 84 19
bind weakly to the enzyme. This suggests that such ligands do not fit the catalytic site or any other binding site of the GP [32].
In order to gain additional data for structure–activity studies of the inhibition gly-cogen phosphorylase, in 2015 Goyard et al. prepared a series of eight GP inhibi-tor candidates from peracetylglucopyranosyl azide 61 by 1,3-dipolar cycloaddition (Scheme 11) [33]. The need for a N-Boc-protected propargylamine was identified in the CuAAC with azide 61 under Meldal’s conditions, while Sharpless’ conditions were better adapted to the CuAAC of azide 61 with propargyl bromide. Cycloaddi-tion of Boc-propargylamine with azide 61 afforded the N-Boc precursor of a 4-ami-nomethyl-1-glucosyl-1,2,3-triazole 62, which gave access to a series of amide and sulfonamide derivatives (Scheme 11). The Boc-protected amine 62 was converted to the free amine 64, which were functionalized with acyl chlorides R2COCl afford-ing the amides 67. The amine 64 was also converted to the sulfonamide derivative 69 using p-toluenesulfonyl chloride TsCl. The sulfonamide 70 was synthesized in order to take advantage of hydrophobic contact in the β-channel of GP and also to have potential additional contacts with the sulfonamide group and the side chain amino acids of the enzyme. Arbuzov reaction of the brominated derivative 71 with triethylphosphite under microwave activation allowed for formation of the acetylated phosphonate 72, which was converted to phosphonate 73 (Scheme 11). Enzymatic studies revealed poor to moderate inhibitions of deacetylated derivatives toward
CuI, iPr2NEtDMF
CuX 2 equiv.DMAP, CH3CN16h, rt
R
R = CH2OAc, 6-MeO-2-naphthylPh, 4-MeO-C6H5, 4-O2N-C6H5
NaOMeMeOH16h, rt
O
OH
HOHO N
NN
ROH
54
O
OAc
AcOAcO N
NN
ROAc
53
O
OAc
AcON3AcO
OAc
51 52O
OAc
AcOAcO N
NN
RXOAc NaOMeMeOH16h, rt O
OH
HOHO N
NN
RXOH
55 56X = I, Br
20-98 % 85-92 %
83-95 %71-82 %
Scheme 9 Synthesis of 4-substituted-1-glucosyl-1,2,3-triazoles 54 and 56 by copper-catalyzed azide–alkyne cycloaddition [32]
15-19 % 5-9 % 16-19 %56-61 %
R1R1 = CH2OAc, Ph
O
OAc
AcON
NN
R1OAc
AcO
53
O
OAc
AcON3AcO
OAc
51 52
O
OR2
R2ON
NN
R1ClOR2
R2O
55
56
O
OR2
R2ON
NN
R1
R1
OR2
R2O
R2 =H
57
58
59
R2 =H R2 =H
CuCl 2 equiv.DMAP, CH3CN16h, rt
NaOMe, MeOH16h, rt
NaOMe, MeOH16h, rt
O
OR2
R2ON
NN
R1
N NNR1
OR2
R2O
O
R2O
OR2OR2
R2O
60
NaOMe, MeOH16h, rt
R2 =Ac R2 =Ac R2 =Ac
Scheme 10 Cycloaddition of azide 51 and acetylenes 52 in the presence of 2 equiv CuCl [32]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 16 of 84
O OR
1
OR
1
R1 O R
1 ON
NN
NH
Boc
O OA
c
OA
c
AcO A
cON
NN
NH
2
Boc
TyrO
H,E
DC
lH
OB
t,C
H2C
l 2/D
MF
(2:1
)-1
0o C,2
h,th
enrt,
16h
64
O OR
1
OR
1
R1 O R
1 ON
NN
NR
2
H
O
O OR
1
OR
1
R1 O R
1 ON
NN
NS
HOO
Me
O OA
c
OA
c
AcO A
cON
NN
Br
O OA
c
OA
c
N3
AcO A
cO
61
71
O OR
1
OR
1
R1 O R
1 ON
NN
PO
Et
EtO
O
1.C
H2C
l 2/TF
A(1
0:1)
,rt,
4h2.
NaO
Me,
MeO
Hrt,
16hO O
R1
OR
1
R1 O R
1 ON
NN
NH
O
NH
R3
OH
65R
1=
Ac,
R3
=B
oc85
%66
R1
=R
3=
H
HC
CC
H2N
HB
ocC
uI,i
PrN
Et2,
DM
F70
o C,4
h
R2
=C
H3,
Ph,C
H2C
l 2/TF
A(1
0:1)
rt,4h
R2 C
OC
l,E
t 3N
,CH
2Cl 2
rt,4h
67R
1=
Ac
68R
1=
HN
aOM
e,M
eOH
rt,16
h
62R
1=
Ac
63R
1=
HN
aOM
e,M
eOH
rt,16
h
TsC
l,E
t 3N
CH
2Cl 2,
rt,4h
69R
1=
Ac
70R
1=
HN
aOM
e,M
eOH
rt,16
h
HC
CC
H2B
r,C
uSO
4so
dium
asco
rbat
et-B
uOH
/H2O
1:1
rt,16
h
P(O
Et) 3
140o C
(mW
),1h
72R
1=
Ac
86%
73R
1=
HN
aOM
e,M
eOH
rt,16
h
95%
85%
100
%
89-9
5%
94%
Sche
me
11
Synt
hesi
s of 4
-am
idom
ethy
l-1-g
luco
syl-1
,2,3
-tria
zole
s [33
]
1 3
Topics in Current Chemistry (2019) 377:19 Page 17 of 84 19
glycogen GP. The N-Boc-protected amine 63 was the best inhibitor (IC50 = 620 μM) unexpectedly slightly better than the 2-naphthylamido 68 substituted analogue (IC50 = 650 μM) [33].
SGLT2 (sodium-dependent glucose co-transporter 2) is a glucose transporter that is responsible for 90% of the renal glucose reabsorption. For the treatment of type 2 diabetes, suppression of glucose reabsorption through the inhibition of SGLT2 is a promising therapeutic approach. Therefore in 2015, Bai et al. developed a con-venient approach to the synthesis of novel triazole-N-glycoside derivatives 78 via CuSCN-catalyzed click reaction and Ullmann-type coupling reaction (Scheme 12) and examined the SGLT2 inhibitory activities of prepared N-glycosides [34]. For carbohydrate azides 74: glucosyl azide, galactosyl azide, ribosyl azide and amino-glucosyl azide, reactions were performed and the triazole-N-glycosides 76 were gen-erated with high selectivity, while mannosylazide and lactosyl azide showed moder-ate selectivity (side product 77). After the successful construction of [6] ring-fused triazole-N-glycosides, the preparation of [6, 7] or [6, 8] ring-fused triazole-N-glyco-sides via this protocol was also tried. Deprotection was carried out in the presence of BCl3 or 1,2-diaminoethane and finally the acetyl-containing N-glycosides were treated with sodium methoxide to obtain the corresponding target compounds 78 and side product 79 (Scheme 12). The SGLT2 inhibitory activities of N-glycosides 78 were evaluated and some compounds showed moderate SGLT2 inhibition activi-ties at 100 nM [34].
3.3 Other N‑Glycosides
In 2016, Chu et al. investigated the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides 83 (Scheme 13) [35]. As they investigated in a previous article [36], results suggested that the C6 position of the sugar moiety may play a critical role in the suppression of SGLT2. Therefore, Chu et al. led optimization of N-glycosides proceeded via modification at the C6 position only, the aglycone unit 4-chloro-3-(4-cyclopropylbenzyl)-1H-indole being fixed. N-Indolylglucosides 83 were prepared according to a synthetic method depicted in Scheme 13, using N-indolylglucoside 80 as the starting material. Treatment of 80 with methanesulfo-nyl chloride (MsCl) in pyridine gave the corresponding 6-OMs N-glycoside, which was sequentially reacted with sodium azide (NaN3) to afford the 6-azido compound 81. Next, the synthesis of amides 83 was carried out via the amine 82, generated by the reduction of azido group in 81 with Zn/AcOH in THF. Amine 82 underwent direct amide bond formation with a variety of acyl chlorides to furnish 6-amide derivatives 83 (Scheme 13). After SAR study 6-amide derivatives 83 (R=acetyl and 3-methoxy-3-oxopropanoyl) were identified as potent SGLT2 inhibitors. The data obtained indicated that 83 (R=acetyl and 3-methoxy-3-oxopropanoyl) are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evalu-ated in a urinary glucose excretion test and pharmacokinetic study. Compound 83 (R=acetyl) was found capable of inducing urinary glucose excretion in rats [35].
A key point for the design of efficient drugs is the characterization of the inter-actions governing its binding to the enzyme. In 2017, Mamais et al. designed and
Topics in Current Chemistry (2019) 377:19
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19 Page 18 of 84
O
N3
m
Cs 2
CO
3,C
uSC
ND
MF/
HM
PA
,70o C
O I
n
n=
1,2,
3
7475
Dep
rote
ctio
nco
nditi
ons:
BC
l 3,C
H2C
l 2,-7
3o Cto
0o Cor
Pd(
OH
) 2/C
,H2,
rt,18
hor
1,2-
diam
inoe
than
e,80
o C,o
vern
ight
then
pyrid
ine,
Ac 2
O,o
vern
ight
,th
enN
aOM
e/M
eOH
,rto
rN
aOM
e/C
H2C
l 2/M
eOH
,rt,
1.5h
ON
NN
Om
n
mON
NN
OI
n
7677
79
HO
mON
NN
OI
nH
OO
N
NN
Om
n
78
72-9
7%
52-1
00%
O
N3
m=
O
OBn
BnO Bn
OO
BnN
3
O
OBn
BnO
OBn
N3
OBn
O
OBn
BnO
N3
BnO
OBn
ON
3
OBn
OBn
BnO
O
OTM
S
TMSO TM
SON
Phth
N3
O
OAc
AcO Ac
ON
HAc
N3
O
OBn
BnO Bn
OO
BnN
3
O
OBn
BnO
OBn
N3
OBn
O
OAc
AcO Ac
OO
AcN
3O
OAc
AcO
OAc
N3
OAc
O
OBn
BnO Bn
OO
BnO
O
OBn
BnO
OBn
N3
Sche
me
12
Synt
hesi
s of t
riazo
le-N
-gly
cosi
de d
eriv
ativ
es 7
8 vi
a C
uSC
N-c
atal
yzed
clic
k re
actio
n an
d U
llman
n-ty
pe c
oupl
ing
reac
tion
[34]
1 3
Topics in Current Chemistry (2019) 377:19 Page 19 of 84 19
77%
91%
O
N
OH
HO
Cl
OH
OH
1.M
sCl,
pyrid
ine,
0o Cto
rt2.
NaN
3,D
MF,
80o C
O
N
OH
H2N
Cl
OH
OH
Zn,A
cOH
,TH
F,rt
O
N
OH
N3
Cl
OH
OH
RC
l,K
2CO
3TH
F,rt
R=
acet
yl,c
hlor
oace
tyl,
dich
loro
acet
yl,3
-chl
orop
ropa
noyl
,3-b
rom
opro
pano
yl,
2-m
ethy
lpro
pano
yl,c
yclo
prop
ylca
rbon
yl,4
-met
hoxy
benz
oyl,
4-(c
hlor
omet
hyl)b
enzo
yl,
1,2-
oxaz
ol-5
-ylc
arbo
nyl,
thio
phen
-2-y
lace
tyl,
(phe
nyls
ulfa
nyl)a
cety
l,m
etho
xy(o
xo)a
cety
let
hoxy
(oxo
)ace
tyl,
3-m
etho
xy-3
-oxo
prop
anoy
l,3-
etho
xy-3
-oxo
prop
anoy
l,4-
etho
xy-4
-oxo
buta
noyl
8081
82
29-8
6%
O
N
OH
N
Cl
OH
OH
R
H
83
Sche
me
13
Synt
hesi
s of N
-indo
lylg
luco
side
s 83
[35]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 20 of 84
prepared a glucose-based acridone derivative (GLAC), which is a potent inhibitor of GP and it allows probing subtle interactions in catalytic site [37]. The design of a catalytic site inhibitor was based on C-4 modification of β-d-glucopyranosyluracil and introducing of flat aromatic substituent, which can increase the binding affinity in the β-channel. Authors utilized an acridone moiety as a possible chromophore as well as fluorophore. β-d-Glucopyranosyluracil 84 was converted to 4-triazolyl derivative 85 and next substitution of 85 by 2-aminoacridone provided the protected adducts 86 (Scheme 14). Final deprotection furnished desired product GLAC 87. Authors reveal that the part of the catalytic site of GP behaves as a highly basic envi-ronment in which GLAC 87 exists as a bis-anion. Authors reassumed that solvent structure of GLAC and the water-bridged hydrogen bonding interactions formed with the catalytic site residues in the β-channel are responsible for the observed inhi-bition potency [37].
Figure 10 shows inhibitory properties of the best GPb and SGLT inhibitors from the N-glycosides: 1,2,3-triazolyl N-glycosides, N-indolylglycosides, and N-uracil glycoside presented in Sects. 3.2 and 3.3. The GLAC compound 87 is one of the
N NH
O
OG
triazole, POCl3, Et3N,CH3CN, 0oC, 95%
G =
N N
OG
NN
N2-aminoacridone, DMSOmicrowave, 114oC, 54 min, 90%
N N
OG
N
N
O
H
H
7M NH3, MeOH,rt, 95%
8485 86
87
O
OAc
AcOOAc
AcO
N N
O
N
N
O
H
H
O
OH
HOOH
HO
Scheme 14 Synthesis of GLAC 87 (N1-(β-d-glucopyranosyl)-N4-[2-acridin-9(10H)-onyl]-cytosine) [37]
56, Scheme 9, [32]
RMGPb IC50 103 mM
O
OHN
NN
OH OAc
HOHO
54, Scheme 9, [32]RMGPb IC50 26 mM
63, Scheme 11, [33]RMGPb IC50 620 mM
87 GLAC, Scheme 14, [37]
N N
O
N
N
H
H
O
O
N
OH
OH
OH
Cl
N
H
O
83, Scheme 13, [35]hSGLT2 EC50 42±23 nMhSGLT1 EC50 1412±241 nM
O
N
OH
OH
OH
Cl
N
H
O
MeO2C
83, Scheme 13, [35]hSGLT2 EC50 39±7 nMhSGLT1 EC50 5424±1357 nM
O
OH
OH
HOHO
O
OH
OH
HOHO
NN
N
I
OMe
O
OH
OH
HOHO
NN
N
NHBoc
GPb Ki 31 nM
Fig. 10 Inhibitory properties of the best GPb and SGLT inhibitors from the N-glycosides described in Sects. 3.2 and 3.3
1 3
Topics in Current Chemistry (2019) 377:19 Page 21 of 84 19
best GPb inhibitors described so far (Ki 31 nM). All compounds are derivatives of glucose. The presence of the cyclopropane ring in the structure of two of the active inhibitors is also noteworthy.
4 C‑Glycosides as Antidiabetic Agents
4.1 Aromatic C‑Glycosyl Derivatives
C-Glycosides are more metabolically stable than O-glycosides and tend to have higher oral bioavailability and plasma exposure without needing to be converted to a prodrug [4]. Among C-glycosyl derivatives, C-glycosylarenes have attracted much attention. In 2007, Praly et al. underwent kinetic and X-ray crystallographic study of two enzyme complexes of rabbit muscle unphosphorylated glycogen phosphorylase b (GPb) with ligands of the C-glucosylbenzo(hydro)quinone type [38]. The synthesis of quinones was accomplished from C-β-d-glycopyranosyl-1,4-dimethoxybenzenes 89, which were prepared by reaction of penta-O-acetyl-β-d-glycopyranoses 88 and 1,4-dimethoxybenzene (Scheme 15). Next, compounds 89 were converted to the corresponding C-glycosylhydro and C-glycosylbenzoquinones, with either an acetylated or deprotected sugar moiety. C-β-d-Glucosylbenzoquinone 91 (R1=H, R2=OH) and C-β-d-glucosylhydroquinone 95 (R1=H, R2=OH) (Scheme 15) were found to be competitive inhibitors of rabbit muscle GPb with Ki values of 1.3 and 0.9 mM, respectively. In order to elucidate the structural basis of inhibition, the authors determined the crystal structures of 91 and 95 in complex with GPb. The complex structures reveal that the inhibitors can be accommodated at the catalytic site at approximately the same position as α-d-glucose and stabilize the transition state conformation of the 280 s loop by making several favorable contacts to Asp283 and Asn284 of this loop [38].
Protein tyrosine phosphatase 1B (PTP1B) has recently been identified as a new drug target for type 2 diabetes [39]. In 2008. Lin et al. synthesized β-C-glycosiduronic acid quinones and β-C-glycosyl compounds as sugar-based PTP1B inhibitors [40]. To prepare 2-carbamoylbenzoic acid derivatives 100 (Scheme 16) and 106 (Scheme 17), β-C-aryl glucosides 96 and 102 were first tritylated at 6-posi-tion, followed by protection of secondary hydroxyl function as benzoyl ester. To avoid intramolecular transesterification reaction, detritylation has been real-ized under acidic condition with TFA to afford 98 and 104. The 6-hydroxy group was transformed into azide via mesylate. Staudinger protocol was then employed to convert azido sugars to carbamoylbenzoic acid derivatives. Reaction of 99 with phthalic anhydride led to a mixture of the desired compound 100 and N-phthalim-ide derivative 101 (Scheme 16). Treatment of 105 with phthalic anhydride in THF afforded 106 (Scheme 17). Benzoyl protected quinone derivatives as well as aryl β-C-glycosyl compounds showed IC50 values of 0.77–5.27 μM against PTP1B, with compounds 100 and 106 bearing an acidic function being the most potent [40].
In 2008, Meng et al. discovered dapagliflozin, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes [41]. Synthesis of dapagliflozin started from Friedel–Crafts acylation of phenetole with
Topics in Current Chemistry (2019) 377:19
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19 Page 22 of 84
AcOR2 O
OAcOAc
R1 OAc
HOR2 O
OH
R1 OH OMe
OH
ClR1 = H, R2 = OAcR1 = OAc, R2 = H
R1 = H, R2 = OHR1 = OH, R2 = H
8892
AcOR2 O
OAc
R1 OAc O
O
R1 = H, R2 = OAcR1 = OAc, R2 = H
93
AcOR2 O
OAc
R1 OAc OMe
OMeR1 = H, R2 = OAcR1 = OAc, R2 = H
89
OMe
OMe (2 equiv.)SnCl4 (3 equiv.)CF3CO2Ag (1.5 equiv.)
