Oral Delivery of Propofol with Methoxymethylphosphonic Acid asthe Delivery VehicleYonggang Wei,* Guanpeng Qiu, Bailin Lei, Linlin Qin, Hongzhu Chu, Yonghua Lu, Guozhi Zhu,Qiu Gao, Qingping Huang, Guofei Qian, Pengfei Liao, Xinfeng Luo, Xiaowei Zhang, Chen Zhang,Yao Li, Suxin Zheng, Yan Yu, Pingming Tang, Jia Ni, Pangke Yan, Yi Zhou, Pan Li, Xia Huang,Aisheng Gong, and Jianyu Liu
Haisco Pharmaceuticals Group Co. Ltd., 136 Baili Road, Wenjiang District, Chengdu, 611130, China
*S Supporting Information
ABSTRACT: Phosphonamidate 3a of methoxymethylphosphonic acid (MMPA) with propofol (1) and L-alanine ethyl ester wasfound to be an efficient scaffold for the oral delivery of compound 1. The synthesis and evaluation of MMPA basedphosphonamidates of compound 1, HSK3486 (2), and other phenolic drugs revealed the general application of MMPA as theeffective delivery vehicle for phenolic drugs. On the basis of plasma concentrations of compound 1 and SN38 (14), the oralbioavailability of compound 3a and 15 in beagle dogs was found to be 97.6% and 34.1%, respectively.
■ INTRODUCTIONWe have recently reported that HSK34862 (2, Figure 1), a closeanalog of propofol1 (1) now in advanced phase II clinical trial
in China, has shown equivalent potency of 1 at 1/5 of thedosage in similar lipid emulsion formulation. Given thatcompounds 1 and 2 may hold therapeutic potentials ininsomnia,3 migraine,4 anxiety,5 analgesia,6 etc., we have decidedto explore the oral delivery of 1 and 2 through prodrug strategyand evaluate the potential clinical usages of these oral prodrugs.Herein we report the discovery of an efficient oral deliveryvehicle for phenolic drugs such as propofol (1) and HSK3486(2).Previous attempts to make 1 orally bioavailable through
formulation and prodrug modifications have met with limitedsuccess.7−11 Our efforts turned to the aryloxyphosphonamidateProTide technology first reported by the McGuigangroup,12−16 which was used subsequently by Gilead Sciencesfor the marketed drug tenofovir alafenamide.17 As illustratedwith the prodrug of tenofovir18 (A, Figure 2), oral absorption is
facilitated by the neutral phosphonamidate A of tenofovir withan amino acid ester and phenol. It was postulated that therelease of the phosphonic acid target drug happened firstthrough hydrolysis of the amino acid ester, affording the releaseof the alcohol fragment A1. This was followed by intra-molecular lactam formation affording the release of the phenolfragment A3. This transient cyclic lactam A4 was thenhydrolyzed through a two step sequence, first the rapidhydrolysis of the P−O bond, followed by a phosphoramidasemediated cleavage19 of the P−N bond in A5, affording therelease of the target drug 9-R-(2-phosphonomethoxypropyl)-adenine and the amino acid A6.We reasoned that if this prodrug system was orally
bioavailable as a whole, each of its fragments would also bedelivered orally just as efficiently, i.e., the alcohol, amino acid,and phenol fragments. We now demonstrate for the first timethat simple replacement of the phenol (A3) with 1 (Figure 2),together with methoxymethylphosphonic acid (B5) as thedelivery vehicle (Figure 2), afforded the oral delivery of 1 withthe release of MMPA (B5), alcohol B1, and amino acid B4.Unlike the tenofovir prodrug, oral bioavailability of MMPAprodrug is not dependent upon collapse of transientintermediate B3 to liberate the target drug. With 1 as themodel phenolic drug, we herein report preliminary results ofthe proof of concept of these MMPA prodrugs with the
Received: August 3, 2017Published: October 2, 2017
syntheses and preliminary pharmacological evaluation of aseries of phosphonamidate prodrugs.
■ RESULTS AND DISCUSSION
Chemistry. Given the pivotal role that amino acid esterhydrolysis plays in the MMPA prodrugs as previously discussed,a series of phosphonamidates of MMPA for 1 (compounds 3−9) and 2 (compound 13) were designed and prepared (Scheme
1). The synthesis started with readily available diethyl(hydroxymethyl)phosphonate 20 that was first methylatedusing iodomethane and NaH in THF to give diethyl(methoxymethyl)phosphonate 21. Reaction of diethyl(methoxymethyl)phosphonate 21 with 2 equiv ofbromotrimethylsilane in CH3CN selectively removed the twoethyl groups to give the crude bistrimethylsilylphosphonate 22that readily underwent chlorination using oxalyl chloride in
Figure 2. MMPA based oral delivery of 1.
Scheme 1. Synthesis of Phosphonamidates 3−9 and 13a
aReagents and conditions: (a) CH3I, NaH, THF, 0 °C to rt, 2 h; (b) TMSBr, CH3CN, 50 °C, 2 h; (c) oxalyl chloride, CH2Cl2, 0 °C to rt, 2 h; (d) 1,Et3N, amino acid ester, CH2Cl2, −10 °C to rt; (e) 2, Et3N, L-alanine ethyl ester, CH2Cl2, −10 °C to rt.
CH2Cl2 to provide the key intermediate methoxymethyl-phosphonic acid dichloride20 23, which could be purified bydistillation. Reaction of the dichloride with compound 1 andvarious amino acid esters in Et3N/CH2Cl2 afforded prodrugs3−9 in 30−51% yield. The phosphonamidate prodrug 13 of 2with L-alanine ethyl ester was prepared in a similar manner.The morpholinomethylphosphonic acid based prodrug of
compound 1 containing L-alanine ethyl ester was prepared(Scheme 2) first by converting diethyl hydroxymethyl-phosphonate 20 into its mesylate 27. Dichloride 28 wasprepared using the previous two step sequence (TMSBr−oxalylchloride), which was reacted with 1 and L-alanine ethyl ester togive the mesylate intermediate 29. Displacement of themesylate 29 with morpholine afforded the morpholino-methylphosphonamidate prodrug 11. Similarly the benzyloxy-methylphosphonamidate intermediate 26 containing 1 and L-alanine ethyl ester was obtained in a similar fashion through thebenzyl ether 24 followed by the two step chlorination sequence(TMSBr−oxalyl chloride) and phosphonamidate formation to26. Debenzylation of 26 under mild conditions afforded thehydroxymethylphosphonamidate prodrug 10. Starting withdiethyl propylphosphonate 30, the propylphosphonic aciddichloride 31 was prepared in the same two step sequence(TMSBr−oxalyl chloride) and reacted with 1 and L-alanineethyl ester to afford the propylphosphonamidate 12.All of the phosphonamidate prodrugs above were isolated as
their diastereoisomeric mixtures. Prodrugs 3 and 13 werefurther purified by SFC (supercritical fluid chromatography) to
produce each pair of diastereoisomers 3a,b and 13a,b,respectively. Since all these compounds were either waxy solidsor liquids, the absolute configuration of 3a was successfullydetermined through the hydroxymethylphosphonamidate ana-log 10a (Scheme 3). Crystallization of the diastereoisomericmixture of 10 from a mixed solvent (ethyl acetate/n-hexane =1/10) afforded 10a, whose absolute stereochemistry wasdetermined by X-ray crystallography to be (S, SP). Methylationof compound 10a under neutral conditions using iodomethaneand silver oxide in dichloromethane at room temperatureproduced compound 32 that has been found to be identical inall aspects to compound 3a. Similarly, the absolute stereo-chemistry of compound 13b was determined through silveroxide mediated methylation of the correspondinghydroxymethylphosphonamidate compound 34b (S, SP) to35b (Scheme 3). For a given amino acid ester, the chemicalshift of the phosphorus atom of the S-stereoisomer has so farbeen found to be always more upfield than the R-stereoisomerin the 31P NMR (see Supporting Information), which is inaccord with the 31P NMR of tenofovir alafenamide.17
Biological Evaluation. Initially, the in vivo anestheticeffects of phosphonamidate prodrugs were evaluated by loss ofrighting reflex (LORR) experiments in ICR mice21 through oraladministration. The onset and duration of anesthesia ofphosphonamidate prodrugs allowed preliminary accessment ofthe impacts of amino acids and esters on the oral delivery of 1and 2. Delightfully, all compounds were found to producemoderate to noticeable anesthetic effects, an indication of at
Table 1. Anesthetic Effect of Prodrugs in ICR Mice