CH2Cl2, 25-30oC, 5h
HOR2 O
OH
R1 OH OMe
OMe
AcOR2 O
OAc
R1 OAc OH
OH
R1 = H, R2 = OHR1 = OH, R2 = H
R1 = H, R2 = OAcR1 = OAc, R2 = H
9094
HOR2 O
OH
R1 OH O
O
HOR2 O
OH
R1 OH OH
OHR1 = H, R2 = OHR1 = OH, R2 = H
R1 = H, R2 = OHR1 = OH, R2 = H
9195
CAN (3 equiv.), H2O, rt, 30 min
CAN (3 equiv.)CH3CN/H2O 1:1, 25 min
0.5% AcCl in MeOH1 week, rt
NaBH4 (2 equiv.)EtOAc, rt, 30 min
0.1M or 0.033M MeONaMeOH, rt, 2hor1% AcCl in MeOH, 5d, rt
Ag2O, propan-2-ol, rt, 2horPhI(OAc)2 (1.5 equiv), MeOH, rt, 40 min
69-81 %
> 95 %
76-79 %
84-93 %
88-91 %
80-100 %
80-94 %
MeOH/NEt3/H2O 8:1:1, rt, 10-12horMeONa/MeOH, rt, 2h
Scheme 15 Synthesis of C-β-d-glucosylbenzoquinones 91 and C-β-d-glucosylhydroquinones 95 [38]
TFACH2Cl2, H2O
1. MsCl, TEA2. NaN3, DMF
phthalic anhydrideMe3P, CH2Cl2 or THF
96 97 61 % 98 79 %
99 83 %100 47 %101 22 %
O
OAc
AcOOAc
OMe
OMe
AcO O
OTr
BzOOBz
OMe
OMe
BzO O
OH
BzOOBz
OMe
OMe
BzO
O
NPhth
BzOOBz
OMe
OMe
BzO O
NH
BzOOBz
OMe
OMe
O
COOH
BzO O
N3
BzOOBz
OMe
OMe
BzO
1. MeONa, MeOH2. TrCl, pyr3. BzCl
Scheme 16 Synthesis 2-carbamoylbenzoic acid derivative of β-C-glycosyl compound 100 as sugar-based PTP1B inhibitor [40]
1 3
Topics in Current Chemistry (2019) 377:19 Page 23 of 84 19
5-bromo-2-chlorobenzoyl chloride, which was formed from 5-bromo-2-chloroben-zoic acid 107 in reaction with oxalyl chloride (Scheme 18). Reduction of p-benzo-phenone 108 by triethylsilane and BF3·OEt2 provided aglycon 109. Lithium halogen exchange, followed by the addition of the nascent lithiated aromatic to 110, gave a mixture of lactols, which were converted in situ to the desilylated O-methyl lactols 111 by treatment with methanesulfonic acid in methanol. Reduction of the anomeric methoxy group of 111 using triethylsilane and BF3·OEt2, followed by peracetylation, yielded tetraacetate 112. Hydrolysis of 112 with lithium hydroxide generated 113 (Scheme 18). Authors resumed that dapagliflozin 113 is a potent, selective SGLT2 inhibitor that is not subject to O-glucosidase degradation. Compound 113 is a much more potent stimulator of glucosuria in normal rats than other SGLT2 inhibitors. The promising significant reduction of blood glucose levels in diabetic rats prompted further evaluation of 113 in the clinic for the treatment of type 2 diabetes [41].
In 2010, Kato and Kawabata synthesized an isoflavone C-glucoside puerarin and several derivatives, which were candidate for treatment of diabetes mellitus [42]. Treatment of TMSOTf to the mixture of glucosyl imidate 114 and an acetophenone 115 afforded a C-glucoside 116 (Scheme 19). Group 6-OH of compound 116 was selectively protected by a benzyl group. Aldol condensation of 117 with an aldehyde 118 gave chalcones 119. Compounds 119 were treated with Tl(NO3)3 and heated in an acidic medium to form isoflavone structure 120. The benzyl group protecting
1. TrCl, pyr2. BzCl
TFA, CH2Cl2H2O
1. MsCl, TEA2. NaN3, DMF
phthalic anhydrideMe3P, THF
102 103 61 % 104 83 %
105 57 %106 90 %
O
OH
HOOH
OMe
OMe
HO O
OTr
BzOOBz
OMe
OMe
BzO O
OH
BzOOBz
OMe
OMe
BzO
O
N3
BzOOBz
OMe
OMe
BzOO
NH
BzOOBz
OMe
OMe
O
COOH
BzO
Scheme 17 Synthesis 2-carbamoylbenzoic acid derivative of β-C-glycosyl compound 106 as sugar-based PTP1B inhibitor [40]
Cl
COOHBr
Cl
Br
OEt
O
Cl
Br
OEt
O
OH
HOHO
OHOMe
Cl OEtO
OR
RO
OR
Cl OEt
RO
107 108 109
110
111 85 %
1. (COCl)2, CH2Cl2, DMF2. Phenetole, AlCl3, 0oC
Et3SiH, BF3.OEt2
ClCH2CH2Cl, CH3CN10-50oC
1. n-BuLi, THF, PhCH3, -78oC
OTMSOTMSO
OTMSO
TMSO
2. MeOH, CH3SO3H
1. Et3SiH, BF3.OEt2
CH2Cl, CH3CN, -10oC2. Ac2O, pyr, CH2Cl2, DMAP
64 % 62 %
55 %
DapagliflozinLiOH.H2O, THFH2O, MeOH, 100 %
112 R = Ac113 R = H
Scheme 18 Synthesis of dapagliflozin 113 SGLT2 inhibitor [41]
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19 Page 24 of 84
OH was selectively removed and after trifluoromethanesulfonylation and subse-quent reaction with Pd(OAc)2 derivative 121a was prepared. Finally, benzyl groups were removed by treatment with BBr3 to give puerarin 122 in 13% overall yield and regioisomer of 122, genistein 6-C-glucoside 123 (Scheme 19). The compound 122 was applied for the structure–activity relationship study. The results of research indi-cated that the C-glucoside part of the compound 122 was not much involved in the activity. The structure responsible for the glucose uptake enhancing activity was the isoflavone moiety. However, the C-glucose may involve in physical properties of 122 and raises solubility in water [42].
In 2010, Nomura et al. discovered that C-glucosides bearing heterocyclic ring formed metabolically more stable inhibitors for sodium-dependent glu-cose cotransporter 2 (SGLT2) than the O-glucoside [43]. To synthesize appropri-ate compounds, aglycones 124 were dissolved in tetrahydrofuran and toluene, and treated with n-butyllithium at − 78 °C to generate aryllithium, followed by addi-tion of 2,3,4,6-tetra-O-trimethylsilyl-β-d-gluconolactone (Scheme 20). The result-ing anomeric mixture of lactols was converted into desilylated methyl ethers 125 by addition of methanesulfonic acid in methanol. C-Glucoside derivatives 126 were obtained by stereoselective reduction of 125 using a combination of triethylsilane and boron trifluoride etherate in methylene chloride. Thiophene derivative 126 canagliflozin (R1=Me in the para position relative to glucose moiety, Het=tiophene
OR1
HO
R2
R3 OOH
122 R1=β-D-Glc, R2=H, R3=H, 71 %123 R1=H, R2=β-D-Glc, R3=OH, 51 %
BBr3, CH2Cl2,-78oCO
OOBn
R1
BnO
R2
R3
1. Tl(NO3)3, (MeO)3CH, MeOH, 40oC2. 10%HClaq, MeOH, 1,4-dioxane, 80oC
NaOMe, MeOH1,4-dioxane
CHO
OBn
118
R1
OH
OBn
R2
BnO
O
117a R1=BnGlc, R2=H, 90 %117b R1=H, R2=BnGlc, 86 % in two stepsBnGlc: 2,3,4,6-tetra-O-benzyl-b-D-glucopyranoside
R1
OH
OBn
R2
BnO
O
OBn
119a R1=BnGlc, R2=H, 60 %119b R1=H, R2= BnGlc, 74 %
117a BnBr, K2CCO3, acetone, 50oC117b 1. TBSCl, imid, DMF
2. BnOH, Ph3P, DIAD, THF then TBA
120a R1=BnGlc, R2=H, R3=OH, 72 %120b R1=H, R2=BnGlc, R3=OH, 30 %
121a R1=BnGlc, R2=H, R3=H,86 % in two steps
1. Tf2O, pyridine, CH2Cl22. Pd(OAc)2, Ph3P, HCOOH, TEA, DMF
70 %
116
BnO OH
OH O
114 115
O
OBn
BnOOBn
BnO
O CCl3
NH
TMSOTfCH2Cl2, 30oC
O
OBn
BnOOBn
BnOOHBnO
OH O
Scheme 19 Synthesis of puerarin 122 and its regioisomer 123 [42]
1 3
Topics in Current Chemistry (2019) 377:19 Page 25 of 84 19
with R2=C6H4-4-F in position 2) was a highly potent and selective SGLT2 inhibi-tor and showed pronounced anti-hyperglycemic effects in high-fat diet-fed mice (IC50 = 2.2 nM). Canagliflozin is the first SGLT2 inhibitor to be approved in the USA and is under regulatory review in the EU [44, 45].
In 2011, Xu and coworkers synthesized a series of C-aryl glucosides with vari-ous substituents at the 4′-position of the distal aryl ring and evaluated for inhibi-tion of human hSGLT1 and hSGLT2 [46]. Scheme 21 depicts the construction of aglycone 132, which is a part of bexagliflozin 134 selective SGLT2 inhibi-tor that reached phase III clinical trials [47]. Friedel–Crafts acylation of benzene with the benzoyl chloride derived from benzoic acid 127 by treatment with oxa-lyl chloride provided the corresponding benzophenone 128, which were reduced by triethylsilane in the presence of TFA and catalytic trifluoromethanesulfonic acid to generate bromodiarylmethane 129. Finally, aglycone 132 was constructed by vinyl ether formation of the alcohol 130 with vinyl acetate in the presence of sodium carbonate and a catalytic amount of [IrCl(COD)]2 (Scheme 21). Lith-ium-bromide exchange of bromodiarylmethane 132 and addition of the resulting aryllithium to 2,3,4,6-tetra-O-trimethylsilyl-d-gluconolactone 133 followed by
Br
HetR2
R1
HetO
=S
NN
S
NN
O
OMeOH
OH
OHHO
HetR2
R1
Et3SiH, BF3.OEt2
CH2Cl2, -78oC to 0oCOOH
OH
OHHO
HetR2
R1
R1= H, Cl, MeR2 = Et, Cl, C6H4-4-F, Ph
124
125
126 35-56 %
1. n-BuLi, THF-toluene,-78oC orn-BuLi, tert-BuLi, THF-toluene, -78oC2. 2,3,4,6-tetra-O-trimethylsilyl-β-D-gluconolactonetoluene, -78oC3. MeSO3H, MeOH
Scheme 20 Synthesis of C-glucoside derivatives 126 selective SGLT2 inhibitors [43]
Cl
OH
O
Br
Cl
O
Br
OAc Et3SiH, cat. CF3SO3HTFA, reflux
Cl
Br
OAc
127128 129K2CO3
MeOH/H2Ort
Cl
Br
OHvinyl acetate, [IrCl(COD)]2Na2CO3, toluene, 100oC
Cl
Br
OZnEt2, CH2I2Et2O, rt
Cl
Br
O
130131132
1. n-BuLi, THF/toluene, -78oC, then 1062. MeSO3H, MeOH, -78oC to rt3. Et3SiH, BF3
.OEt2, MeCN/CH2Cl2-30 to -10oC 133
134 Bexaglifliozin
TMSO
TMSO
O
TMSOO
TMSO
HO O
OH
HOOH
OO
Cl
oxalyl chloride, cat. DMF, AlCl3toluene, CH2Cl2, -5oC to rt
99 % 98 %
77 %
82 %96 %
58 % in three steps
Scheme 21 Synthesis of bexagliflozin 134 selective SGLT2 inhibitor [47]
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19 Page 26 of 84
etherification with methanol in the presence of methylsulfonic acid provided desi-lylated O-methyl lactols, which were reduced with triethylsilane and BF3.OEt2 to give desired C-aryl glucoside 134. The IC50 values for bexagliflozin against human SGLT1 and SGLT2 are 5.6 μM and 2 nM, respectively [47].
In 2012, Imamura and coworkers discovered a novel benzothiophene deriva-tives 139, among them ipragliflozin (R1=H, R2=F), which are a highly potent and selective SGLT2 inhibitors (Scheme 22) [48]. Lithiation of 135 followed by the addition of aromatic benzaldehydes, yielded alcohols those were reduced with Et3SiH and BF3.OEt2 to give aglycones 136. Lithium halogen exchange fol-lowed by the addition of a lithiated aromatic to compound 137 yielded lactols those were reduced by treatment with Et3SiH and BF3 etherate to give compounds 138. Successive removal of the benzyl groups generated compounds 139. Ipragli-flozin (R1=H, R2=F) was a highly potent and selective human SGLT2 inhibitor (IC50 = 7.4 nM).
Figure 11 contains the best inhibitors GPb, PTP1B, and SGLT2 having the aromatic C-glycoside structure that are described in Sect. 4.1. The analysis of the structure of the C-glycosyl derivatives presented in Fig. 11 shows that the presence of a chlorine or fluorine atom as well as the presence of sulfur-con-taining heteroaromatic ring guarantees an increased antidiabetic activity of the compound. All inhibitors shown in Fig. 11 are derivatives of glucose. Thus, also taking into account the structures of previously presented the best inhibitors, it can be concluded that this glucose molecule guarantees high inhibitor activity. Referring to the structure of the best inhibitors shown in Fig. 10, it can also be concluded that the cyclopropane ring is a structural element that guarantees high inhibitor activity. The repeating structural element is also the 1,4-dihydroxy or dimethoxyphenyl system.
R1 = H, R2 = F
O
OBn
OBnBnO
BnO
R1 R2
S
S
R2R1
Br S
R1 = H, F, ClR2 = H, F, Cl
O
OBnOBnBnO
BnO CHO1.n-BuLi, THF, -78oC,2. Et3SiH, BF3
.OEt2CH2Cl2, 0oC
O
OH
OHHO
HO
R1 R2
S
135 136 36-64 %
137
138 14-61 %139 24-86 %
1.n-BuLi, THF, -78oCbenzaldehydes2. Et3SiH, BF3
.OEt2CH2Cl2, 0oC
Ipragliflozin
BCl3/heptanepentametylbenzeneCH2Cl2, -78oC
Scheme 22 Synthesis of benzothiophene derivatives 139 selective SGLT2 inhibitors [48]
1 3
Topics in Current Chemistry (2019) 377:19 Page 27 of 84 19
4.2 Heteroaromatic C‑Glycosyl Derivatives
In 2001, Somsák et al. described highly chemo-, regio-, and stereoselective proce-dure that allows for the preparation of d-gluco- and d-xylopyranosylidene-spiro-hydantoins and thiohydantoins in six steps from the corresponding free sugar [49]. In the key step of the syntheses C-(1-bromo-1-deoxy-β-d-glycopyranosyl)forma-mides 142 and 143 were reacted with cyanate ion to give spiro-hydantoins 144 and 145 with a retained configuration at the anomeric center as the major products (Scheme 23). Thiocyanate ions gave spiro-thiohydantoins 144 with an inverted ano-meric carbon as the only products. The acetylated compounds were deprotected by the Zemplen procedure. Enzyme assays with a and b forms of muscle and liver gly-cogen phosphorylases showed spiro-hydantoin 144 (R1=CH2OH, R2=H, X=O) and spirothiohydantoin 144 (R1=CH2OH, R2=H, X=S) to be the best and equipotent inhibitors with Ki values in the low micromolar range. The study of epimeric pairs of d-gluco and d-xylo spiro-hydantoins and N-(d-glucopyranosyl)amides indicated the role of specific hydrogen bridges in binding the inhibitors to the enzyme [49].
In 2004, Somsak et al. have decided to prepare C-(β-d-glucopyranosyl) hetero-cycles exhibiting acidic, basic, and neutral properties in the heterocyclic moieties
O
NH
BzOOBz
OMe
OMe
O
COOH
BzO
HO
O
OH
OH OH
OH
OH
HO
GPb Ki 0.9 mM95, Scheme 15, [38]
100, Scheme 16, [40]
HO
O
OH
OH O
O
OH
HO
GPb Ki 1.3 mM91, Scheme 15, [38]
PTP1B IC50 2.44±0.2 mM
O
NH
BzOOBz
OMe
OMe
O
COOH
BzO
106, Scheme 17, [40]PTP1B IC50 0.77±0.09 mM
OOH
OH
OHHO
Me
S
F
O
OH
HO
OH
Cl OEt
HO
OOH
OH
OHHO
Cl
S
Cl
126 , Scheme 20, [43]hSGLT2 IC50 2.4 nM
O
OH
HOOH
OO
ClHO
113 Dapagliflozin, Scheme 18, [41]hSGLT2 EC50 1.1±0.06 nMhSGLT1 EC50 1390±7 nM
134 Bexagliflozin, Scheme 21, [47]
126 Canagliflozin, Scheme 20, [43]hSGLT2 IC50 2.2 nMhSGLT1 IC50 910 nM
hSGLT2 IC50 2.0 nMhSGLT1 IC50 5.6 µM
O
OH
OHHO
HO
F
S
139 Ipragliflozin, Scheme 22, [48]hSGLT2 IC50 7.4 nM
Fig. 11 Inhibitory properties of the best inhibitors from the aromatic C-glycosyl derivatives described in Sect. 4.1
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19 Page 28 of 84
R1
=C
H2O
Ac,H
CN
Br
AcO
AcO
O OA
c
R1
O
Br
CN
OA
c
OA
c
OA
c14
014
1
O
Br
CO
NH
2
OA
c
OA
c
OA
c
CO
NH
2
R3
R2 O
R2 O
O OR
2
R1
142
143
TiC
l 4,H
2OA
cOH
,0o C
-rt
AgO
CN
(4eq
uiv)
,CH
3NO
2,80
o C,X
=O
KS
CN
(4eq
uiv)
,S8,
CH
3NO
2,80
o C,N
2at
m.,
X=
S
144
145
R2 O
R2 O
O OR
2
R1
NH
NH
O
XR
2 OR
2 OO OR
2
R1
NH
NH
O
O
66-6
8%
4-25
%
R1
=C
H2O
Ac,R
2=
Ac,
R3
=B
rR
1=
CH
2OAc
,R2
=A
c,R
3=
OH
R1
=C
H2O
H,R
2=
H,R
3=
OH
R1
=H
,R2
=A
c,R
3=
Br
R1
=H
,R2
=A
c,R
3=
OH
R1
=R
2=
H,R
3=
OH
Ag 2
O,H
2O(1
equi
v),D
MS
O,r
t
Ag 2
O,H
2O(1
equi
v),D
MS
O,r
t
NaO
Me,
MeO
H,r
t
NaO
Me,
MeO
H,r
t
R1
=C
H2O
Ac,R
2=
Ac,
X=
Oor
SR
1=
CH
2OH
,R2
=H
,X=
Oor
SN
aOM
e,M
eOH
,rt
Sche
me
23
Synt
hesi
s of g
lyco
pyra
nosy
liden
espi
ro-h
ydan
toin
s and
thio
hyda
ntoi
ns 1
44 a
nd 1
45 [4
9]
1 3
Topics in Current Chemistry (2019) 377:19 Page 29 of 84 19
[50]. They transformed per-O-acetylated and -benzoylated β-d-glucopyranosyl cyanides 146 into the corresponding 5-(β-d-glucopyranosyl)tetrazoles 147, 2-(β-d-glucopyranosyl)benzothiazoles 153 and 2-(β-d-glucopyranosyl)-benzimidazoles 151 (Scheme 24). Acylation of the tetrazoles 147, either by acetic or trifluoroacetic anhydride, gave 5-(β-d-glucopyranosyl)-2-methyl- and -2-trifluoromethyl-1,3,4-oxadiazoles 148, respectively. Removal of the protect-ing groups furnished inhibitors 147 (R=H), 149, 152, and 154 exhibiting inhibi-tor constants in the micromolar range. The tetrazole 147 (R=H) ring of slightly acidic character was unfavorable for the binding of this compound to the GP enzyme. The neutral aglycones in 149 (Ki = 212 μM) and 154 (Ki = 229 μM) result in moderate inhibitors. The most efficient inhibitor was benzimidazole 152 (Ki = 11 μM) [50].
In 2005, Chrysina et al. examined inhibitors with enhanced affinity for glyco-gen phosphorylase that might control hyperglycemia in type 2 diabetes [51]. Three analogs of β-d-glucopyranose: 2-(β-d-glucopyranosyl)-5-methyl-1,3,4-oxadiazole 155, 2-(β-d-glucopyranosyl)-benzothiazole 156 and 2-(β-d-glucopyranosyl)-benzimidazole 157 were examined (Fig. 12). The compounds showed competitive inhibition with Ki values of 145.2 μM, 76 μM and 8.6 μM, respectively. In order to establish the mechanism of this inhibition, crystallographic studies were carried out and the structures of GPb in complex with the three analogs were determined. The complex structures revealed that the inhibitors can be accommodated in the catalytic site of T-state GPb with very little change of the tertiary structure [51].
In 2010, Kang and coworkers designed and synthesized pyridazinyl and thiazolyl derivative of C-glycosides [52]. They wanted to check if replacement of the phe-nyl ring with the corresponding heterocyclic ring could improve the GLT2 inhibi-tor. As shown in Scheme 25, the lithiated thiazolylglucoside 158 was converted to 5-chlorothiazolylglucoside or 5-bromothiazolylglucoside 159 by electrophilic halo-genation using CCl4 and CBr4, respectively. Lithiation of 5-bromothiazole interme-diate 159 was performed by treatment of LDA, and the resulting anion underwent a metal–halogen exchange reaction so that a bromine atom moved to a new position on the thiazole ring. The lithiated intermediate 160 was subjected to coupling with aldehydes to produce the desired products 161. The same conditions were applied to 5-chlorothiazole 159. The chlorine atom did not move to the 4-position but main-tained the original position. The coupling reactions of 5-chlorothiazole intermediate 159 with aldehydes produced 163. Both debenzylation and reduction were concur-rently performed to prepare the final products 162 and 164 (Scheme 25). Introduc-tion of the pyridazine ring at the anomeric carbon of d-glucopyranose was carried out in a stereoselective fashion [52]. Cyclization from γ-keto ester 165 to dihydro-pyridazinone 166 was accomplished with hydrazine monohydrate (Scheme 26). Dihydropyridazinone 166 was oxidized to pyridazinone 167 using bromine under acetic acid. Pyridazinone 167 was converted to 6-chloro-5-benzylpyridazine 168 by treatment with POCl3. Final removal of the four benzyl groups to produce the target compound 169 was accomplished with application TMSI (Scheme 26).
Biological activities of the compounds 162, 164 (Scheme 25) and 169 (Scheme 26) were evaluated by in vitro SGLT2 inhibition assay. While dapagliflozin (Scheme 18) shows highly potent inhibitory activity against human hSGLT2, it was
Topics in Current Chemistry (2019) 377:19
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19 Page 30 of 84
O OR
RO R
O
OR
CN
146
R=
Ac,
Bz,
H
NaN
3,N
H4C
l,D
MF
80o C
,3h
O OR
RO R
O
OR
NN
NH
N
R=
Ac,
Bz,
H
EtS
H,E
t 2O
,HC
l0o C
,4h
R=
Bz
147
150
Ac 2
O60
o C,7
dor (C
F 3C
O) 2
OC
HC
l 360
o C,1
h
O OR
RO R
O
OR
ONN
R'
R=
Bz,
R'=
CH
3,C
F 314
8
NaO
Me
MeO
Hrt
O OH
HO H
O
OH
ONN
R'
R'=
CH
3,C
F 3
149
O OR
RO R
O
OR
S
N
R=
Ac
153 NaO
Me
MeO
Hrt
O OH
HO H
O
OH
S
N
154
NH
2
NH
2py
ridin
ert,
24h O OR
RO R
O
OR
NH
N
NaO
Me
MeO
Hrt
O OH
HO H
O
OH
NH
N
151
152
O OR
RO R
O
OR
NH
SE
t
HC
l
SH
NH
2
EtO
H,A
rre
flux,
6h
100
%55
-100
%
34%
84%
68%
73%
53%
65-9
2%
Sche
me
24
Synt
hesi
s of
5-(
β-d
-glu
copy
rano
syl)t
etra
zole
s 14
7, 5
-(β-
d-g
luco
pyra
nosy
l)-1,
3,4-
oxad
iazo
les
149,
2-(
β-d
-glu
copy
rano
syl)b
enzo
thia
zole
s 15
4 an
d 2-
(β-d
-gl
ucop
yran
osyl
)-be
nzim
idaz
oles
152
[50]
1 3
Topics in Current Chemistry (2019) 377:19 Page 31 of 84 19
discovered that neither pyridazinyl nor thiazolyl analogs improved hSGLT2 inhibi-tion [52].
In 2010, Handlon and coworkers described a method of obtaining C-linked het-erocyclic glucosides that could inhibit human SGLT2 [53]. The authors used the bromo heterocycles 170 and the glucal boronate 171 to obtain a series of benzi-sothiazole- and indolizine-β-d-glucopyranosides 174 (Scheme 27). The key step of the reactions was a palladium-catalyzed cross-coupling leading to intermediates 172. Subsequent hydroboration–oxidation reactions followed by an acidic deprotec-tion of the sugar rings in the molecules of 173 provided the final products 174. The substrates 170 were obtained in three various ways, depending on their heterocyclic cores. The compounds were evaluated for their human SGLT1 and SGLT2 inhibi-tion potential by monitoring the suppression of the uptake of 14C-labeled α-methyl-d-glucopyranoside by COS-7 cells, which transiently expressed human SGLT2 or SGLT1, using BacMam technology [54]. The authors focused mostly on the influ-ence of the character of the substituents R1 and R2 and the basicity of the aromatic core on the inhibition potential of the compounds. It was found that their oral absorptions were good enough to avoid a transformation into the corresponding pro-drugs prior to the intake. Finally, the compound 174 (X=C, Y=S, Z=N, R1=t-Bu, R2=H) was found to be an inhibitor of SGLT2 with an IC50 of 10 nM [53].
In 2012, Yao et al. based on previous research into usage of N-indolylxylosides as SGLT2 inhibitors [55] and knowledge about metabolic stability of the C-glycosidic bond, synthesized the C-indolylxylosides as a result of a five-step synthesis. It is noteworthy that their SAR studies disclosed the key role of two substituents in the indole moiety. The presence of both a distal p-cyclopropylphenyl group and substit-uent in 7-position is necessary to achieve potent inhibitory activity. Using 2,3,4-tri-O-benzyl-d-xylonolactone 175 and diverse 3-bromo-1-tosyl-1H-indoles 176 as a starting material in lithium halogen exchange reaction, a variety of lactols 177 were received. Reduction with trietylsilane and boron trifluoride etherate gave C-linked β-xylosides 178 (Scheme 28). During heating of the previously obtained compounds 178 over KOH in THF/EtOH, detosylation took place, providing free indoles 179. Benzyl ether groups of 179 were removed under hydrogenolysis to furnish 180. Xylopyranosyl indoles 180 underwent N-alkylation with p-cyclopropylbenzyl bro-mide and gave the final products 181. Evaluation of biological activity demonstrated that from among C-indolylxylosides, compound 181 (R=F) turned out to be the strongest and metabolically stable SGLT2 and SGLT1 inhibitor. In compliance with SAR studies bearing two groups most significant for inhibition activity, it exhib-its an SGLT2 EC50 value of 47 nM and SGLT1 EC50 value of 282 nM. Moreover
O
OH
HOHO
OHO
NN
CH3
O
OH
HOHO
OH
N
S O
OH
HOHO
OH
NH
N
155 156 157
Fig. 12 2-(β-d-glucopyranosyl)-5-methyl-1,3,4-oxadiazole 155, 2-(β-d-glucopyranosyl)-benzothiazole 156 and 2-(β-d-glucopyranosyl)-benzimidazole 157 [51]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 32 of 84
O OB
n
BnO
OB
nS
N
BnO
XO O
Bn
BnO
OB
nS
N
BnO
X=
Cl,
Br
O OB
n
BnO
OB
nS
N
BnO
Li
Br
LDA
,TH
F,-7
8o CO O
Bn
BnO
OB
nS
N
BnO
Br
R
OH
X=
Br
TMS
I(ne
at),
50o C
O OH
HO
OH
S
N
HO
Br
RR
=be
nzyl
,4-m
ethy
lben
zyl
4-et
hylb
enzy
l,4-tert-
buty
lben
zyl
4-ch
loro
benz
ylp-su
bstit
uted
benz
alde
hyde
THF,
-78o C
tort
p-su
bstit
uted
benz
alde
hyde
THF,
-78o C
tort
O OB
nB
nOO
BnS
N
BnO
Cl
RH
O
R=
4-m
ethy
lben
zyl
4-et
hylb
enzy
l,4-n-
buty
lben
zyl
biph
enyl
-4-y
lmet
hyl
O OH
HO
OH
S
N
HO
Cl
R
158
159
160
161
162
163
164
trim
ethy
lsily
liod
ide
(nea
t),50
o C
n-B
uLi
CC
l 4or
CB
r 4TH
F-7
8o Cto
-10o C
18-3
4%
70-8
4%
10-4
0%
70-8
0%
10-4
0%
Sche
me
25
Synt
hesi
s of b
enzy
lthia
zoly
l-C-g
luco
side
s 162
and
164
[52]
1 3
Topics in Current Chemistry (2019) 377:19 Page 33 of 84 19
O OB
nB
nOO
Bn
BnO
O
OM
eO
OM
e
hydr
azin
em
onoh
ydra
teM
eOH
,ref
lux
O OB
nB
nOO
Bn
BnO
NN
OO
Me
H
O OB
nB
nOO
Bn
BnO
NN
OH
OM
e
PO
Cl 3,
tolu
ene
reflu
x
O OB
nB
nOO
Bn
BnO
NN
Cl
OM
e
O OH
HO
OH
HO
NN
Cl
OM
e
165
166
167
168
169
trim
ethy
lsily
liod
ide
CH
3CN
,rt
brom
ine,
acet
icac
id80
o C89
%
75%
84%
42%
Sche
me
26
Synt
hesi
s of b
enzy
lpyr
idaz
inyl
-C-g
luco
side
s 169
[52]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 34 of 84
pharmacokinetic studies showed that molecule 181 (R=7-F) is metabolically stable after intravenous and oral administration to rats [55].
In 2012 Li et al. designed and synthesized analogs of SGLT2 inhibitors con-taining the 1,2,3-triazole motif [56]. Substituted 1,2,3-triazole is a very important building block for more complex bioactive compounds, such as tazobactam, antivi-ral, anti-HIV, antibacterial, and antiallergic agents [56]. The C-glucosides with tria-zole aglycone were constructed by click chemistry. The synthesis of the key alkyne intermediate is outlined in Scheme 29. Alkyne 187 was obtained from 2,3,4,6-tetra-O-benzyl-d-glucopyranose 182 in five steps. 2,3,4,6-Tetra-O-benzyl-d-(+)-glucono-1,5-lactone 183 was prepared by Swern oxidation of benzyl protected d-glucopyra-nose 182. Trimethylsilylacetylene was deprotonated with n-BuLi and treated with lactone 183 to provide ketose 184. The free hydroxyl group was reduced and the trimethylsilyl group was removed easily by stirring in a mixture of NaOH, metha-nol, and dichloromethane, yielding the benzyl-protected alkyne 186. Alkyne 186 and azides were used directly to construct triazole aglycon by click chemistry. Compound 186 was transformed into the acetyl-protected form 187. Triazoles 188 were then synthesized through CuAAC with the corresponding azides (Scheme 29). Finally, the acetyl protecting groups were removed to give the triazole-linked C-glycosides compounds 189. Most of the synthesized compounds demonstrated increased urinary glucose excretion in SD rats, but they increased urine volume to a lesser degree than that of dapagliflozin [56].
In 2013, Bokor et al. elaborated a new method for the synthesis of 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles [57]. The starting compound was O-perbenzoylated β-d-glucopyranosyl formimidate 190, which reacted with tosyl-hydrazide to give tosylamidrazone 191 (Scheme 30). 3-(β-d-Glucopyranosyl)-5-substituted-1,2,4-triazoles 194 were prepared by acylation of O-perbenzoylated
XBr
YZ
R1
R2 O BO
O
OOTIPS
SiO
t-But-Bu
170
171
Pd(PPh3)2Cl2, DME, Na2CO3, 85°C O
OOTIPS
SiO
t-But-Bu
X
YZ
R1
R2
172
1. BH3, THF, from 0°C to rt2. H2O2, NaOH, THF, from 0°C to rt
O
OOTIPS
SiO
t-But-Bu
X
YZ
R1
R2
HOH
173
HF TEA, THF, 60°Cor TBAF, THF, rt
.O
OHOH
OHX
YZ
R1
R2
HOH
174
X = C, N+; Y = C, N, S; Z = C, N; R1 = H, Me, Et, iPr, t-Bu, Ph, Cl, F, OMe, OEt, CF3; R2 = H, Me
63-100 %
23-41 %in twosteps
3-60 %
Scheme 27 Synthesis of benzisothiazole- and indolizine-β-d-glucopyranosides 174 as SGLT2 inhibitors [53]
1 3
Topics in Current Chemistry (2019) 377:19 Page 35 of 84 19
O
BnO
OB
n
OB
n
O
+O
BnO
OB
n
OB
nOH
NTs
R
O
BnO
OB
n
OB
n
NTs
R
n BuL
i, TH
F/to
luen
e,fr
om -7
8o C to
rt, 2
,5h
Et3S
iH, B
F 3O
Et2,
CH
3CN
from
0o C
to rt
, 1h
ON
H
R
OB
nB
nO
OB
n
ON
H
R
OH
HO
OH
ON
R
OH
HO
OH
KO
H, T
HF/
EtO
H,
60o C
, 20h
10%
Pd/
C, H
2(g)
,M
eOH
/TH
F, rt
, 3h
4-cy
clop
ropy
lben
zyl b
rom
ide
Cs 2
CO
3, D
MF,
rt, 2
4h
175
176
177
178
181
180
179
N Ts
R
Br R
= H
, F, M
e15
-54
%in
two
step
s
63-8
8 %
10-5
1 %
in tw
o st
eps
Sche
me
28
Synt
hesi
s of C
-indo
lylx
ylos
ides
181
bea
ring
p-cy
klop
ropy
lben
zyl g
roup
[55]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 36 of 84
182
183
185
186
62%
inth
ree
step
s
O OB
n
BnO B
nO
OB
n
OH
O OB
n
BnO B
nO
OB
n
O
O OB
n
BnO B
nO
OB
nS
i
OH
184
O OB
n
BnO B
nO
OB
nS
iO OB
n
BnO B
nO
OB
nO OA
c
AcO A
cO
OA
c
187
DM
SO
Ac 2
O,r
ttri
met
hyls
ilyla
cety
lene
n-B
uLi,
THF,
-78o C
Et 3
SiH
BF 3
. Et 2
OC
H3C
N/C
H2C
l 2-1
5o C
NaO
HC
H3O
H/C
H2C
l 2,rt
Ac 2
O
BF 3
. Et 2
O,r
t
93%
79%
188N
3
R
sodi
umas
corb
ate
CuS
O4,
H2O
/CH
2Cl 2,
rt
Cl
CN
CH
3N
O2
FO
CH
3C
F 3N
S
Cl
S
NS
F
R=
CH
3ON
a,C
H3O
H,r
t
189
75-8
7%
intw
ost
eps
O OA
c
AcO A
cO
OA
c
NN
N
R
O OH
HO H
O
OH
NN
N
R
Sche
me
29
Synt
hesi
s of C
-glu
cosi
des w
ith tr
iazo
le a
glyc
one
189
[56]
1 3
Topics in Current Chemistry (2019) 377:19 Page 37 of 84 19
N1-tosyl-C-β-d-glucopyranosyl formamidrazone 191 and subsequent removal of the protecting groups. The best inhibitor was 3-(β-d-glucopyranosyl)-5-(2-naphthyl)-1,2,4-triazole 194 (Ki = 0.41 μM against rabbit muscle glycogen phos-phorylase b).
In 2013, Sakamaki and coworkers described the synthesis and structure–activ-ity relationship of thiophene-C-glucosides [58]. The synthetic route to thiophene-C-glucosides 199 is shown in Scheme 31, based on the reaction of aryl halide 196 with glucal-boronate ester 195. Coupling reaction with using dichlorobis (triph-enylphosphine) palladium between aglycones 195 and glucal-boronate 196 gave 197, followed by stereoselective hydroboration and oxidation in alkaline condi-tions yielded 198 with the desired β-configuration. O-silyl groups of 198 were deprotected with tetra-n-butylammonium fluoride (TBAF) to afford thiophene-C-glucosides 199 (Scheme 31). The human hSGLT2 inhibitory activities and rat urinary glucose excretion (UGE) effects of 199 were evaluated. As a result,
O
OBz
BzOBzO
OBz
190
R = CH3, CH2OCOCH3, CH2OHPh, C6H4-4-tBu, 2-naphtyl
TsNHNH2,CH2Cl2, rt
NNHTs
NH2 RCOCl, pyridineCHCl3, 0oC, rt
191
NaOMe, MeOH, rt
192 56-88 %
194 62-93 %
TBAF, THFreflux
193 69 %
O
OBz
BzOBzO
OBz
OEt
NHO
OBz
BzOBzO
OBz
N
NNH
RO
OBz
BzOBzO
OBz
N
NNH
RO
OH
HOHO
OHN
NNR
Ts
76 %
Scheme 30 Synthesis of 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles 194 [57]
O
OTIPSOO
SitBu tBu
BOO
BH3.THF, THF, 0oC
30% aq. H2O23M aq NaOHR = H, Cl
195
196
197
198199
PdCl2(PPh3)2,2 M aq. DME, 80oC
16-68 %
22-66 %
33-92 %
SR Et
Br
O
OTIPSOO
SitBu tBu
O
OTIPSOO
SitBu tBu
OHTBAF, THF
SR Et
SR Et
O
OHHO
OH
OH
SR Et
Scheme 31 Synthesis of thiophene-C-glucosides 199 [58]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 38 of 84
they showed good hSGLT2 inhibitory activities. In particular, the chlorothio-phene derivative 199 showed remarkable inhibitory activity against hSGLT2 (IC50 = 4.0 nM) [58].