least some oral bioavailability for all compounds. Compound 3produced the most pronounced anesthetic action with an onsetof anesthesia (4.50 ± 1.58 min) and duration time (60.31 ±57.76 min) (Table 1). The bulkier the ester moiety of theprodrug was, the slower was the onset of anesthesia(compound 3 vs compound, 4, 5, and 6), which might bethe result of the relative rate of hydrolysis of different estergroups (ethyl > isobutyl > benzyl > isopropyl). It is interestingto note that the ester moiety could also affect the duration ofanesthetic action, as compound 6 with a benzyl ester exhibiteda much longer duration than compounds 3, 4, and 5.Furthermore, phosphonamidate prodrugs containing differ-
ent amino acids were investigated. With the incorporation of anunnatural amino acid, compound 7 showed similar potencywhen compared with compound 3. However, it showed aslower onset of anesthetic action than its L-alanine analog. Thismay be due to the unnatural amino acid used in 7 not being thenatural substrate for the esterase responsible in the first step ofhydrolysis.Compound 8 exhibited a 2-fold longer anesthetic duration
with a comparable LORR effect to compound 3. This muchlonger duration of anesthetic action might be due to sterichindrance of the bulkier dimethyl amino acid in the hydrolysisstep. It is somewhat surprising that compound 9 with a lessbulky glycine ester produced a significantly slower onset ofanesthesia than 3, which has relatively more steric bulk at the αposition of the amino acid. This observation is in accord with areport22 that a substituted amino acid such as alanine is themore preferable substrate than glycine for the esteraseresponsible in the first step of hydrolysis.The effect of substituents on the methoxymethylphosphonic
acid (MMPA) moiety was also studied. Compounds 10, 11,and 12 had slower onset of anesthetic action and shorteranesthetic duration times compared with compound 3. Thismight indicate that the electronic and relative steric effect of
those substituents could also be rate-determining in thehydrolysis−cyclization sequence of phosphonamidate prodrugs(Figure 2). More in-depth investigation is required to delineatethe scope and utilities for such substitutions.It is noted that prodrug 13 showed a similar anesthetic action
at a lower dose of 100 mg/kg, which could be attributed to thehigher potency of 2 compared with compound 1. Also, thehigher ratio of mortality caused by 13 might be due to thelower LD50 of 2 compared with 1 as reported in our previouswork,2 and a more detailed dose−response study will have to beconducted.With the results discussed above, we demonstrated that the
rate of activation and the duration time of these phosphona-midate prodrugs were tunable through modifications of theester moiety and the substituents on MMPA. These propertiesare critical for selecting the right substitutions for the oraldelivery of 1 and 2 based on the therapeutic demands. Theseresults have also built the foundation of expanding the scope ofthis MMPA based prodrug technology onto other phenolicdrugs with diverse indications and clinical demands.To further investigate the effect of the chirality on the
phosphorus, the anesthetic effects of each pair of enantiomericpure compounds 3a,b and 13a,b were studied with resultsshown in Table 2. Compounds 3a (S, SP) and 3b (S, RP)produced a similar anesthetic duration time but a significantdifference in the onset of anesthetic action and LORR (3a, 4.38± 0.55, 100% vs 3b, 9.68 ± 1.19, 33%). These results indicatedthat the chirality of the phosphorus had pronounced effect onthe pharmacological behavior. Either the esterase mediatedhydrolysis or formation of the transient lactam intermediate B3or both could have been affected by the chirality on thephosphorus. Meanwhile, compounds 13a (S, SP) and 13b (S,RP) showed a slight difference in the onset of anesthetic actionand duration. The higher potency of 2 might have masked thedifference. The pharmacological difference could be more
Table 2. Anesthetic Effect of 3a, 3b, 13a, and 13b in ICR Mice
obvious at lower dose that will be one of the subjects for furtherstudies.The pharmacokinetic profiles of prodrugs 3a (S, SP) and 13a