In 2014, Somsak et al. synthesized derivatives of d-xylose with aglycones of the most efficient glucose-derived inhibitors of glycogen phosphorylase to explore the specificity of the enzyme towards the structure of the sugar part of the molecules [59]. 2-(β-d-Xylopyranosyl)benzimidazole 204 (Scheme 32) and 3-substituted-5-(β-d-xylopyranosyl)-1,2,4-triazoles 209 (Scheme 33) were obtained in multistep proce-dures from O-perbenzoylated β-d-xylopyranosyl cyanide 200.
Cycloadditions of nitrile-oxides and O-peracetylated exo-xylal 212 obtained from the corresponding β-d-xylopyranosyl cyanide 210 furnished xylopyranosylidene-spiro-isoxazoline derivatives 214 (Scheme 34) [59].
Oxidative ring closure of O-peracetylated β-d-xylopyranosyl-thiohydroximates prepared from 1-thio-β-d-xylopyranose 215 and nitrile-oxides gave xylopyrano-sylidene-spiro-oxathiazoles 217 and 218 (Scheme 35) [59]. The fully deprotected test compounds 204, 209, 214, 219, and 220 were assayed against rabbit muscle gly-cogen phosphorylase b. Evaluation showed very weak inhibition for 3-(2-naphthyl)-5-(β-d-xylopyranosyl)-1,2,4-triazole 209 only, while all other compounds proved ineffective in a concentration of 625 μM. Observations showed that the aglycones rendering their glucose derivatives to nanomolar inhibitors are not yet capable of completely overriding the effect of losing the side chain of the glucose moiety [59].
Investigations on the inhibitory and binding properties of different monosac-charides indicated the superior effectiveness of d-glucose [60, 61]. Changes in the sugar configuration as well as removal or replacement of substituents of the glucose moiety proved detrimental for the inhibition. Therefore, in 2015 Bokor et al. elabo-rated synthetic methods for D-glucal attached to oxadiazoles by a C–C bond [62]. For the preparation of the target compounds 226, two main routes were used; the functionalized glucal 226 was made by the formation of the heterocycle in the final stage (Scheme 36) or the 1,2-double bond can be introduced into a preformed C-glu-copyranosyl heterocycle 227 (Scheme 37). Introduction of the double bond was effected by either DBU induced elimination of benzoic acid from O-perbenzoylated glucopyranosyl precursors 221 (X=H) or Zn/N-methylimidazole mediated reduc-tive elimination from the 1-bromoglucopyranosyl starting compounds 221 (X=Br) (Scheme 36). Test compounds 226 were obtained by Zemplen debenzoylation.
O
OBz
BzOBzO CN
HBr, AcOH O
OBz
BzOBzO CONH2
Et3OBF4, CH2Cl2 O
OBz
BzOBzO C
NH
OEt
NH2
NH2
CH2Cl2reflux
200 201 202
O
OBz
BzOBzO
N
NH
NaOMe, MeOHO
OH
HOHO
N
NH
203204
51 % 96 %
80 %
81 %
Scheme 32 Synthesis of 2-(β-d-xylopyranosyl)benzimidazole 204 [59]
1 3
Topics in Current Chemistry (2019) 377:19 Page 39 of 84 19
O OBz
BzO Bz
OC
N
200
O OBz
BzO Bz
ON
NNH
NTM
SN3,
Bu2S
nOto
luen
e,80
o C
205
SOC
l 2
tolu
ene
orxy
lene
reflu
x
Ar=
Ph,4
-t-B
u-C
6H4
2-na
phth
yl11
1
ArN
O
Bn
HO OBz
BzO Bz
ONN
N
A r
Bn20
7
NaO
Me
MeO
H
O OH
HOHO
NNN
Ar
Bn
H2/
Pd(
C),
MeO
H,r
eflu
xO OH
HOHO
NNN
Ar
H20
820
9
91%
42-6
8%
63-9
1%
77-9
1%
Sche
me
33
Synt
hesi
s of 3
-(β-
d-x
ylop
yran
osyl
)-5-
subs
titut
ed-1
,2,4
-tria
zole
s 209
[59]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 40 of 84
O OAc
AcO Ac
OC
N
210
O OAc
AcO Ac
ON
NTs
HN
aH1,
4-di
oxan
ere
flux
OAc
O AcO
OAc
211
63%
212
99%
ArC
HN
OH
NaO
Cl,
THF O OAc
AcO Ac
O
ON
ArN
aOM
e,M
eOH
O OH
HOHO
ON
Ar
213
44-7
4%
214
65-9
8%
TsN
HN
H2,
Ran
ey-N
iN
aH2P
O2,
H2O
,AcO
Hpy
ridin
e
Ar=
Ph,4
-tBu-
C6H
4,4-
CF 3
-C6H
4,1-
naph
thyl
2-na
phth
yl,2
-ben
zoth
iazo
lyl
Sche
me
34
Synt
hesi
s of x
ylop
yran
osyl
iden
e-sp
iro-is
oxaz
olin
e de
rivat
ives
214
[59]
1 3
Topics in Current Chemistry (2019) 377:19 Page 41 of 84 19
Unfortunately, none of these showed significant inhibition of rabbit muscle glycogen phosphorylase b, indicating that the binding of the aglycones was not strong enough to override the detrimental effects of the changes in the sugar parts of the molecules [62].
In 2016, Bokor et al. designed various C-glucopyranosyl-1,2,4-triazolones as potential inhibitors of GP [63]. Syntheses of these compounds were performed with O-perbenzoylated glucose derivatives 228, 230, and 233 as precursors (Scheme 38). Boiling a solution of carbamoyl-C-β-d-glucopyranosyl formamidrazone 228 in m-xylene gave 3-β-d-glucopyranosyl-1,2,4-triazol-5-one 229. Cyclization of 230 in boiling DMF produced the expected triazolone 231. Reaction of tosyl-C-β-d-glucopyranosyl formamidrazone 233 with ethyl chloroformate furnished 3-β-d-glucopyranosyl-1-tosyl-1,2,4-triazol-5-one 234 (Scheme 38). In situ prepared β-d-glucopyranosylcarbonyl isocyanate 237 was transformed by PhNHNHBoc into 3-β-d-glucopyranosyl-1-phenyl-1,2,4-triazol-5-one 240, while the analogous 1-(2-naphthyl) derivative 243 was obtained from the unsubstituted triazolone 242 by naphthalene-2-boronic acid in a Cu(II) catalyzed N-arylation (Scheme 39). Test compounds were prepared by Zemplen deacylation. The new glucose derivatives had weak or no inhibition of rabbit muscle glycogen phosphorylase b. The best inhibi-tor was 3-β-d-glucopyranosyl-1-(2-naphthyl)-1,2,4-triazol-5-one 244 (Ki = 80 μM) (Scheme 39) [63].
Glucose-based spiro-isoxazolines can be considered as anti-hyperglycemic agents against type 2 diabetes through GP inhibition. In 2016, d-glucopyranosylidene-spiro-isoxazolines 252 were prepared by 1,3-dipolar cycloaddition of nitrile oxides 249 generated in situ to methylene exo-glucals 250 (Scheme 40) [64]. Reagents 249 were generated by reaction of a sodium hypochlorite 246 and oximes 245.
Ar = Ph, 1-naphthyl2-naphthyl
O
OAc
AcOAcO SH
215
O
OAc
AcOAcO S Ar
NOH
O
OAc
AcOAcO
S
NO
Ar
O
OAc
AcOAcO
O N
S Ar
NBSCHCl3hν
O
OH
HOHO
S
NO
Ar
O
OH
HOHO
O N
S Ar
216 63-91 %
217 23-32 % 218 7-12 %
219 60-75 % 220 60-70 %
NaOMeMeOH
NaOMeMeOH
orAr C(Cl) NOHEt3N, CH2Cl2Ar CH NOHNaOCl, Et3N, CH2Cl2
Scheme 35 Synthesis of xylopyranosylidene-spiro-oxathiazoles 219 and 220 [59]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 42 of 84
BzO
221
X=
H,B
r
O
OB
z
BzO B
zOC
N
222
O
OB
z
BzO B
zOCN
OH N
H2
223
RC
OC
l,1,
4-di
oxan
e,rt
X=H
,DB
U,C
H2C
l 2,rt,
50%
X=
Br,
Zn,N
-met
hylim
idaz
ole
EtO
Ac,
reflu
x,92
%N
H2O
H. H
Cl,
pyrid
ine,
rtO
X
CN
OB
z
BzO
BzO
84%
O
OB
z
BzO B
zOCN
OC
OR
NH
222
4
O
OB
z
BzO B
zO
N
ON
R22
5
O
OH
HO H
O
N
ON
R22
6
NaO
Me/
MeO
H,r
tTB
AF/
THF,
tolu
ene,
reflu
x
R=P
h,99
%R
=2-N
apht
yl,8
8%
R=P
h,72
%R
=2-N
apht
yl,8
5%
R=P
h,85
%R
=2-N
apht
yl,8
5%
Sche
me
36
Firs
t met
hod
of c
ompo
unds
226
synt
hesi
s [62
]
1 3
Topics in Current Chemistry (2019) 377:19 Page 43 of 84 19
226
O
OB
z
BzO B
zO
N
ON
R22
5
O
OH
HO H
O
N
ON
RR
=P
h,60
%R
=2-
Nap
htyl
,50%
[RC
N+
O- ]
RC
(Cl)N
OH
,tol
uene
,Ar,
reflu
xN
aOM
e/M
eOH
,rt
O
OB
z
BzO B
zOC
N
222
R=
Ph,
89%
R=
2-N
apht
yl,9
6%
R=
Ph,
78%
R=
2-N
apht
yl,7
0%O
NNO
R
OB
zB
zOB
zO
OB
z
227
DB
U,C
H2C
l 2,rt
Sche
me
37
Seco
nd m
etho
d of
com
poun
ds 2
26 sy
nthe
sis [
62]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 44 of 84
O OB
z
OB
z
CNH
2 N
BzO B
zON
HC
OO
Et
228
229
O
OB
z
BzO B
zO
NN
HN
O H
m-x
ylen
e,re
flux
230
NaO
Me
MeO
H,r
tO OB
z
OB
z
CNH
2 N
BzO B
zON
HC
ON
H2
O OB
z
OB
z
BzO B
zON
NH
HN
OO OH
OH
HO H
ON
NH
HN
O
O OB
z
OB
z
CNH
2 N
BzO B
zON
HTs
ClC
OO
Et,
CH
Cl 3
pyrid
ine,
0o C-2
0o CO OB
z
OB
z
BzO B
zON
N
HN
O Ts
231
232
233
234
235
NaO
Me
MeO
H,r
tO OH
OH
HO H
ON
N
HN
O Ts
DM
F,re
flux
37%
69%
60%
70%
56%
Sche
me
38
Synt
hese
s of C
-glu
copy
rano
syl-1
,2,4
-tria
zolo
nes 2
29, 2
32, a
nd 2
35 [6
3]
1 3
Topics in Current Chemistry (2019) 377:19 Page 45 of 84 19
66%
fort
wo
step
s
O OB
z
OB
z
CB
zO BzO
O
NH
2
236
O OB
z
OB
z
BzO B
zON
N
HN
O Ph
237
239
240
O OB
z
OB
z
CB
zO BzO
O
N
O
NN
HP
h
H
O
OtB
u
PhN
HN
HC
OO
tBu
THF,
0o C-2
0o C
(CO
Cl) 2
,ClC
H2C
H2C
lre
flux
O OB
z
OB
z
CB
zO BzO
O
NC
O
O OB
z
OB
z
CB
zO BzO
O
N
O
NN
Ph
HH
H
238
PhN
HN
H2,
THF
0o C-2
0o C
m-k
syle
nere
flux
CF 3
CO
OH
CH
2Cl 2,
rtN
aOM
eM
eOH
,rt
37%
from
238
87%
from
239
O OH
OH
HO H
ON
N
HN
O Ph
241
95%
69%
fort
wo
step
s
O OB
z
OB
z
BzO B
zON
N
HN
O H
B(O
H) 2
Cu(
OA
c)2,
Et 3
N,C
H2C
l 2,rt
O OB
z
OB
z
BzO B
zON
N
HN
ON
aOM
eM
eOH
,rt
O OH
OH
HO H
ON
N
HN
O
242
243
20%
244
84%
Sche
me
39
Synt
hesi
s of 3
-β-D
-glu
copy
rano
syl-1
-phe
nyl-1
,2,4
-tria
zol-5
-one
241
and
1-(
2-na
phth
yl) d
eriv
ativ
e 24
4 [6
3]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 46 of 84
54-9
9 %
251
NAr H
OH
NaO
Cl
Ar =
4-F
3C-C
6H4,
4-M
eS-C
6H4,
2,4
-diM
eO-C
6H3,
2-n
apht
hyl
NAr H
OH
HC
lN
Ar Cl
OH
Ar =
4-F
3C-C
6H4,
4-O
2N-C
6H4,
C6H
5, 4
-Me-
C6H
5, 4
-MeS
-C6H
4, 2
,4-d
iMeO
-C6H
3, 2
-nap
hthy
l
245
246
245
247
MeO
iPrS
iOS
OSN
NN
O O
O O
MeO
iPrS
iOS
OSN
NN
O O
O O
Et3N
248
249
250
R =
Ac,
Bz
R =
Ac,
Bz
NaO
Me
MeO
H
252
NO O
Cl
O OR
OR
RO R
OO OR
OR
RO R
O
ON
Ar
O OR
OR
RO R
O
ON
Ar
ArC
NO
55-1
00 %
Sche
me
40
Synt
hesi
s of s
piro
-isoo
xazo
lines
252
by
1,3-
dipo
lar c
yclo
addi
tion
of n
itrile
oxi
des 2
49 to
exo
-glu
cals
250
[64]
1 3
Topics in Current Chemistry (2019) 377:19 Page 47 of 84 19
Appropriate oximes 245 reacted also with NCS 247 and aryl α-chloroaldoximes 248 were prepared. Hydrochloric acid elimination in the presence of NEt3 afforded reac-tive nitrile oxides 249. O-unprotected spiro-isooxazolines 252 were evaluated as GP inhibitors and exhibited IC50 values ranging from 1 to 800 μM. The tetra-O-acety-lated spiro-isoxazoline 251 bearing 2-naphthyl residue shoved a much lower value compared to that of the O-unprotected analog 252 [64]. The 2-naphthyl substituted glucopyranosylidene-spiro-isoxazoline 252 was the best compound identified in this study (GPb Ki = 0.63 μM).
Syntheses of a series of C-glucopyranosyl pyrroles, indole, and an improved prep-aration of C-glucopyranosyl imidazoles allowed in 2016 Kantsadi et al. to study and compare their inhibitory efficiency against GP [65]. C-β-D-Glucopyranosyl pyrrole derivatives 258, 260, and 262 were prepared in the reactions of pyrrole 254, 2-aryl-pyroles 255, and 3-aryl-pyrroles 256 with O-peracetylated β-d-glucopyranosyl trichloroacetimidate 253 (Scheme 41). (2β-d-Glucopyranosyl) indole 267 was obtained by a cross-coupling of O-perbenzylated β-d-glucopyranosyl acetylene 263 with N-tosyl-2-iodoaniline 264 followed by spontaneous ring closure (Scheme 42) [65]. An improved synthesis of O-perbenzoylated 2-(β-d-glucopyranosyl) imi-dazoles 270 was achieved by reacting C-glucopyranosyl formimidates 268 with α-aminoketones 269 (Scheme 43) [65]. The deprotected compounds were assayed with isoforms of glycogen phosphorylase to show no activity of the pyrroles 258, 260, 262, and indole 267 against rabbit muscle GPb [65]. The imidazoles 271 proved to be the best-known glucose-derived inhibitors of not only the mus-cle enzymes (both a and b) but also of the pharmacologically relevant human liver hlGPa (Ki = 156 and 26 nM for the phenyl and 2-naphthyl derivatives, respectively). An X-ray crystallographic study of the rmGPb-imidazole complexes revealed struc-tural features of the strong binding, and also allowed explaining the absence of inhi-bition for the pyrrole and indole derivatives [65].
Figure 13 shows the structure of the best inhibitors from heteroaromatic C-glyco-side derivatives described in Sect. 4.2. Again, the analysis of the structure of the best inhibitors leads to the conclusion that the highest activity is ensured by the presence of glucose as a structural element. Only in the case of compounds 181 and 209 is it xylose. It can also be seen that the high inhibitor activity is guaranteed by the pres-ence of a structural element such as a five-membered heteroaromatic ring contain-ing two or three nitrogen atoms. The high activity of the inhibitor is also ensured by the presence of such heteroaromatic rings as: 1,3,4-oxadiazole (compound 149), benzisothiazole (compound 174), indole (compound 181), thiophene (compound 199), and isoxazoline (compound 252). Again, presents a distal p-cyclopropylphenyl group (compound 181) is necessary to achieve potent inhibitory activity. Also, the glycone and aglycone spiro combination (compounds 144) ensures high inhibitor activity.
4.3 Other C‑Glycosyl Derivatives
In 2009, Bisht and coworkers described the synthesis of aryl butenoyl C-glycosides 277 by aldol condensation of peracetylated glycosyl acetones 275 with aromatic
Topics in Current Chemistry (2019) 377:19
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19 Page 48 of 84
84%
N H N HAr
N H
Ar
AcO
AcO
O OAc
OAc
OC
Cl 3
NH25
3
BF3. Et
2O,M
SD
CM
,-50
o C-r
t
BF3. Et
2O,M
SD
CM
,-50
o C-r
t
BF3. Et
2O,M
SD
CM
,-50
o C-r
t
AcO
AcO
O OAc
OAc
N H
AcO
AcO
O OAc
OAc
N H
Ar
AcO
AcO
O OAc
OAc
N H
Ar
NaO
Me
MeO
H,rt
NaO
Me
MeO
H,rt
NaO
Me
MeO
H,rt
HOHO
O OH
OH
N H
HOHO
O OH
OH
N H
Ar
HOHO
O OH
OH
N H
Ar
Ar=
phen
yl,2
-nap
htyl
254
255
256
257
258
259
260
261
262
51-5
7%
44-6
9%
68%
58-8
0%
70-7
8%
Sche
me
41
Synt
hesi
s of C
-β-d
-glu
copy
rano
syl p
yrro
le d
eriv
ativ
es 2
58, 2
60, a
nd 2
62 [6
5]
1 3
Topics in Current Chemistry (2019) 377:19 Page 49 of 84 19
aldehydes followed by deacetylation with methanolic NaOMe (Scheme 44) [66]. β-C-Glycosidic ketones 274 were prepared in one step directly from the unprotected sugar 272 and pentane-2,4-dione 273 under aqueous conditions by Knoevenagel condensation [67]. Compounds 275 on aldol reaction with different aldehydes under ambient reaction conditions resulted in (E)-4-aryl-1-(glycopyranosyl)-but-3-en-2-ones 276 [68]. Prepared C-glycosides 277 were evaluated for their α-glucosidase, glucose-6-phosphatse, and glycogen phosphorylase enzyme inhibitory activi-ties in vitro and in vivo. Three of the compounds 277 (Ar=2-naphthyl, phenyl, 3,4-dimethoxyphenyl) showed potent enzyme inhibitory activities as compared to standard drugs such as acarbose and metformin. These C-glycosides caused a sig-nificant decline in the hyperglycemia of the diabetic rats post sucrose-load [66].
Another approach for the inhibition of GP could take advantage of multiva-lency. In 2009, Cecioni and coworkers examined influence multivalency for the inhibition of GP [69]. They synthesized two distinct trivalent inhibitors of GP through Cu(I)-assisted 1,3-dipolar cycloaddition and by formation of a trisoxa-diazole derivative. The perbenzoylated glucosyl cyanide 278 was reacted with hydroxylamine hydrochloride in pyridine to afford the desired amidoxime 279 (Scheme 45). The formation of the O-acyl-amidoxime 280 was achieved with 4-pentynoic acid in the presence of EDCI/HOBt as coupling agents. The use of thermal activation combined with TBAF catalysis provided the cyclic oxadia-zole 281. The alkyne-terminated oxadiazole 281 was then engaged in a Huisgen’s Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction under microwaves activation with benzyl azide to afford 1,4-disubstituted 1,2,3-triazole 282. Debenzoylation
NHTs
IPd(PPh3)4, CuIPPh3, TEA, 75oC
Bu4NF, THFreflux
H2, Pd(C), EtOAc, rt
264
O
OBn
OBnH
BnOBnO
263
O
OBn
OBn
N
Ts
BnOBnO
265
O
OBn
OBn
N
H
BnOBnO
266
HOO
OH
OH
N
H
HO
267
66 %
50 %
68 %
Scheme 42 Synthesis of 2-(β-d-glucopyranosyl) indole 267 [65]
O
OBz
OBz
C
NH
OEt
BzOBzO
268
Ar = phenyl, 2-naphtyl
269
Ar
O
NH2 HClN
rt
BzOBzO
O
OBz
OBz
N
HN
Ar
NaOMeMeOH, rt
HOHO
O
OH
OH
N
HN
Ar
270 271
42-45 % 74-77 %
Scheme 43 Synthesis of 2-(β-d-glucopyranosyl) imidazoles 271 [65]
Topics in Current Chemistry (2019) 377:19
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19 Page 50 of 84
N
HNO
OH
OH
HOHO
271, Scheme 43, [65]hlGPa Ki 26 nMrm GPa Ki 65 nMrm GPb Ki 31 nM
N
HNO
OH
OH
HOHO
271, Scheme 43, [65]hlGPa Ki 156 nMrmGPa Ki 226 nMrmGPb Ki 280 nM
O
OH
OH
HOHO
ON
252, Scheme 40, [64]GPb Ki 0.63 µM
O
OH
OH
HOHO
NN
HNO
244, Scheme 39, [63]GPb Ki 80 µM
O
OH
HOHO
N
NN
H209, Scheme 33, [59]GPb IC50 0.9 mMO
OH
OH
OH
HO
S
ClEt
199, Scheme 31, [58]hSGLT2 IC50 4 nM
N
NNHO
OH
HOHO
OH
194, Scheme 30, [57]GPb Ki 0.41 µM
HO
O
OH
OHOH
HO
NH
N
157, Fig. 12, [51]GPb Ki 8.6 µM
HO
O
OH
OHOH
HO NS
t-Bu174, Scheme 27, [53]SGLT2 IC50 10 nM
O
OHHO
OH
N
F
181, Scheme 28, [55]hSGLT2 EC50 47±3 nMhSGLT1 EC50 282±11 nM
HO
O
OH
OHOH
HO
N
N
O
H
H
O
GPb Ki 3.1 µM144, Scheme 23, [49]
HO
O
OH
OHOH
HO
N
N
O
H
H
S
144, Scheme 23, [49]GPb Ki 4.2 µM
HO
O
OH
OHOH
HO
O
NN
Me
149, Scheme 24, [50]
GPb Ki 212 µM
Fig. 13 Inhibitory properties of the best inhibitors from the heteroaromatic C-glycosyl derivatives described in Sect. 4.2
O
OH3C
H3C
NaHCO3H2O, 90oC
Ar = C6H5, 4-Cl-C6H4, 4-H3CO-C6H4, 4-HO-C6H4,3-O2N-C6H4, 3,4-(H3CO)2-C6H3, 3,4,5-(H3CO)3-C6H2,2-naphthyl, 3-pyridyl
Ar CHOCH2Cl2pyrrolidinert, 8h
NaOMe, MeOHrt, 2-3h
272 273 274 275
276277
Ac2O, pyridine, rtO
OH
HOHO
OH
OH
O
OH
HOHO
OH
O
CH3
O
OAc
AcOAcO
OAc
O
CH3
O
ArO
OAc
AcOAcO
OAc
O
ArO
OH
HOHO
OH
60-85 %
96 %
66-75 %
95 %
Scheme 44 Synthesis of (E)-4-aryl-1-(β-d-glucopyranosyl)-but-3-en-2-ones 277 [66]
1 3
Topics in Current Chemistry (2019) 377:19 Page 51 of 84 19
278
279
HCC
(CH 2
) 2C
OO
H, E
DC
I, HO
Bt1.
CH
2Cl 2/
DM
F, -8
o C,
2. rt
, 16
h
280
PhM
e, T
BA
Fm
icro
wav
e
281
C6H
3(C
H2N
3)3
CuI
, Et 3
Nm
icro
wav
e
284
R =
Bz
285
R =
HN
aOM
eM
eOH
NON
NNN
PhC
H2N
3C
uI, E
t 3N
mic
row
ave
NH
2OH
. HC
lC
5H5N
, 50o C
, 5h
282
R =
Bz
283
R =
HN
aOM
eM
eOH
O OBz
BzO
OBz
CN
BzO
O OBz
BzO
OBz
BzO
NH2
NO
H
NH2
NO
O
O OBz
BzO
OBz
BzO
NON
O OBz
BzO
OBz
BzO
O
OR
OR OR
RO
NN
N
NN
NN
N N
ON
N
ON
N
ON
N
O OR
RO
OR
RO
O
RO
OR ROO
R
O OBz
BzO
OBz
BzO
99 %
67 %
97 %
98 %
88 %
Sche
me
45
Synt
hesi
s of i
nhib
itors
of G
P 28
3 an
d 28
5 th
roug
h C
u(I)
-ass
isted
1,3
-dip
olar
cyc
load
ditio
n [6
9]
Topics in Current Chemistry (2019) 377:19
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19 Page 52 of 84
of compound 282 afforded hydroxylated GP inhibitor candidate 283. The reaction of 1,3,5-tris(azidomethyl)benzene with the alkyne derivative 281 under micro-wave activation and Cu(I) catalysis afforded the cycloadduct 284. The saponifi-cation of the benzoate ester 284 provided the fully hydroxylated macromolecule 285. Also, a more condensed trifunctional macromolecule was prepared in which the C-glucosyl-oxadiazole moiety was directly attached to a benzene ring. A bio-logical study of the inhibiting properties of these trivalent inhibitors of GP have shown that the valency of the molecules influences slightly the inhibition of the enzyme, whereas the presence of a spacer arm between the core and the pharma-cophore moieties does not. Authors reassumed that multivalent inhibitors were always superior to their monovalent counterparts [69].
In 2010, Kakinuma et al. gave considerable attention to 5-thioglucose—derived SGLT2 inhibitors, which have a sulfur atom in place of the oxygen atom in the glu-cose ring [70]. It is known that 5′-thio-N-acetyllactosamine is 200 times more resist-ant to digestion by β-galactosidase [71], and methyl α-5′-thiomaltoside is not hydro-lyzed at all by glucoamylase [72]. In previous articles [73, 74], it was also described that O-aryl 5-thio-β-glucoside is a SGLT inhibitor. Kakinuma et al. developed a synthetic strategy for preparing C-phenyl 1-thio-d-glucitol derivatives 290, as it is outlined in Scheme 46 [70]. Compounds 288 were obtained by adding thiolactone 287 to Grignard reagents prepared from compounds 286 and magnesium powder. The hydroxyl group of 288 was reduced β-stereoselectively to afford compounds 289. Finally, the benzyl ether of compounds 289 was removed by catalytic hydro-genation with palladium hydroxide under a hydrogen atmosphere or, alternatively, compounds 290 were obtained by removal of the benzyl group using Lewis acid conditions to prevent reduction of the chloride (Scheme 46). (1S)-1,5-Anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-d-glucitol 290 (R1=OMe, R2=Me, R3=OEt) exhibited potent SGLT2 inhibition activity (IC50 = 2.26 nM) [70]. Since 2014, this 1-thio-d-glucitol 290 has been known as luseogliflozin, and it is an orally active SGLT2 inhibitor developed by Taisho Pharmaceutical for the treatment of patients with type 2 diabetes mellitus [75].
34-92 %
49-99 %
Br
R1 R2 R3
S
OBnOBnBnO
BnO OH
R1 R2 R3
Et3SiH, BF3.OEt2
CH3CN or CH3CN/CHCl3
S
OBnOBnBnO
BnO
R1 R2 R3
S
OHOHHO
HO
R1 R2 R3
286
287
288
289290 7-83 %
R1 = H, OMe, OBnR2 = H, F, Cl, Me, OMe, OBnR3 = Me, Et, OEt, iPr, tBu, SMe
LuseogliflozinR1 = OMe, R2 = Me, R3 = OEt
Pd(OH)2/H2 orAlCl3 in anisole orCF3COOH, Me2S, m-cresol1,2-ethanedithiol, TfOH
S
OBnOBnBnO
BnOO
1. Mg, THF
2.
Scheme 46 Synthesis of C-phenyl 1-thio-d-glucitols 290 selective SGLT2 inhibitors [70]
1 3
Topics in Current Chemistry (2019) 377:19 Page 53 of 84 19
An approach to controlling blood glucose levels in individuals with type 2 diabe-tes is to target R-amylases and intestinal glucosidases using R-glucosidase inhibitors acarbose and miglitol. One of the intestinal glucosidases targeted is the N-terminal catalytic domain of maltase-glucoamylase (ntMGAM), one of the four intestinal glycoside hydrolase 31 enzyme activities responsible for the hydrolysis of terminal starch products into glucose [76]. In 2010, Sim and coworkers presented the X-ray crystallographic studies of ntMGAM in complex with a new class of R-glucosidase inhibitors derived from natural extracts of Salacia reticulata, a plant used tradition-ally in Ayurvedic medicine for the treatment of type 2 diabetes [76]. In extracts, active compounds were: salacinol 291, kotalanol 292, and de-O-sulfonated kotalanol 293 (Fig. 14). This study revealed that kotalanol 293 is the most potent ntMGAM inhibitor reported to date (Ki = 0.03 μM), some 2000-fold better than the compounds currently used in the clinic, and highlights the potential of the salacinol class of inhibitors as future drug candidates [76].
In 2011, Wang et al. synthesized triazolyl phenylalanine and tyrosine-aryl C-gly-coside hybrids via microwave-assisted Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition [77]. Successive enzymatic assay identified the synthesized glycocon-jugates as novel PTP1B inhibitors with low micromole-ranged inhibitory activity and at least several-fold selectivity over other homologous PTPs tested. As shown in Scheme 47, the azido phenylalaninyl or tyrosinyl derivatives 297 were synthesized according to the literature [78]. For the synthesis of the O-propynyl C-glycoside 296, the known C-glucosyl 1,4-dimethoxybenzene 294 was first regioselectively silylated on its 6-position with TBDMSCl followed by full O-benzylation with NaH and BnBr. Then, the TBS group was desilylated with AcCl to give the free 6-OH, which was propargylated in the presence of NaH and propargyl bromide. Huisgen [3 + 2] cycloaddition between the azides 297 and the sugar alkyne 296 was catalyzed by sodium ascorbate and CuSO4·5H2O yielding the click adducts 298 (Scheme 47). The saponification with LiOH led to the carboxylic acids 299. The following hydrogenolysis gave the fully deprotected amino acid-sugar hybrid 300. Benzyl groups on glucosyl moiety of compounds were found crucial for PTP1B inhibition. The biological assay identified the glycoconjugates that contain the carboxylic acid and benzyl moieties as more active PTP1B inhibitors compared to their ester and debenzylated counterparts [77].
In 2011, Kim et al. designed and synthesized novel macrocyclic C-aryl gluco-side SGLT2 inhibitors [79]. Two different synthetic routes of macrocyclization were
S OH
OH
HO
HO OH
OSO3-
S
OH
HO
HO OH
OH
OH
OH
OSO3-
OH
S
OH
HO
HO OH
OH
OH
OH
OHOHCl -
291 292 293
Fig. 14 Structures of R-glucosidase inhibitors from Salacia reticulata: salacinol 291, kotalanol 292, and de-O-sulfonated kotalanol 293 [76]
Topics in Current Chemistry (2019) 377:19
1 3
19 Page 54 of 84
O
OH
HOHO
OH
OM
e
OM
e29
429
552
%29
659
%
1.TB
SCl,
pyrid
ine
2.N
aH,B
nBr,
DM
F
1.Ac
Cl,
MeO
H2.
NaH
,pro
parg
ylbr
omid
eD
MF
297
298
299
RN 3
O
MeO
R=
H,O
H
Na
asco
rbat
eC
uSO
4. 5H2O
CH
2Cl 2/
H2O
mic
row
ave
irrad
iatio
n
PdC
l 2/C
H2,
MeO
HLi
OH
MeO
H/H
2O
300
OBn
O BnO
OBn
OM
e
OM
e
TBSO
OM
e
O
OBn
O BnO
OBn
OM
e
ON
NNR
OM
eO
OBn
O BnO
OBn
OM
e
OM
e
ON
NNR
OHO
OBn
O BnO
OBn
OM
e
OM
e
ON
NNR
OHO
OHO
HOO
H
OM
e
OM
e
R=
H92
%R
=O
H92
%R
=H
92%
R=
OH
90%
R=
H44
%R
=O
H43
%
Sche
me
47
Synt
hesi
s of
tria
zoly
l phe
nyla
lani
ne a
nd ty
rosi
ne-a
ryl C
-gly
cosi
de h
ybrid
s 30
0 vi
a m
icro
wav
e-as
siste
d C
u(I)
-cat
alyz
ed a
zide
-alk
yne
1,3-
dipo
lar c
yclo
addi
tion
[77]
1 3
Topics in Current Chemistry (2019) 377:19 Page 55 of 84 19
42%
OHO
BnO
OBn
OBnO
Cl
O
BrO
TBD
PS
OO Bn
OO
Bn
OBnO
Cl
O
OTB
DPS
OO Bn
OO
Bn
OBnO
Cl
O
OH
NaB
H4,
Pd(P
Ph 3
) 4TH
F
OO Bn
OO
Bn
OBnHO
Cl
O
OH
OO Bn
OO
Bn
OBnHO
Cl
O
IO
BnO
OBn
OBnO
Cl
OO
O
HOO
H
OHO
Cl
OO
301
302
303
304
305
306
307
308
NaH
,DM
F
I 2,P
Ph3
imid
azol
ebe
nzen
e
K 2C
O3
18-c
row
n-6
DM
F
BCl 3,
DC
Mor P
d/C
,H2
MeO
H/T
HF
93%
TBAF
,TH
F
93%
64%
20%
Sche
me
48
Synt
hesi
s of m
acro
cycl
ic C
-ary
l glu
cosi
de S
GLT
2 in
hibi
tor 3
08 [7
9]
Topics in Current Chemistry (2019) 377:19
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19 Page 56 of 84
adopted. Alkylation of alcohol 301 with (5-bromopentyloxy)(tert-butyl)-diphenyl-silane 302 in the presence of sodium hydride in DMF produced 303 (Scheme 48). Desilylation of 303 with TBAF gave alcohol 304. Removal of the allyl group was carried out using NaBH4 in the presence of tetrakis(triphenylphosphine) palla-dium(0) to give phenol 305 in quantitative yield. The primary alcohol of 305 was transformed into the corresponding iodide 306 by action of iodine, triphenylphos-phine, and imidazole in benzene. The iodide 306 underwent macrocyclization to 307 under conditions of potassium carbonate and 18-crown-6 in DMF. Removal of the benzyl groups on the carbohydrate moiety proceeded with either BCl3 in methyl-ene chloride or hydrogenolysis on Pd/C in MeOH and THF to produce the target compound 308 (Scheme 48). Among the compounds tested, [1, 7] dioxacyclopenta-decine macrocycles 308 possessing ethoxyphenyl at the distal ring showed the best in vitro inhibitory activity (IC50 = 0.778 nM) against human hSGLT2 [79].
In 2012, Ohtake et al. discovered a novel class of inhibitors, which have an O-spiroketal C-arylglucoside scaffold [80]. Compound 312 (R1=Et)—tofogliflozin (Scheme 49) is a selective SGLT2 inhibitor that is one of the inhibitors for the treat-ment of type 2 diabetes. Ohtake et al. worked on synthesis of tofogliflozin using the computational modeling and comparing other pharmacophore models that were derived from earlier inhibitors. O-Spiroketal C-arylglucosides 312 were prepared from 309 through two pathways, as outlined in Scheme 49. Compounds 311 were synthesized from the aldehyde 310, which could be obtained by oxidation of 309, followed by addition of Grignard reagents or lithiated benzenes and reduction. Com-pounds 314 were prepared utilizing the Suzuki coupling reactions. After debenzyla-tion of 309 using boron trichloride, benzyl alcohol moiety was selectively chlorin-ated by treatment of chlorotrimethylsilane with dimethyl sulfoxide. Four hydroxyl groups of the resulting benzyl chloride were acetylated to afford 313. Suzuki cou-pling reactions of 313 with the corresponding 4-substituted phenylboronic acids gave 314. Deprotections (debenzylation for 311 or deacetylation for 314) afforded the test compounds 312. Two products 312 (R=Et or iPr) were submitted to clinical trials. Both products showed a similar degree of increase in renal glucose excretion after oral dosing [80]. However, the next clinical trials turned out the 312 (R=Et) is much better, because it had more desirable profiles in oral bioavailability and renal excretion than 314 (R=iPr).