(S, SP) in beagle dogs were investigated (Table 3). Oralbioavailability was calculated as a percentage of the activecompound quantitated in plasma after oral dosing of theprodrug versus intravenously administered active compound bymeasuring plasma concentrations of the active compound. Onthe basis of AUC(0−t), the oral bioavailability (F) of 3a and 13ain beagle dog was found to be 97.6% and 29.5%, respectively.On the basis of the pharmacokinetic profile of 3a, we
proposed that compound 3a might be used for otherindications such as insomnia. The hypnotic potency of 3awas evaluated based on the prolongation of sleep induced bypentobarbital in ICR mice,23 at the dosages where compound3a alone caused no LORR. Compound 3a produced a dosedependent prolongation of pentobarbital-induced sleep time atdosages of 55, 65, and 75 mg/kg (Figure 3). At dosages of 65.0and 75.0 mg/kg, compound 3a remarkably increased sleepduration to 69 ± 20 min and 82 ± 53 min, respectively,compared to the vehicle group of 33 ± 20 min.The generality of the MMPA platform to other phenolic
drugs with more complicated structures was investigated.Phosphonamidate prodrugs of phenolic drugs SN3824 (14),estradiol25 (16), and naloxone26 (18) (Figure 4) weresynthesized by using the same method as described forcompounds 3−9 (Scheme 1). The pharmacokinetic profiles
of compounds 15, 17, and 19, each as a mixture of itsdiastereoisomeric pair, were evaluated in beagle dogs via oraladministration (Table 4). As an active metabolite ofirinotecan,27 14 was not orally active. To our delight, the oralbioavailability of 14 as its MMPA prodrug 15 was found to be34.1%. Even 16 was taken orally in clinic; its plasmaconcentration was not measurable in our hands when givenorally. However, as its MMPA prodrug 17, the bioavailability of16 was found to be 18.6%. The oral bioavailability of 19 as itsMMPA prodrug was found to be 15.7%, a moderate increasefrom 9.6% for compound 18. These results provide support onthe generality of MMPA prodrug platform on phenolic drugsand warrant additional studies for other linking atoms andmethods in this platform.
■ CONCLUSIONThis work disclosed above has demonstrated how MMPAcould be used as delivery vehicle for oral administration ofphenolic drugs such as 1 and 2. The oral bioavailability of 1 willallow further studies for other indications. Prodrugs 3a and 13awere chosen for further preclinical development. MMPAplatform has shown promising results to other phenolic drugswith more sophisticated structures including 14, 16, and 18.MMPA platform may allow oral delivery of drug targets ofinterest through different linking atoms and linkers. Efforts inexploring different linkers and linkages to different functionalgroups in the MMPA platform are currently underway as wellas the oral delivery of the B1 alcohol and B4 amino acid(Figure 2) through this technology. The ongoing mechanisticstudies of MMPA platform and all related biologicalintermediates and metabolites will be reported in due course.
■ EXPERIMENTAL SECTIONAnesthetic Effects. Loss of righting reflex (LORR), a validated
rodent model of general anesthesia, was applied to evaluate theanesthetic effects of the prodrugs of 1 and 2 in ICR mice. Animalswere fasted overnight before experiment and administered withprodrugs in 10% of dimethyl sulfoxide, 20% of Solutol HS-15, and 70%of saline by gavage (n = 10/dose group for diastereoisomeric mixtures,n = 6/dose group for enantiopure compounds 3a, 3b, 13a, and 13b).Then the mice were placed on their backs continually until theystopped righting themselves. Anesthetic effects were assessed usingonset of LORR and anesthetic duration.
Table 3. Pharmacokinetic Parameters of 3a and 13a in Beagle Dogs
Figure 3. Effects of 3a on sleep duration in pentobarbital-treated mice((∗) p < 0.05, (∗∗) p < 0.001) compared to vehicle group.
Animals. Male and female ICR mice (20 ± 2 g) were purchasedfrom Chengdu Dossy Experimental Animals Co., Ltd. Animal facilities,animal care, and study programs were conducted in conformity within-house guidelines of Institute of Laboratory Animal Resources,Commission on Life Science, National Research Council (NationalAcademy Press, Washington, DC, 2010). All animals were housed incages at 21 ± 2 °C and provided free access to food and water. Roomswith constant temperature and humidity were in a cycle of 12 h of lightand 12 h of dark.Pharmacokinetic profiles of prodrugs in beagle dogs were
investigated. Parent drugs which were formulated in 5% of dimethylsulfoxide, 5% of Solutol HS-15 (30%, w/v) and 90% of saline wereadministered a single iv bolus injection to beagle dogs (n = 3/group),and blood samples were collected into heparinized tubes at predoseand at 2, 5, 10, 20, 30 min and 1, 2, 4, 6, 8, 10, 12, and 24 h postdose.After a week washout, the prodrugs which were prepared in 5% ofdimethyl sulfoxide, 5% of Solutol HS-15 (30%, w/v), and 90% ofsaline were administered to the same beagle dogs via ig and bloodsamples were collected into heparinized tubes at predose and at 5, 10,20, 30 min and 1, 2, 4, 6, 8, 10, 12, and 24 h postdose afteradministration. All blood samples were centrifuged at 5500 rpm for 10min to obtain plasma at 2−8 °C. Plasma samples were stored at −80°C until analysis. Parent drugs concentrations in all plasma sampleswere determined by liquid chromatography−tandem mass spectrom-etry (LC−MS/MS). Pharmacokinetic parameters were analyzed by theWinNonlin version 6.3 software (Pharsight, Mountain View, CA,USA) using noncompartmental analysis.Pentobarbital-Induced Sleep. Hypnotic potency of compound
3a was evaluated based on the prolongation of sleep induced bypentobarbital in ICR mice. Fasted male and female mice wererandomly divided into four groups, including vehicle group and threedose groups (55, 65, 75 mg/kg, n = 10/group). Compound 3a wasformulated in 10% of dimethyl sulfoxide, 20% of Solutol HS-15 (30%,w/v), and 70% of saline and was administrated orally 5 min before thepentobarbital injection. After the intraperitoneal injection of 40 mg/kgpentobarbital, the mice were observed for measurement of sleep
duration. The sleep duration was defined as period from falling intosleep to recovering the righting reflex. Data were expressed as themean ± SEM. Statistical analysis was performed with Sigma Statsoftware (SPSS Inc., Chicago, IL, USA).
Synthetic Procedures in Chemistry. All purchased startingmaterials were used without further purification. 1H NMR and 13CNMR spectra were acquired at ambient temperature on a BrukerAvance HD 400 spectrometer (400 and 101 MHz) in CDCl3 andCD3OD with residual solvent signal (CHCl3 and CD2HOD) asreference (7.26 and 77.16, 3.31, and 49.00, respectively). 31P NMRspectra were recorded at ambient temperature on a Bruker Avance HD400 spectrometer (162 MHz) with proton decoupling. Chemical shiftswere reported relative to external 85% H3PO4. Chemical shifts areexpressed in parts per million (ppm, δ units), and coupling constantsare reported in hertz (Hz). Hight resolution mass spectra (HRMS)were obtained on LTQ FT Ultra of Thermo Fisher Scientific from theNational Center for Organic Mass Spectrometry in Shanghai, ShanghaiInstitute of Organic Chemistry, Chinese Academy of Sciences. Massspectra were obtained on FinniganLCQAd instrument (ESI). Mostmasses were reported as those of the protonated parent ions.Preparative column chromatography was performed using 200−300mesh silica. Purities of title compounds were ≥95% by HPLC.
Ethyl (2S)-2-[[(2,6-Diisopropylphenoxy)(methoxymethyl)-phosphoryl]amino]propanoate (3). Under nitrogen atmosphere,to a stirred solution of 23 (4.5 g, 21 mmol) in 50 mL ofdichloromethane was added a solution of 1 (3.7 g, 21 mmol) andtriethylamine (8.7 g, 86 mmol) in dichloromethane (50 mL) at −10°C. The reaction mixture was allowed to warm to room temperature,stirred for 1 h, and L-alanine ethyl ester (5.0 g, 43 mmol) was thenadded. After 2 h, the reaction mixture was quenched with a saturatedsolution of sodium dihydrogen phosphate (100 mL), and the organiclayer was dried with anhydrous sodium sulfate and concentrated invacuum. The residue was purified by flash column chromatography(1:10 to 1:1 ethyl acetate/hexanes). The title compound was obtainedas yellow oil (2.5 g) in 30.9% yield. Rf = 0.50 (1:2 ethyl acetate/
Figure 4. Chemical structures of 14−19.