The discovery of structurally distinct SGLT2 inhibitors has been mainly focused on the modification of the aglycones, while modification to the glucose residue is less known. Therefore, in 2016 Yan and coworkers decided to examine a series of C-aryl glucosides containing dioxa-bicycle for inhibition activity against hSGLT2 [81]. Ertugliflozin [82], bearing a unique dioxa-bicycle in place of the glucose resi-due of dapagliflozin, is distinct from other inhibitors and shows even better SGLT2 inhibitory activity, which is currently under phase III clinical trial. The synthesis of dioxa-bicycle C-aryl glucoside 327 is outlined in Scheme 50. Allylation of 315 in the presence of boron trifluoride etherate formed compound 316, which was con-verted to ether 318. Conversion of the allyl intermediate 318 to aldehyde 320 using a Pd-catalyzed double-bond migration and next reaction with K2Os2O4 and sodium periodate was made. Aldehyde 320 was then reduced to the alcohol 321, which was then protected as the methoxymethyl ether 322. Deprotection of TBSO ether
1 3
Topics in Current Chemistry (2019) 377:19 Page 57 of 84 19
Sche
me
49
Synt
hesi
s of O
-spi
roke
tal C
-ary
lglu
cosi
de sc
affol
d 31
2 [8
0]
Topics in Current Chemistry (2019) 377:19
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19 Page 58 of 84
gave alcohol 323, and the primary hydroxyl group of 323 was subjected to iodina-tion using Ph3P, imidazole and iodine to give 324, which upon elimination using DBU in toluene furnished 325. Sharpless dihydroxylation and acid-promoted one-pot MOM removal followed by stereoselective intramolecular trapping of the puta-tive oxonium ion intermediate gave compound 326. Hydrogenolysis of the benzyl-protecting groups yielded target compound 327 (Scheme 50). The target compound 327 was subsequently subjected to biological evaluation as novel C-aryl glucoside SGLT2 inhibitor. Compound 327 showed good inhibitory activity against hSGLT2 IC50 = 714 nM [81].
According to our group interest of synthesis of C-glycosyl derivatives we also occupied in the synthesis of some derivatives. In 2013, we developed a conveni-ent and efficient procedure for the preparation of fused uracils - pyrano[2,3-d]pyrimidines with sugar moiety [83]. The reaction sequence was: Knoevenagel con-densation of unprotected sugars 328 and 1,3-dimethylbarbituric acid 329 in water, acetylation of C-glycosides 330 and hetero-Diels–Alder reaction (Scheme 51). O-Acetylated 1,3-dimethyl-2,4,6-trioxo-pyrimidin-5-ylidene derivatives 331 were used as new heterodienes in the synthesis of pyrano[2,3-d]pyrimidines 333 and 334 containing a sugar moiety. Solvent-free hetero-Diels–Alder cycloadditions of O-acetylated pyrimidin-5-ylidene alditols 331 with enol ethers 332 were investigated at room temperature. New, enantiomerically pure cis and trans diastereoisomers of
76 %
89 %
75 %69 %
89 %
78 % 75 %
67 %
O
OBn
Ar
BnO OBn
O
AcOAllyl TMS, BF3
.Et2OCH2Cl2, -15oC to rt
O
OBn
Ar
BnO OBn
RO
315316 R = Ac317 R = OH
NaOMeMeOH
TBDMSClimidazole, THF
O
OBn
Ar
BnO OBn
TBSO
PdCl2, toluene110oC
O
OBn
Ar
BnO OBn
TBSO
1.K2Os2O4, NMO acetone/water2. NaIO4, THF
O
OBn
Ar
BnO OBn
TBSO
CHO
NaBH4, MeOH
O
OBn
Ar
BnO OBn
TBSO
OH
O
OBn
Ar
BnO OBn
TBSO
OMOM
MOMCl, DIPEACH2Cl2
TBAF, THFO
OBn
Ar
BnO OBn
HO
OMOMI2, imidazolePh3P, THF
O
OBn
Ar
BnO OBn
I
OMOM
DBU, toluene110oC
O
OBn
Ar
BnO OBn
OMOMO
OBn
Ar
BnO OBn
HOO
H2, Pd/C, THF
O
OH
HO OH
HOO
Cl OEt
1.K2Os2O4, NMO acetone/water2. TFA, CH2Cl2, rt
318
319320321
322 323 324
325326 60 %327 Ertugliflozin 55 %
Scheme 50 Synthesis of ertugliflozin 327 [81]
1 3
Topics in Current Chemistry (2019) 377:19 Page 59 of 84 19
pyrano[2,3-d]pyrimidines 333 with alditol moiety were obtained. The same pyrimi-din-5-ylidene alditols 331 underwent conjugate Michael addition-cyclizations with malononitrile 335 at room temperature to afford optically active uracils 336—diastereoisomers of pyrano[2,3-d]pyrimidine-6-carbonitriles with a sugar moiety (Scheme 52) [83]. None of the C-glycosyl derivatives of pyrano[2,3-d]pyrimidines presented in Schemes 51 and 52 have been evaluated for their pharmacological activity as inhibitors in treatment of type 2 diabetes mellitus.
Our group also described a convenient and efficient method for the synthesis of chromeno[2,3-d]pyrimidine-2,4-diones containing different sugar moieties [84]. Dimedone enamines were used as dienophiles in hetero-Diels–Alder reactions. The cycloaddition reactions of O-acetylated 1,3-dimethyl-2,4,6-trioxo-pyrimidin-5-ylidene alditols 337, representing a 1-oxa-1,3-butadiene system, with dimedone enamines 338 afforded only one enantiomerically pure cis diastereoisomer of
330
N
NO
O
O
Na
O
OH
HO
OH328
O
R2
R5
R6 R1
R4
R3
R7
OH
OOH
OH
HO
OH
328 L-(-)-Xylose, R1=R4=R5=OH, R2=R3=R6=R7=HL-(+)-Arabinose, R1=R4=R6=R7=H, R2=R3=R5=OHD-(+)-Glucose, R1=R4=R5=H, R2=R3=R6=OH, R7=CH2OHD-(+)-Galactose, R1=R4=R6=H, R2=R3=R5=OH, R7=CH2OHD-(-)-Ribose
N
NO
O
O
Na
O
R2
R5
R6 R1
R4
R3
R7
N
NO
O
O
329
5R
minorcis 334
+
7S
7R
minor 17 %major 54-73 %
332
+
OR10
331 L-Xylo, R1=R4=R5=R8=OAc, R2=R3=R6=R7=R9=HL-Arabino, R1=R4=R6=R7=R9=H, R2=R3=R5=R8=OAcD-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OAcD-Galacto, R1=R4=R6=R8=H, R2=R3=R5=R9=OAc, R7=CH2OAcD-Ribo, R1=R3=R5=R7=R9=H, R2=R4=R6=R8=OAc
332 R10=Et, isoBu
331
N
N OO
R2 R1
R4 R3
R6 R5
R8R9
R7
O
330 N
N OO
R2 R1
R4 R3
R6 R5
O
R9 R8
OR10
R7
H
H
trans 333cis 333
N
N OO
R2 R1
R4 R3
R6 R5
O
R9 R8
OR10
R7
H
H
+5R
5S
7S
N
N OO
R2 R1
R4 R3
R6 R5
O
R9 R8
OR10
R7
H
H
5S
7R
N
N OO
R2 R1
R4 R3
R6 R5
O
R9 R8
OR10
R7
H
H
H2O, 80oCNa2CO3
75-93 %
75-93 %
Ac2O, ZnCl2r.t.
stirring
majortrans 334 65-72 %
Scheme 51 Synthesis of pyrano[2,3-d]pyrimidines 333 and 334 with sugar moiety [83]
Topics in Current Chemistry (2019) 377:19
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19 Page 60 of 84
chromeno[2,3-d]pyrimidine-2,4-diones 339 in each reaction (Scheme 53). Analysis of NMR spectra allowed the determination that prepared fused uracils containing amino and enol functional groups exist as a mixture of the neutral form (NF) and zwitterions—dipolar ions (DI). By this simple hetero-Diels–Alder reaction, we can introduce into fused uracil systems such important for biological interaction groups as: different sugar moieties, enol moiety, and different amino groups. The prepared fused uracils contain both amine and enol functional groups, so share amphiprotic properties, and they are zwitterions in solid state [84]. None of the C-glycosyl deriv-atives of chromeno[2,3-d]pyrimidines 339 have been examined as inhibitors in the treatment of type 2 diabetes.
Figure 15 presents inhibitory properties of the best inhibitors from the other C-glycosyl derivatives described in Sect. 4.3. The variety of active inhibitor struc-tures is in this case greater than in the above-mentioned groups of glycosides. For
5SN
N OO
R2 R1
R4 R3
R6 R5
O
R9 R8
R7
CN
NH2
H
(5S)-336 minor
+5RN
N OO
R2 R1
R4 R3
R6 R5
O
R9 R8
R7
CN
NH2
H
(5R)-336 major
N
N OO
R2 R1
R4 R3
R6 R5
R8R9
R7
O
CH2CN
CN
335
+
331 L-Xylo, R1=R4=R5=R8=OAc, R2=R3=R6=R7=R9=HL-Arabino, R1=R4=R6=R7=R9=H, R2=R3=R5=R8=OAcD-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OACD-Galacto, R1=R4=R6=R8=H, R2=R3=R5=R9=OAc, R7=CH2OAc
C2H5OHN
78-84 %
Scheme 52 Synthesis of pyrano[2,3-d]pyrimidine-6-carbonitriles 336 with a sugar moiety [83]
X = H, Me 339 NF 339 DI
N
N OO
X
X
R2 R1
R4 R3
R6 R5
R8R9
R7
O
337 339
N
N OO
X
X
R2 R1
R4 R3
R6 R5
R8R9
R7
O OH
NH Y
O
NH
Y
+
338
N
N OO
X
X
R2 R1
R4 R3
R6 R5
R8R9
R7
O O
NH Y
H
337 L-Xylo, R1=R4=R5=R8=OAc, R2=R3=R6=R7=R9=HL-Arabino, R1=R4=R6=R7=R9=H, R2=R3=R5=R8=OAcD-Gluco, R1=R4=R5=R8=H, R2=R3=R6=R9=OAc, R7=CH2OACD-Galacto, R1=R4=R6=R8=H, R2=R3=R5=R9=OAc, R7=CH2OAc
Y-NH = C6H5-NH, 4-MeC6H4-NH, 4-MeOC6H4-NH
MeMe
NH
MeMe
NH
MeMe
NH
OH
73-87 %
CH2Cl2rt
Scheme 53 Synthesis of C-glycosides-chromeno[2,3-d]pyrimidines 339 containing different sugar moie-ties [84]
1 3
Topics in Current Chemistry (2019) 377:19 Page 61 of 84 19
example, aryl butenoyl C-glycosides 277 can cause a significant decline in the hyperglycemia of the diabetic rats post sucrose-load. 5-Thioglucose—derived inhib-itor 290, which has a sulfur atom in place of the oxygen atom in the glucose ring, is known as luseogliflozin and it is an orally active SGLT2 inhibitor for the treat-ment of patients with type 2 diabetes mellitus. The activity of inhibitors may also be influenced by multivalency. On the basis of tests of trivalent inhibitors activity (for example compound 285), it was found that valency of the molecules influences slightly the inhibition of the enzyme, whereas the presence of a spacer arm between the core and the pharmacophore moieties does not. Multivalent inhibitors were
Multivalent inhibitors werealways superior to theirmonovalent counterparts.
O
O
OH
HOHO
OH
O
OH
HOHO
OH
O
OCH3
OCH3
O
OH
HOHO
OH
O
277, Scheme 44, [66]C-Glycosides 277 showed potent enzyme inhibitory activities as compared to standard drugs such as acarbose and metformin.
285, Scheme 45, [69]
ntMGAM Ki 0.03 µM
S
OHOHHO
HO
MeO Me OEt
S
OHHO
HO
OH
OH
OHOH
OH OH
293, Fig. 14, [76]
Cl-
ON
N NO
HO
OBnOBnO
OBn
OMe
OMe
290 Luseogliflozin, Scheme 46, [70]
hSGLT2 IC50 2.3 nMhSGLT1 IC50 3990 nM
ON
N NO
HO
OH
OBnOBnO
OBn
OMe
OMe
299, Scheme 47, [77]PTP1B IC50 5.6 µM
299, Scheme 47, [77]PTP1B IC50 5.5 µM
O
HO OH
OH
O Cl OO
308, Scheme 48, [79]hSGLT2 IC50 0.778 nM
O
O
312 Tofogliflozin, Scheme 49, [80]hSGLT2 IC50 2.9 nMhSGLT1 IC50 8.444 nM
O
OH
HO OH
HOO
Cl OEt
327 Ertugliflozin, Scheme 50, [81]hSGLT2 IC50 714 nM
O
RO
OR
RO
OR
O
OR
OR
ORRO
N N
N
NN
NN
NN
ON
N
ON
N
ON
N
O
ORRO
OR
RO
Fig. 15 Inhibitory properties of the best inhibitors from the other C-glycosyl derivatives described in Sect. 4.3
Topics in Current Chemistry (2019) 377:19
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19 Page 62 of 84
always superior to their monovalent counterparts. In turn, the natural C-glycoside kotalanol 293, which structures comprise a 1,4-anhydro-4-thio-d-arabinitol core and polyhydroxylated acyclic chain, is the most potent ntMGAM inhibitor reported to date (Ki = 0.03 μM) and highlights the potential of the salacinol class of inhibitors as future drug candidates. Active inhibitors can also be glycoconjugates, such as triazolyl phenylalanine and tyrosine-aryl C-glycoside hybrids (compound 299). Bio-logical assay identified the glycoconjugates 299 that contain the carboxylic acid and benzyl moieties as more active PTP1B inhibitors compared to their ester and deben-zylated counterparts. Also, macrocyclic C-glycosides may be active inhibitors. For example, [1, 7] dioxacyclopentadecine macrocycle 308 possessing ethoxyphenyl at the distal ring showed the best in vitro inhibitory activity (IC50 = 0.778 nM) against human hSGLT2. Compound 312—tofogliflozin represents a novel class of SGLT2 inhibitors, which have an O-spiroketal C-arylglucoside scaffold. In turn, ertugliflo-zin 327 contains a unique dioxa-bicycle in place of the glucose residue of dapagli-flozin, and is distinct from other inhibitors, and shows even better SGLT2 inhibitory activity.
5 Directions of the Latest Research in 2018–2019
In order to show the latest research directions, papers from 2018 to 2019 are described in a separate Sect. 5. When searching for articles on subject this publica-tion, it was noted that the number of articles describing the synthesis of new inhibi-tors decreased, and at the same time the number of publications depicting the extrac-tion of active natural O-glycosides from plant materials increased. This trend applies in particular to 2018 and 2019. Sect. 5 presents articles on the latest modifications of the C-glycosides structure aimed at increasing their effectiveness as inhibitors. Suitable modifications were made to previously tested C-glycosides, in the agly-cone structure as well as in the sugar molecule structure. Next, the latest proposals concerning the structure of N-glycosides as antidiabetic agents were presented and finally the structures of active O-glycosides isolated from plants were presented.
In 2018, Kerru et al. published a review article about current antidiabetic agents and their molecular targets [85]. In this review, authors described the use of hetero-cyclic scaffolds, which have been evaluated for their biological response as inhibi-tors against their respective antidiabetic molecular targets over the 5-year period from 2012 to 2017. Investigation reveals a diverse target set which includes pro-tein tyrosine phosphatase 1 B (PTP1B), dipeptidly peptidase-4 (DPP-4), free fatty acid receptors 1 (FFAR1), G protein-coupled receptors (GPCR), peroxisome pro-liferator activated receptor-g (PPARg), sodium glucose co-transporter-2 (SGLT2), α-glucosidase, aldose reductase, glycogen phosphorylase (GP), fructose-1,6-bispho-sphatase (FBPase), glucagon receptor (GCGr), and phosphoenolpyruvate carbox-ykinase (PEPCK). The article presents the structures of various active heterocyclic compounds, of which glycoside derivatives constitute a small group.
Kun and coworkers examined 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles, which have been revealed as an effective scaffold for the development of potent glycogen phosphorylase inhibitors [86]. The potency of these compounds
1 3
Topics in Current Chemistry (2019) 377:19 Page 63 of 84 19
is very sensitive to the nature of the alkyl/aryl 5-substituent. Authors have chosen for synthesis nine predicted candidates after in silico screening of 2335 new ana-logues. The compounds 349 were prepared in O-perbenzoylated forms by either ring transformation of 5-β-d-glucopyranosyl tetrazole 340 by N-benzyl-arenecar-boximidoyl chlorides, ring closure of C-(β-d-glucopyranosyl)formamidrazone 341 with aroyl chlorides, or that of N-(β-d-glucopyranosylcarbonyl)arenethio-carboxamides 347 by hydrazine, followed by deprotections (Scheme 54). Five compounds had Ki’s < 10 μM (349 a–e) with potent low μM inhibitors (rmGPa, hlGPa) and three of these (349a–c) on the submicromolar range for rmGPa [86]. The 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles described by Kun et al. are predicted to have drug-like potential with only permeability flagged as a potential issue to efficacy.
In 2018, Kyriakis et al. studied the inhibitory effect of different groups, in size and hydrophobicity, at the para position of 3-(β-d-glucopyranosyl)-5-phenyl-1, 2, 4-triazoles 350 in hlGP by kinetics and X-ray crystallography (Fig. 16) [87]. The most bioactive compound was the one with an amine substituent to show a Ki value of 0.43 μM. The best C-β-d glucopyranosyl triazole GP inhibitor reported
O
OBz
OBzBzO
BzO
NN
NHN O
OBz
OBzBzO
BzONH
NHNHTs
O
OBz
OBzBzO
BzOO
X
O
OBz
OBzBzO
BzO
N
NHN
Bn
Ar
O
OH
OHHO
HO
N
NHN
Bn
Ar
O
OBz
OBzBzO
BzO
N
HN
Ar
N
O
OH
OHHO
HO
N
HN
Ar
N
340 341
345 346 347
348 349
S
H2N Ar
O
OBz
OBzBzO
BzOO
N
H
S
Ar
NaOMeMeOH, rt
NaOMeMeOH, rt
344
SOCl2
MeCN, pyridine, rt
Aroyl chlorideCHCl3, pyridinert, 2 days
Ar
O
N Bn
H
SOCl2xylenereflux Ar
Cl
N Bn
DMF, Et3NBnBr, 24h, rt
349d
349e
COOH
COOH
349a
349b
349c
MeOH/EtOAc10% Pd/C, H2reflux
hydrazinemonohydratepyridine, rt
342 X= OH343 X= Cl
Scheme 54 Synthesis of 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles 349 [86]. The collected yields for individual synthesis steps are not given in the article
O
OH
HOOH
HO
N
NN
HR
R = H, Me, COOH, CF3, NO2, OCH3, OH, NH2
350
Fig. 16 Structure of 3-(β-d-glucopyranosyl)-5-phenyl-1, 2, 4-triazoles 350 [87]
Topics in Current Chemistry (2019) 377:19
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19 Page 64 of 84
thus far is the compound which has a 2-napthyl group and displays a Ki value of 0.172 μM for the liver enzyme. Structural studies have revealed the physicochem-ical diversity of the β-pocket providing information for future rational inhibitor design studies. Comparison of the Ki values of the inhibitors studied and their structural mode of binding revealed that the addition of the para group led to significant increments in potency only when this group exploited hydrophilic or hydrophobic interactions within the β-pocket [87].
Szennyes et al. performed a systematic study on the preparation of 2-C-(β-d-glucopyranosyl)pyrimidines [88]. Pinner-type cyclization of O-perbenzylated C-(β-d-glucopyranosyl)formamidine 351 with β-ketoesters, dimethyl malonate, and β-diketone-derived α,β-unsaturated β-chloroketones followed by catalytic hydro-genation resulted in various substituted 2-C-(β-d-glucopyranosyl)-pyrimidin-4(3H)-ones 354 (Scheme 55), and 2-C-(β-d-glucopyranosyl)-4,6-disubstituted-pyrimidines, respectively, in moderate to good yields. These pyrimidine derivatives were also obtained by ring closure of the unprotected C-(β-d-glucopyranosyl)formamidine 352 with the same 1,3-dielectrophiles (Scheme 55). A continuous one-pot three-step procedure starting from O-peracylated d-glycopyranosyl cyanides was also elaborated to give pyrimidines with various sugar configurations in overall yields (25–94%). These synthetic routes represent the first expansible method to obtain the target compounds. The C-glycopyranosyl pyrimidines showed moderate inhibition against α-glucosidase and β-galactosidase enzymes, and no activity against glycogen phosphorylase [88].
Kuo et al. identified a good-in-class SGLT1/SGLT2 dual inhibitor to improve blood glucose control in type 2 diabetes [89]. The synthesis of benzocyclobutane-C-glycosides 362 is described in Scheme 56. Lithium-halogen exchange of com-pound 355 with n-BuLi, followed by the aldol condensation with compound 356 formed 357. Reduction of compound 357 with TFA/Et3SiH gave 358. Treatment of
O
OBn
BnOOBn
BnONH.HCl
NH2
O
OH
HOOH
HONH.HCl
NH299 %
R1
O
R2
O
OEt3-ketoester (2 equiv.)NaOMe/MeOH (3 equiv.)MeOH, rt
3-ketoester (2 equiv.)NaOMe/MeOH (3 equiv.)MeOH, rt
O
OBn
BnOOBn
BnO
N
N
O
R1
R2
H
O
OH
HOOH
HO
N
N
O
H
R1
R2
351 352
353 354
43-87 % 59-88 %
52-77 %
H2, Pd(OH)2/CEtOAc/EtOH (1:2)1 drop conc. HCl, rt
H2, Pd(OH)2/CEtOAc/EtOH (1:2)reflux
Scheme 55 Synthesis of 2-C-(β-d-glucopyranosyl)-pyrimidin-4(3H)-ones 354 [88]
1 3
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358 with n-BuLi, followed by the condensation with lactone 359, resulted in the for-mation of lactol 360. Removal of the 1-OH group with BF3.Et2O/Et3SiH provided compound 361. Deprotection of the benzyl-protecting groups with BCl3/penta-meth-ylbenzene gave benzocyclobutane-C-glycosides 362. The biological experiments were carried out on mice, rats, dogs, and monkeys. The best inhibitor 362 (R1=H, R2=Cl) displayed very high inhibitory potency at both SGLT1 (IC50 = 45 nM) and SGLT2 (IC50 = 1 nM). New compounds have high in vivo efficacies in different ani-mal model species [89].
In 2019, Kuroda and co-authors reported a discovery of an SGLT1 inhibitor C-phe-nyl d-glucitol derivative 378 (R1=OMe, R2=H, R3=N,N-dimethylethylenediamine) (Scheme 57 and 58), with a glucose-lowering effect at a dose of 0.3 mg/kg (p.o.) in Sprague–Dawley (SD) rats [90]. The authors’ aim was to obtain a derivative that excretes mostly in bile to avoid retention of the drug in kidneys. The way of achiev-ing this was imparting greater lipophilicity into the molecule by balancing ClogP and topological polar surface area (TPSA) together with the absorbability. The inhibitor 378 was obtained in a multi-step synthesis in which as staring materials were used: 3-isopropylphenol 363, lactone 366, and the compounds 370 and 371 (Schemes 57 and 58). Compound 378 (R1=OMe, R2=H, R3=N,N-dimethylethylenediamine) showed hSGLT1 IC50 = 29 nM, hSGLT2 IC50 = 20 nM, ClogP = 3.66, and TPSA = 161 Å2. The authors concluded that the compound 378 could potentially be useful as a therapeutic agent for patients with T2DM [90].
In the next two articles discussed in the review, attempts were made to syn-thesize active inhibitors by modifying the sugar part of the C-glycoside. In 2018, Yuan and coworkers published an article which concerned the synthesis of 27 aryl C-glycosides bearing a C=N/C–N linkage at the glucosyl C6 posi-tion [91]. All of these compounds were tested for their inhibitory activity against
BrOH
R2R1
Br355 357
TFA, Et3SiHDCM, 0oC
R2
R1
CHOBr
1. n-BuLi, THF,-78oC2. 356, THF,-78oC
356
R2R1
Br358
1. n-BuLi, THF, -78oC2. 359, THF, -78oC
O O
OBnBnOOBn
BnO
359
O
R1 R2
OH
OBnBnO
BnO
OBn
360
R1 = H, OH, OCH3, FR2 = CH3, OCH3, C2H5, Cl, cyclic-C3H5
BF3.Et2O, Et3SiH, DCM, OoC
O
R1 R2
OBnBnO
BnO
OBn
361
BCl3, pentamethylbenzeneDCM, -78oC
O
R1 R2
OHHO
HO
OH 362
Scheme 56 Synthesis of benzocyclobutane-C-glycosides 362 [89]. The collected yields for individual synthesis steps are not given in the article
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sodium-dependent glucose co-transporter 2 (SGLT2). Among all obtained oxime ether derivatives 385, oxime (R=H) showed the best in vitro inhibitory activity (hSGLT2 EC50 = 46 nM, hSGLT1 EC50 = 3576 nM) and moreover no significant cytotoxicity and low human ether-à-go–go-related gene (hERG) inhibition. The mentioned oxime ether derivatives 385 were prepared starting from 5-bromo-2-chloro-benzoic acid 379 as outlined in Scheme 59. A mixture of α- and β-C-glucosides 380 was obtained in accordance with the procedure described in [41].
iPr
OAcO
AcOOAc
OAc
R1
367: R1 = OMe, OBn
1. BuLi, THF, −78 °C2. Compound 366 3. MsOH, MeOH, rt4. Ac2O, Py, DMAP, rt5. Et3SiH, BF3·OEt2, CH3CN/CHCl3, 4 °C
366:
O OTMSO
TMSOOTMS
OTMS
40-59%
R1 iPr
I365: R1 = OMe, OBn
BnBr (R1 = OBn) or MeI (R1 = OMe), K2CO3, MeCN, rt85%
OH iPr
I364
OH iPr
363
KI, I2, H2O, AcOH, rt57%
Br
iPr
OTMSO
TMSOOTMS
OTMS
R1
369: R1 = OMe, OTMS
Br
iPr
OAcO
AcOOAc
OAc
R1
368: R1 = OH, OMe
2. TMSCl, Et3N, DMF, 4 °C
1. 10%Pd–C, H2, MeOH, rt; 2. Br2, AcOH, rt. (R1 = OBn)or Br2, AcOH, rt (R1 = OMe)
52% (R1 = OBn)96% (R1 = OMe)
1. Et3N, MeOH/H2O, 50 °C or NaOMe, MeOH, rt
O
NH
OH
O
373
O
OH
370 NH2 OMe
O371:
DMF (cat.), CHCl3, rt2. Et3N3. Compound 371
93%O
NH
OMe
O
372
NaOH, H2O, MeOH, rt
94%
1. (COCl)2,
Scheme 57 The synthesis of potent, low-absorbable SGLT1 inhibitor [90] (part 1)
1 3
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The next step included regioselective 6-O-silylation and per-O-acetylation of 380 to synthesize the fully protected β-C-glucoside 381. Then a reaction with boron trifluoride etherate in CH2Cl2 and oxidation with Dess–Martin periodinane were carried out to introduce the aldehyde at C6 position. At the end, a conden-sation of aldehyde 383 with different hydroxylamines in pyridine, followed by
1. BuLi, THF, –78 °C
2.
3. MsOH, MeOH, rt
iPr
OOH
OHOH
OH
R1
R2
O
NH
R3
O
378
377, 378: R1 = OH, OMe; R3 = H, Me; R3 = N,N-dimethylethylenediamine, piperazine, 1-methylpiperazine, 1,2-diamino-2-methylpropane
iPr
OAcO
AcOOAc
OAc
R1
R2
O
NH
R3
O
NaOMe, MeOH, rt or Et3N, H2O, MeOH, rt47-98%
377
iPr
OAcO
AcOOAc
OAc
R1
R2
O
NH
OH
O
water soluble carbodiimide·HCl,HOBt·H2O, resp. amine, CHCl3, rtor carbonyldiimidazole, CDCl3, rt21-95%
376
iPr
OAcO
AcOOAc
OAc
R1
R2
Br
375
iPr
OOH
OHOH
OH
R1
R2
Br
OH
374
Br
iPr
OTMSO
TMSOOTMS
OTMS
R1
369: R1 = OMe, OTMS
water soluble carbodiimide (WSCI) =
NC
N N
1. Ac2O, Py, rt2. Et3SiH, BF3·OEt2MeCN, CHCl334-56% from 368
BrR2
OHC(R2 = H, Me)
O
NH
OH
O
(373)
Pd(OAc)2, (2-tolyl)3P
60-87%Et3N, MeCN, 120 °C
375, 376: R1 = OMe, OAc; R2 = H, Me
Scheme 58 The synthesis of potent, low-absorbable SGLT1 inhibitor 378 [90] (part 2)
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deacetylation under Zemplén conditions led to obtain the desired oxime ether derivatives 385 [91].
The next article from 2018 from Sadurní et al. concerned the influence of molecular editing with fluorine at the C2 position of the pyranose ring of phlori-zin analogues to concurrently direct β-selective glycosylation [92]. The authors pro-posed the methodology of fluorine-directed glycosylation to synthesize the selec-tive SGLT2 inhibitors for type 2 diabetes. The mentioned phlorizin analogues were remogliflozin etabonate and dapagliflozin. These compounds, 396 and 397, con-taining fluorine at C2 position were prepared starting from triacetyl-d-glucal 386 as outlined in Scheme 60. A derivative 387 was obtained by the method described in Ref. [93]. The two glycosyl donors 388 and 389, required to access both target
Scheme 59 Synthetic pathway of oxime ether derivatives 385 [91]
Scheme 60 Synthesis of remogliflozin etabonate and dapagliflozin analogues 396 and 397 [92]
1 3
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scaffolds, were formed according to the procedures presented in Scheme 60. The next steps in the synthesis of remogliflozin etabonate analogue included: glycosyla-tion, benzyl-deprotection, and selective creation of the primary carbamate. Finally, the remogliflozin etabonate surrogate 396 was obtained. In the case of dapagliflo-zin surrogate 397, the next steps involved the activation of 391 by halogen-lithium exchange and addition to the donor lactone 389, reduction with triethylsilane and BF3·OEt2, benzyl-deprotection. Based on the conducted biological tests, it was found that the fluorinated dapagliflozin analogue 397 better selectively inhibited human SGLT2 over SGLT1 than remogliflozin etabonate analogue 396 [92].
Kun et al. extended the structure–activity relationships of β-d-glucopyranosyl azole type inhibitors and revealed the extreme sensitivity of such type of inhibitor towards the structure of the azole moiety [94]. Actually, these compounds are the best glucose analogue inhibitors of GP known to date. Their efficiency, among other factors, is due to the formation of an H-bridge between the heterocycle and the His-377 main chain carbonyl group in the active site of the enzyme [94]. 1-Aryl-4-β-d-gluco-pyranosyl-1,2,3-triazoles were prepared by copper-catalyzed azide-alkyne cycloadditions between O-perbenzylated or O-peracetylated-β-d-glucopyranosyl ethynes and aryl azides. 1-β-d-Gluco-pyranosyl-4-phenyl imidazole was obtained in a glycosylation of 4(5)-phenylimidazole with O-peracetylated α-d-glucopyranosyl bromide. C-β-d-Glucopyranosyl-N-substituted-tetrazoles were synthesized by alkylation/arylation of O-perbenzoylated 5-β-d-glucopyranosyl-tetrazole or from a 2,6-anhydroheptose tosylhydrazone and arenediazonium salts. 5-Substituted tetra-zoles were glycosylated by O-peracetylated α-d-glucopyranosyl bromide 398 to give N-β-d-glucopyranosyl-C-substituted-tetrazoles 399 and 401 (Scheme 61) [94]. Standard deprotections gave test compounds that were assayed against rabbit muscle glycogen phosphorylase b. Most of the compounds proved inactive; the best inhibi-tor was 2-β-d-glucopyranosyl-5-phenyltetrazole 400 (R1=Ph) (IC50 600 μM).
Scheme 62 presents N-glucosyl indole derivatives, which were designed and syn-thesized by Chu et al. in 2019 as sodium-dependent glucose co-transporter 2 inhibi-tors [95]. The aim of the research was to check how modifications in the sugar part of the N-glucosyl indoles will affect their inhibitory properties. The synthesis of compounds 408 and 410 started from N-glucosyl indole 404. 6-Aldehyde 406 was obtained by selective protection of the primary alcohol 404 with tert-butylchlo-rodimethylsilane (TBDMSCl), followed by immediate peracetylation by addition of acetic anhydride. Prepared the fully protected N-glucoside underwent desilyla-tion under acidic conditions yielded the free primary alcohol 405. Dess–Martin periodinane (DMP) oxidation gave the desired aldehyde 406. Condensation of 406
26-79 %
O
OR2
OR2R2O
R2ON
N
NN
R1
O
OAc
AcOAcO
BrAcO398
399 R2 = Ac400 R2 = H
NaOMeMeOH, rt
O
OR2
OR2R2O
R2ON N
NN
R1
401 R2 = Ac402 R2 = H
NaOMeMeOH, rt
N
HN N
NR1
K2CO3, molecular sievesdry acetone, reflux
R1 = Phenyl, Methyl
O
OAc
AcOAcO
OAc
40317 % 45 %
86 %85 %
Scheme 61 Synthesis of the best inhibitor 2-β-d-glucopyranosyl 5-substituted tetrazole 400 [94]
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with hydroxylamines and hydrazides followed by deacetylation gave oxime ethers 407 and N-acylhydrazones 409. Reduction products, hydroxylamine N-glucosyl indoles 408 and hydrazide N-glucosyl indoles 410, were also synthesized using sodium cyanoborohydride (NaBH3CN) under acidic conditions. Authors studied inhibitory activities (EC50) of all synthesized N-glucosyl indole derivatives 407,
O
N
OH
OH
OH
OH
Cl
1. TBDMSCl, DMAP, pyridine, 70oC, 18h2. Ac2O, rt, 2h, 83 % over two steps3. BF3
.OEt2, DCM, 0oC, 20 min, 91 %O
N
OAc
OAc
OAc
OH
Cl
Dess-Martin periodinaneDCM, rt, 2h
O
N
OAc
OAc
OAc
Cl
O
H
1. hydroxylamines, pyridine, rt, 2h2. NaOMe, MeOH/DCM 2:1, 0oC to rt, 2h
33-66 % over two steps
O
N
OH
OH
OH
Cl
H
RN
404 405
406407
408409
NaBH3CN, MeOH/HCl0oC to rt, 1h27-82 %
O
N
OH
OH
OH
Cl
H
N
H
R
1. hydrazides, EtOH, rt, 2h2. LiOH(aq), THF/MeOH/DCM
0oC, 2h43-78 % over two steps
O
N
OH
OH
OH
Cl
H
NN
H
O
R
NaBH3CN, MeOH/HCl0oC to rt, 1h78-87 %
410
O
N
OH
OH
OH
Cl
H
NN
H
O
R
H
R = OH, Me, OMe, OEt, O-tert-Bu, Ph
Scheme 62 Synthesis of N-glucosyl indole derivatives 408 and 410 [95]
1 3
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408, 409, 410, which were determined by measuring the inhibition by uptake of [14C]-labeled α-methyl-d-glucopyranoside into hamster ovary cells stably expressing human hSGLT2 or hSGLT1 [95]. The compounds 407 and 409 had similar potency (EC50 = 212–286 nM) except 409 (R=OEt, EC50 = 1162 nM) and 409 (R=O-tert-Bu, EC50 = 867 nM). Compound 409 (R = Ph, EC50 = 258 nM) was the most potent inhibitor of SGLT2. The next step was the examination of hydroxylamine deriva-tives 408 and hydrazides 410. The products 408 and 410 are better inhibitors than substrates 407 and 409. The hydroxylamine derivatives 408 have similar potency (EC50 = 45–294 nM). Taking into account the group of hydrazides 410, the most activite for hSGLT2 was compoud 410 (R=Me, EC50 = 33 nM). Other hydrazides 410 had their power within range (EC50 = 63–1761 nM). Compound 410 (R=Me) was advanced into selectivity, pharmacokinetic, and in vivo glucosuria studies. Unfortunately, it was found that this hydrazide has poor pharmacokinetic properties and increases glucosuria in rats only at high doses [95].
A variety of medicinal plants and their active compounds have been used to treat diabetes and related chronic disorders since ancient times. Recently, there is a grow-ing interest in developing natural antidiabetic drugs to manage diabetic complica-tions, especially from plant sources. Thus, due to the return to nature, attention was again paid to the structure of natural O-glycosides with antidiabetic action.
In 2018, Rosas-Ramírez et al. postulated that resin glycosides from the morn-ing glory family (Convolvulaceae) may be a source of phytotherapeutic agents with antihyperglycemic properties for the prophylaxis and treatment of non-insulin-dependent type 2 diabetes mellitus [96]. Twenty-seven individual resin glycosides were evaluated for their α-glucosidase inhibitory potential. Four of these compounds displayed an inhibitory activity comparable to acarbose. In Fig. 17, compound 411 presents the structure of one of the four active glycosides isolated from the morning glory family. Based on molecular modeling studies performed by docking analysis, it was predicted that the active compounds and acarbose bind to the α-1,4-glucosidase enzyme catalytic site of MAL12 from the yeast Saccharomyces cerevisiae through stable hydrogen bonds primarily with the amino acid residues HIS279 and GLN322 [96]. Docking studies with the human maltase-glucoamylase (MGAM) also identi-fied binding modes for resin glycosides inside the catalytic site in the proximity of TYR1251. Resin glycosides could help to control postprandial glucose levels due to their inhibitory activity of α-glucosidases, which play a crucial role in the produc-tion of glucose [96].