Table 4. Pharmacokinetic Parameters of Selected Prodrugs (15, 17, and 19) in Beagle Dogsa
hexanes, TLC), major isomer/minor isomer = 1.18:1.00. HRMS(ESI): calcd for C19H33NO5P [M + H]+, 386.2091. Found: 386.2090.The diastereoisomeric mixture was separated by SFC to afford two
phosphoryl]amino]propanoate (10). To a stirred solution of 26(15.0 g, 32.5 mmol) in 100 mL of dichloromethane was added Pd/C(10.0 g, 10 wt %). The mixture was stirred under hydrogenatmosphere at room temperature for 8 h. The resulting solution wasfiltered. The solvent was removed under reduced pressure. The titlecompound was obtained as yellow oil (8.0 g) in 66.3% yield. Rf = 0.40(1:1 ethyl acetate/hexanes, TLC), major isomer/minor isomer =1.75:1.00. HRMS (ESI): calcd for C18H30NO5P [M + H]+ 371.1856.Found: 371.1858. The diastereoisomeric mixture was separated bychiral preparative HPLC to afford two optical isomers. Major isomer:chiral retention time = 7.81 min. 1H NMR (400 MHz, CD3OD): δ7.16−7.09 (m, 3H), 4.19−4.11 (m, 2H), 4.10−4.05 (m, 2H), 4.03 (dq,J = 7.2, 7.2 Hz, 1H), 3.61 (hept, J = 6.8 Hz, 2H), 1.27 (d, J = 7.2 Hz,3H), 1.26 (t, J = 7.2 Hz, 3H), 1.23 (d, J = 6.8 Hz, 6H), 1.22 (d, J = 6.8Hz, 6H). 13C NMR (101 MHz, CD3OD): δ 175.85 (d, J = 3.9 Hz),146.17 (d, J = 11.7 Hz), 142.04 (d, J = 3.0 Hz), 126.58 (d, J = 1.8 Hz),125.11 (d, J = 1.8 Hz), 62.43, 59.71 (d, J = 152.9 Hz), 50.88, 28.06,24.07, 23.95, 20.71 (d, J = 5.3 Hz), 14.44. 31P NMR (162 MHz,CD3OD): δ 28.02. MS m/z (ESI): 394.2 [M + Na]+. Minor isomer:chiral HPLC retention time = 12.41 min. This isomer can also beisolated by crystallization method. 10 (3.0 g) was dissolved in 10 mLof ethyl acetate/n-hexane (v:v = 1:10) at 70 °C, cooled down to roomtemperature, and stayed overnight. After filtration, 10a was obtained aswhite crystals (0.70 g) in 23.3% yield. The optical purity of the isolateddiastereoisomer was determined by chiral HPLC to be 100%. 1HNMR (400 MHz, CD3OD): δ 7.16−7.07 (m, 3H), 4.10−3.98 (m,5H), 3.57 (hept, J = 6.8 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H), 1.21(d, J =6.8 Hz, 12H), 1.19 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz,CD3OD): δ 175.02 (d, J = 5.3 Hz), 146.25 (d, J = 11.6 Hz), 141.61 (d,J = 3.1 Hz), 126.52 (d, J = 1.8 Hz), 125.10 (d, J = 1.8 Hz), 62.19, 59.74(d, J = 156.2 Hz), 50.82, 28.14, 24.08, 23.82, 21.49 (d, J = 4.0 Hz),14.42. 31P NMR (162 MHz, CD3OD): δ 27.01. MS m/z (ESI): 394.2[M + Na]+.E t h y l ( 2 S ) - 2 - [ [ ( 2 , 6 - D i i s o p r o p y l p h e n o x y ) -
(morpholinomethyl)phosphoryl]amino]propanoate (11). To astirred solution of 29 (4.94 g, 11.0 mmol) in 20 mL of tetrahydrofuranwere added morpholine (2.87 g, 33.0 mmol) and triethylamine (5.67g, 56.0 mmol). The reaction mixture was heated to 80 °C and stirred
■ ASSOCIATED CONTENT*S Supporting InformationThe Supporting Information is available free of charge on theACS Publications website at DOI: 10.1021/acs.jmed-chem.7b01133.
General chemistry information, absolute configurationdetermination, 31P NMR chemical shifts for S-stereo-isomer and R-stereoisomer, HPLC analytical and
■ ACKNOWLEDGMENTSWe thank Mr. Wei Zheng from Haisco Pharmaceutical GroupCo. Ltd. for continuous support. We also thank Dr. ToddMiller for helpful discussions.
■ ABBREVIATIONS USEDAUC, area under the curve; BnBr, benzyl bromide; CH3I,iodomethane; DMSO, dimethyl sulfoxide; Et3N, triethylamine;ESI, electrospray ionization; H2, hydrogen; HPLC, high-performance liquid chromatography; ICR, Institute of CancerResearch; ig, intragastric; iv, intravenous; LD50, median lethaldose; MsCl, methanesulfonyl chloride; NaH, sodium hydride;TLC, thin-layer chromatography; TMSBr, bromotrimethylsi-lane; THF, tetrahydrofuran
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