In 2018, Kim and coworkers isolated from the seeds of Lens culinaris Medikus (Fabaceae) three flavonol glycosides and tested them for their DPP-IV–inhibitory activity [97]. Figure 17 contains the structure of one of the three active glycosides (compound 412) isolated from the morning glory family. Dipeptidyl peptidase IV (DPP-IV) is a new target for the treatment of type 2 diabetes mellitus. DPP-IV inhib-itors shorten the inactivation of glucagon-like peptide 1 (GLP-1), permitting the incretin to stimulate insulin release, thereby combating hyperglycemia. It was dem-onstrated for the first time that three isolated flavonol glycosides inhibited DPP-IV activity in a concentration-dependent manner in vitro bioassay system [97]. Molecu-lar docking experiments of these compounds within the binding pocket of DPP-IV were also conducted. All investigated compounds readily fit within the active sites
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of DPP-IV, in low-energy conformations characterized by the flavone core structure having optimal electrostatic attractive interactions with the catalytic triad residues of DPP-IV.
The use of steviol glycosides as non-caloric sweeteners has proven to be benefi-cial for patients with type 2 diabetes mellitus, obesity, and metabolic syndrome [98]. Figure 17 shows the structure of one of the natural antidiabetic O-glycosides 413 isolated from Stevia leaves. Recent data also demonstrate that steviol and stevioside might act as glucocorticoid receptor (GR) agonists and thus correlate with adverse effects on metabolism. In 2018, Panagiotou et al. provided strong evidence that ste-viol and steviol glycosides exert GR-mediated effects in cancer Jurkat cells [98].
In 2018, Pham and coworkers examined the chemical composition of Gynostemma longipes, an ethnomedicinal plant used to treat type 2 diabetes mel-litus by local communities in Vietnam [99]. Ten new dammarane triterpenes, including two hexanordammarane glycosides and five other dammarane glyco-sides, were isolated from a ethanolic extract of the whole G. longipes plant. The
416
411
O O
O O
O O
O
OHO
HO
HOOH
OHO
O
OHOH
OHO
OO
OHO
413
418
O
O
OH O
HOOH
O
OH
OH
OH
OHO
OOH
OHOHHO
O
OH
OH
HOOH
OO
O
OHHO
HO
OH
OH
OCOOH
O OH
OHOH
419
O
OH
HO O
HO
O
OH
OH O
O
O
OH
OH
OHO
O
OH
HO
HO
HO
412
O
OH
HOOH
HOO
OCH3
H
CH3
H
CH2
O O
HOO
OH
OH
O
OHHO
HO
OH
O
OH
OOH
HO
O
HHO
OHHO
OH
415414O
HOHO
OH
H
CH3
O
OHO
O
OH
O
HOOO
HOHO
OH
OHO
OH OO
OH
O
HOOH
HO
O
HOOH
OHO
417
Fig. 17 Structures of natural O-glycosides with antidiabetic action isolated from plant sources: 411 (morning glory family) [96], 412 (seeds of Lens culinaris Medikus) [97], 413 (leaves of Stevia rebaudi-ana bertoni) [98], 414 (Gynostemma longipes) [99], 415 (Ficus species) [100], 416 (Leea indica) [101], 417 (Lu’an GuaPian tea- Camellia sinensis L.O. Kuntze) [102], 418 (onion solid waste) [103], 419 [104]
1 3
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structures of the new compounds were elucidated using diverse spectroscopic methods. All of the isolates were evaluated for their stimulatory activities on glucose uptake. Compound 414 (Fig. 17) showed particularly potent stimulatory effects [99].
Deepa et al. presented in the review paper that extracts from various species of Ficus and isolated compounds significantly have enhanced insulin secretion and subsequently reduced blood glucose level [100]. O-Glycosides (for example com-pound 415, Fig. 17) isolated from Ficus species exhibited remarkable antidiabetic properties.
In 2018, Kekuda et al. prepared a comprehensive review about traditional uses, chemistry and pharmacological activities of Leea indica (Burm. f.) Merr.(Vita-ceae) [101]. The plant L. indica is traditionally used, inter alia, as a medicine for diabetes. Hypoglycemic activity of alcoholic and hydroalcoholic extracts of L. indica leaves using glucose tolerance test and alloxan-induced diabetes model in rats, was evaluated. The extract administration significantly reduced blood glu-cose levels, indicating hypoglycemic activity of leaf extracts [101]. Figure 17 shows the structure of one of the natural O-glycosides (mollic acid arabinoside 416) that have been isolated from the plant L. indica.
In another paper from 2018, Hua and coworkers have proven that green tea may favorably modulate blood glucose homeostasis, and regular consumption of green tea can prevent the development of type 2 diabetes mellitus [102]. Authors described the inhibition of α-glucosidase and α-amylase by flavonoid glyco-sides from Lu’an GuaPian tea. The kaempferol monoglycoside showed inhibi-tory activity against α-glucosidase with IC50 at 40.02 ± 4.61 μM, and kaempferol diglycoside (Fig. 17, O-glycoside 417) showed α-amylase inhibition with IC50 at 0.09 ± 0.02 μM [95]. Application of Lu’an GuaPian green tea as a functional food ingredient can regulate postprandial hyperglycemia through inhibition of α-glucosidase/α-amylase by the mono and diglycosides of kaempferol [102].
Nile et al. described valorization of onion solid waste and their flavonols for assessment of cytotoxicity, enzyme inhibitory, and antioxidant activities [103]. Onion (Allium cepa L.) is rich in flavonols like quercetin and quercetin glyco-sides. These glycosides have been extracted and tested against enzymes of clini-cal importance in diabetes. The samples exhibited significant antidiabetic effects. Results indicated that OSW (onion solid waste) and flavonol glycosides are poten-tial antidiabetic agents [103]. Figure 17 shows the structure of one of the natural O-glycosides (quercetin-3,4′-O-diglucoside QDG 418) that have been isolated from onion solid waste.
Jayachandran and coworkers have designed studies to accumulate the experi-mental evidence in support of antidiabetic effects of isoquercetin 419 (Fig. 17) [104]. Supplementation with isoquercetin significantly normalized blood sugar levels, insulin, and regulated the mRNA expression of insulin signaling genes and carbohydrate-metabolizing enzyme genes. The results achieved with isoquercetin are similar to that of the standard drug glibenclamide [104]. The findings suggest isoquercetin could be a possible therapeutic agent for treating diabetes mellitus in the near future.
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6 Biological Action of the Glycosides Described in this Review and Patents of Marketed Drugs
At present, the normalization of glycemia in diabetes is a rather complicated and problematic issue of diabetology. Despite the growing knowledge of vari-ous chemical and biochemical aspects of diabetes mellitus, the specific molecular mechanisms leading to T2DM are still unknown. Current pharmacological treat-ments are symptomatic and aim at maintaining blood glucose levels close to the fasting normoglycemic range of 3.5–6 mM/l. A large number of oral antidiabetic drugs, which exert their effects through various mechanisms, aimed at eliminat-ing three major metabolic disorders leading to hyperglycemia: dysfunction of β-cells, peripheral insulin resistance, excessive hepatic glucose production [7]. Promising direction for design of new drugs for the treatment of diabetes mellitus is the regulation of key carbohydrate metabolism enzymes: inhibition of glycogen phosphorylase (GP), sodium-dependent glucose transporters (SGLT), and protein tyrosine phosphatase (PTP).
Depending on the binding site of the enzyme molecule, GP inhibitors are divided into compounds that block the catalytic site and compounds that block the allosteric sites [105, 106]. The following groups of chemical compounds were studied as inhibitors of the catalytic site of GP: N-acyl-β-(d-glucopyranosylamine derivatives, N-β-d-glucopyranosyl ureas, 2-(d-glucopyranosyl)-5-methyl-1,3,4-oxadiazole derivatives, 2-(d-glucopyranosyl)-benzimidazoles, 3-substituted 5-β-d-glucopyranosyl-1,2,4-oxadiazoles, glucopyranosyliden-spiro-thiohydan-toins. Efforts in identifying the best heterocyclic junction between the glucose and pharmacophore units were patented, taking into account 1,2,4-triazole and imidazole moieties [107].
Inhibitors of sodium-dependent glucose co-transporter 2 (SGLT2) are an attractive method of type 2 diabetes treatment because of their distinct mecha-nism of action, in which blood glucose levels are reduced independently of insu-lin secretion [108]. In healthy individuals, greater than 99% of the plasma glucose that is filtered in the kidney is reabsorbed, resulting in less than 1% of the total fil-tered glucose being excreted in urine [41]. This reabsorption process is mediated by two sodium-dependent glucose cotransporters (SGLTs): SGLT1, a low-capac-ity, high-affinity transporter and SGLT2, a high-capacity, low-affinity transporter that is expressed mainly in the kidney [41]. It is estimated that 90% of renal glu-cose reabsorption is facilitated by SGLT2 residing on the surface of the epithelial cells lining the S1 segment of the proximal tubule; the remaining 10% is likely mediated by SGLT1 localized on the more distal S3 segment of the proximal tubule [41]. Several selective SGLT2 inhibitors have been developed by structural modification of phlorizin, the first known SGLT inhibitor. C-Linked β-glycosides (gliflozins) are at advanced stages of development because of their metabolic stability, high oral bioavailability, and plasma exposure. Of these, dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, tofogliflozin, luseogliflozin, ertugli-flozin, and sotagliflozin have been approved for the treatment of type 2 diabetes mellitus recently [108]. These compounds are now approved as marketed drugs
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(Fig. 18). For example, inhibition of SGLT2 with Forxiga (dapagliflozin) reduces renal glucose reabsorption and thereby increases urinary glucose exretion [109]. From 2014, Forxiga is indicated by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes and is not recommended for patients with type 1 diabetes mellitus.
Of particular importance to the downregulation of insulin signaling is pro-tein tyrosine phosphatase 1B (PTP1B), which dephosphorylates the receptor (IR) on the surface of a cell [110]. Inhibition of PTP1B may represent a practical strat-egy for the treatment of type 2 diabetes [111]. Various strategies have been devel-oped to design and synthesize potent and selective PTP1B inhibitors. The principal approach is based on mimicking the phosphotyrosine moiety. Many PTP inhibitors contain a quinone functionality. Series of C-glucosyl 1,4-benzo- and 1,4-naphtho-quinones were found as better PTP1B inhibitors than their analogues displaying 1,4-dimethoxybenzene or -naphthalene residues [40]. Modifications of molecules at
O
OH
OH
HOHO
OEtCl
DapagliflozinAstraZenecaForxiga® / 2013
O
OH
OH
HOHO
Me
S FCanagliflozinJansenInvokana® / 2013
O
OH
OH
HOHO
F
S
IpragliflozinAstellas PharmaSuglat® / 2014
O
OH
OH
HOHO
OCl
O
EmpagliflozinBoehringer Ingelheim / Eli LillyJardiance® / 2014
O
OH
OH
HOHO
O
Me
TofogliflozinSanofiApleway® / 2014
S
OH
OH
HOHO
MeO Me OEt
LuseogliflozinLusefi® / 2014
ErtugliflozinSteglatro® / 2018
O
OH
HOHO
Cl OEtOH
O
O
OH
MeSHO
HO
Cl OEt
Zynquista® / 2019
SotagliflozinSanofi & Lexicon
Fig. 18 SGLT2 inhibitors approved as marketed drugs. Name, company, brand name, and year for approval are provided
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the primary 6-position were made by transformation to either carboxylic, azido, or benzamido groups, or elongation by azide-alkyne click chemistry to triazole ring formation [112].
7 Conclusions
In this review, we disclosed studies on the preparation of glycosides that can be applied as inhibitors of glycogen phosphorylase, sodium glucose cotransporter 2, protein tyrosine phosphatase 1B and other more specific enzymes. The natural prod-uct phlorizin was identified as the first type 2 diabetes mellitus inhibitor. Because O-glycosides are usually hydrolytically unstable, many carbohydrate analogues such as N-glycosides and C-glycosides have been synthesized and used as enzyme inhibi-tors. In comparison to O-glycosides, the C-glycosides are structurally more stable against acidic and enzymatic cleavage due to the existence of their C–C glycosidic bond. Among glycomimetics, C-glycosyl compounds have attracted much attention. By use of structure–activity relationships, several new glycosides have been devel-oped as inhibitors and studied in clinical trials. Some of the described glycoside-based molecules, for example dapagliflozin, canagliflozin, ipragliflozin, empagliflo-zin, tofogliflozin, luseogliflozin, ertugliflozin, and sotagliflozin, have been approved as marketed drugs.
Figure 19 shows the best GPb inhibitors described in this article, which were selected from Figs. 7, 9, 10, 11, 13, and 15 presenting activity of inhibitors having a specific O, N, or C-glycoside structure and from Sect. 5 describing directions of the latest research from 2018 to 2019. Below each compound there is information
Chapter 3.3 Other N-Glycosides
87 GLAC, Scheme 14, [37]
N N
O
N
N
H
H
O
O
OH
OH
HOHO
GPb Ki 31 nM
Chapter 4.2 HeteroaromaticC-Glycosyl Derivatives
N
NNHO
OH
HOHO
OH
194, Scheme 30, [57]GPb Ki 0.41 µM
Chaper 4.1 Aromatic C-Glycosyl Derivatives Chapter 4.2 HeteroaromaticC-Glycosyl Derivatives
Chapter 3.2 1,2,3-Triazolyl N-Glycosides
O
OHN
NN
OH OAc
HOHO
54, Scheme 9, [32]RMGPb IC50 26 mM
O
OH
HOHO
N
NN
H
209, Scheme 33, [59]GPb IC50 0.9 mM
HO
O
OH
OH OH
OH
OH
HO
GPb Ki 0.9 mM95, Scheme 15, [38]
O
OH
HOOH
HO
N
NN
HNH2
350, Fig 16, [87]
Chapter 5GPb Ki 0.43 µM
O
OH
OHNH
O
NH
O
HOHO
Chapter 3.1 N-(β-D-Glucopyranosyl)-Urea Derivatives
17, Fig 8, [23]
GPb Ki 0.4 µM
O
OH
OH
HOHO
ON
252, Scheme 40, [64]GPb Ki 0.63 µMChapter 4.2 HeteroaromaticC-Glycosyl Derivatives
Fig. 19 The best GPb inhibitors selected from the figures summarizing the activity of inhibitors dis-cussed in a given Sects
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Topics in Current Chemistry (2019) 377:19 Page 77 of 84 19
about what type of glycoside it represents. The compounds were ranked in order from the inhibitor with the highest activity (the lowest Ki) to the inhibitor with the lowest activity (the highest Ki). Where the Ki values were not reported in the publi-cation, the inhibitory properties were compared based on the IC50 values. Seven of the eight inhibitors shown in Fig. 19 are derivatives of d-glucose. Changes in the sugar configuration as well as removal or replacement of substituents of the glucose moiety proved detrimental for the inhibition. The crucial role of the aglycon in the efficiency of the inhibitors is also presented in this article. Based on the analysis of the structure of compounds that are the best GPb inhibitors, it can be concluded that a high activity is ensured by the presence of the 2-naphthol group. Four of the eight compounds shown in Fig. 19 have a 2-naphthol group. Analysis of the structures of the best GPb inhibitors (Fig. 19) leads to the conclusion that the highest activity is possessed by inhibitors containing, as aglycones, heterocyclic rings with nitrogen atoms.
In turn, Fig. 20 presents the best SGLT2 inhibitors. They were selected from Figs. 7, 9, 10, 11, 13, and 15 as representatives of glycosides with the structure described in the given Sects and from Sect. 5 describing directions of the latest research from 2018 to 2019. The compounds were arranged in order from the best inhibitor (the lowest IC50) to the inhibitor with lower activity (the highest IC50). The activity of inhibitors for which no IC50 values were reported in the publica-tion was evaluated by comparing the EC50 values. Analysis of the structure of
O
HO OHOH
O Cl OO
Chapter 3.3 Other N-Glycosides
O
OH
OH
HO
HO
Cl
Chapter 5
352, Scheme 56, [89]SGLT2 IC50 1 nMSGLT1 IC50 45 nM
Chapter 4.2 HeteroaromaticC-Glycosyl Derivatives
O
OHHOOH
N
F
181, Scheme 28, [55]hSGLT2 EC50 47±3 nMhSGLT1 EC50 282±11 nM
O
OH
OH
HO
HO
MeO iPr
O
N
H O
N
H
N
Chapter 5
378, Scheme 58, [90]hSGLT2 IC50 29 nMhSGLT1 IC50 20 nM
O
N
OH
OH
OH
Cl
NH
O
MeO2C
83, Scheme 13, [35]hSGLT2 EC50 39±7 nMhSGLT1 EC50 5424±1357 nM
Chapter 4.1 Aromatic C-Glycosyl Derivatives
O
OH
HO
OH
Cl OEt
HO
113 Dapagliflozin, Scheme 18, [41]hSGLT2 EC50 1.1±0.06 nMhSGLT1 EC50 1390±7 nM
O
OH
HOHO
OHO
HO OH
O
OH
Phlorizin, Fig. 4, [17]hSGLT1 IC50 400 nMhSGLT2 IC50 65 nMChapter 2 O-Glycosides
OOH
OH
OHHO
Me
S
F
126 Canagliflozin, Scheme 20, [43]hSGLT2 IC50 2.2 nMhSGLT1 IC50 910 nMChapter 4.1 Aromatic C-GlycosylDerivatives
Chaper 4.3 Other C-GlycosylDerivatives
308, Scheme 48, [79]hSGLT2 IC50 0.778 nM
O
OH
OH
OH
HO
S
ClEt
199, Scheme 31, [58]hSGLT2 IC50 4 nMChapter 4.2 HeteroaromaticC-Glycosyl Derivatives
O
OH
OH
HO
N
Cl
HO
OEt
Chapter 5
385, Scheme 59, [91]hSGLT2 EC50 46 nMhSGLT1 EC50 3576 nM
Fig. 20 The best SGLT2 inhibitors selected from the figures summarizing the activity of inhibitors dis-cussed in a given Sects
Topics in Current Chemistry (2019) 377:19
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the best SGLT2 inhibitors allows the conclusion that not only glucose but also its derivatives or xylose provide inhibitory activity. Looking at the structure of active SGLT2 inhibitors from Fig. 20, it can also be seen that each of them has one or two phenyl groups in its structure. Considering the structure of the agly-cone, one cannot distinguish a specific heteroaromatic system whose structure would be repeated in the structure of the inhibitors considered. However, it can be seen that in two cases there is a thiophene ring and in the other two an indole system. Eight of the ten SGLT2 inhibitors shown in Fig. 20 have a chlorine or fluorine atom in their structure.
The conclusions drawn from the analysis of the structure of the best inhibitors should be taken into account when designing antidiabetic drugs. We sincerely hope that this article will stimulate further research in glycoside derivatives synthesis and will encourage scientists to design novel inhibitors in the treatment of type 2 diabe-tes mellitus.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 Interna-tional License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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Affiliations
Aleksandra Pałasz1 · Dariusz Cież1 · Bartosz Trzewik1 · Katarzyna Miszczak1 · Grzegorz Tynor1 · Bartłomiej Bazan1
* Aleksandra Pałasz [email protected]
Dariusz Cież [email protected]
Bartosz Trzewik [email protected]
Katarzyna Miszczak [email protected]
Grzegorz Tynor [email protected]
Bartłomiej Bazan [email protected]
1 Department of Organic Chemistry, Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland