Bioorganic & Medicinal Chemistry Letters Volume 23, Issue 24, 2013 Contents BMCL Digests PDE2 inhibition: Potential for the treatment of cognitive disorders pp 6522–6527 Laurent Gomez, J. Guy Breitenbucher* HN N N N Me OH MeO OMe O Me BAY-60-7550 N N N N N Me N N N CF3 PF-999 Phosphodiesterase inhibition has received much attention in the past 20 years for the potential treatment of CNS disorders. A primary focus of this work is the enhancement of memory and/or cognitive functioning. The role of PDEs in the augmentation of cyclic nucleotide signaling makes these enzymes attractive targets for enhancing the effects of neuronal communication. This review focuses on recent findings with respect to the role of PDE2 inhibition in cognitive functioning. Special attention is paid to recently disclosed, selective tool compounds and the use of these tool compounds to support the role of PDE2 inhibition in cognition. Recently reported SAR and modeling work will be presented along with discussion of the entry of new PDE2 inhibitors into the clinic. Tissue transglutaminase: An emerging target for therapy and imaging pp 6528–6543 Markus Pietsch, Robert Wodtke, Jens Pietzsch, Reik Löser* The prerequisite for the development of both inhibitors and substrate-based imaging agents for TGase 2 is the establishment of reliable assay methods to measure the enzymatic activity. Herein, we summarize the assays for this enzyme described so far accompanied by a brief overview of its roles in physiological and pathophysiological processes and a discussion of recent progress in the design of inhibitors and imaging probes. REGULAR ARTICLES ‘Caged’ peptide nucleic acids activated by red light in a singlet oxygen mediated process pp 6544–6548 Sandra G. König, Andriy Mokhir* cyclic PNA Photosensitizer red light, O 2 micro RNA "caged" state uncaged state Bioorganic & Medicinal Chemistry Letters 23 (2013) 6501–6521 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl
PDE2 inhibition: Potential for the treatment of cognitive disorders pp 6522–6527
Laurent Gomez, J. Guy Breitenbucher*
HN
NN
N
Me
OH
MeOOMe O Me
BAY-60-7550
N
NN
N
N
Me
NN
N
CF3
PF-999
Phosphodiesterase inhibition has received much attention in the past 20 years for the potential treatment of CNS disorders. A primary focus of this work is the enhancement ofmemory and/or cognitive functioning. The role of PDEs in the augmentation of cyclic nucleotide signaling makes these enzymes attractive targets for enhancing the effects ofneuronal communication. This review focuses on recent findings with respect to the role of PDE2 inhibition in cognitive functioning. Special attention is paid to recently disclosed,selective tool compounds and the use of these tool compounds to support the role of PDE2 inhibition in cognition. Recently reported SAR and modeling work will be presentedalong with discussion of the entry of new PDE2 inhibitors into the clinic.
Tissue transglutaminase: An emerging target for therapy and imaging pp 6528–6543
Markus Pietsch, Robert Wodtke, Jens Pietzsch, Reik Löser*
The prerequisite for the development of both inhibitors and substrate-based imagingagents for TGase 2 is the establishment of reliable assay methods to measure theenzymatic activity. Herein, we summarize the assays for this enzyme described so faraccompanied by a brief overview of its roles in physiological and pathophysiologicalprocesses and a discussion of recent progress in the design of inhibitors and imagingprobes.
REGULAR ARTICLES
‘Caged’ peptide nucleic acids activated by red light in a singlet oxygen mediated process pp 6544–6548
Discovery and SAR studies of methionine–proline anilides as dengue virus NS2B-NS3 protease inhibitors pp 6549–6554
Guo-Chun Zhou*, Zhibing Weng, Xiaoxia Shao, Fang Liu, Xin Nie, Jinsong Liu, Decai Wang, Chunguang Wang, Kai Guo*
1, X = H, Y = empty, Ki = 4.9 µM2, X = Boc, Y = empty, Ki = 10.5 µM
N
S
HN
O
Y
O
HNNO2X
A series of methionine–proline anilides and their analogues were designed, synthesized and discovered as DENV 2 NS2B-NS3 inhibitors, and the mostactive NS2B-NS3 competitive inhibitors 1 and 2 with Ki values of 4.9 and 10.5 lM.
Enhanced estrogen receptor beta (ERb) selectivity of fluorinated carborane-containing ER modulators pp 6555–6558
R = Ph; 4-F-Ph; 4-Cl-Ph; 4-Br-Ph; 2-OH-Ph; 4-OH-Ph; 2,4-(OH)2-Ph;
3-OCH3-4-OH-Ph; 4-CH3-Ph; 4-N(CH3)2-Ph; 4-NO2-Ph
New series of 1,3-selenazole-containing 1,3,4-thiadiazole derivatives bearing Schiff base moieties 6(a–k) were synthesized. The newly synthesizedcompounds were evaluated for their in vitro antiproliferative activities against MCF-7 and L1210 cells by CCK-8 assay.
Synthesis, antioxidant capacity, and structure–activity relationships of tri-O-methylnorbergeninanalogues on tyrosinase inhibition
pp 6580–6584
Yusei Kashima, Mitsuo Miyazawa*
Discovery of an irreversible HCV NS5B polymerase inhibitor pp 6585–6587
Qingbei Zeng*, Anilkumar G. Nair*, Stuart B. Rosenblum, Hsueh-Cheng Huang,Charles A. Lesburg, Yueheng Jiang, Oleg Selyutin, Tin-Yau Chan, Frank Bennett,Kevin X. Chen, Srikanth Venkatraman, Mousumi Sannigrahi, Francisco Velazquez,Jose S. Duca, Stephen Gavalas, Yuhua Huang, Haiyan Pu, Li Wang, Patrick Pinto,Bancha Vibulbhan, Sony Agrawal, Eric Ferrari, Chuan-kui Jiang, Cheng Li,David Hesk, Jennifer Gesell, Steve Sorota, Neng-Yang Shih,F. George Njoroge, Joseph A. Kozlowski N
NH
OH
O
N
O
2e, NS5B IC50 = 0.013 μMReplicon EC50 = 0.003 μM
N
NH
OH
O
N
O
Cl
F F
SCys 366
HCV RdRp
The discovery of lead compound 2e was described. Its covalent binding to HCV NS5Bpolymerase enzyme was investigated by X-ray analysis. The results of distribution,metabolism and pharmacokinetics were reported. Compound 2e was demonstratedto be potent (replicon GT-1b EC50 = 0.003 lM), highly selective, and safe in in vitroand in vivo assays.
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6503
Discovery of an intravenous hepatoselective glucokinase activator for the treatment of inpatienthyperglycemia
pp 6588–6592
Benjamin D. Stevens*, John Litchfield, Jeffrey A. Pfefferkorn, Karen Atkinson, Christian Perreault, Paul Amor, Kevin Bahnck,Martin A. Berliner, Jessica Calloway, Anthony Carlo, David R. Derksen, Kevin J. Filipski, Mike Gumkowski, Charanjeet Jassal,Margit MacDougall, Brendan Murphy, Paul Nkansah, John Pettersen, Charles Rotter, Yan Zhang
N
CO2H
HN
ON
NF3C
N
CO2H
HN
ON
NS
O O
1: PF-04991532
ReducePassive
Permeability
7
Novel piperidinylamino-diarylpyrimidine derivatives with dual structural conformations as potentHIV-1 non-nucleoside reverse transcriptase inhibitors
pp 6593–6597
Xuwang Chen, Xin Liu, Qing Meng, Ding Wang, Huiqing Liu, Erik De Clercq,Christophe Pannecouque, Jan Balzarini, Xinyong Liu*
Compound 10b3 with dual binding conformations
Leu234
HN
O
Lys101
Val179
Pro236
Hydrogen bondN N
O NH
NH
CN
N
NC
N
N
O
NH
NH
N
CNCN
PDB code: 3M8Q PDB code: 3MEC
Val106
Glu138
Leu234
HN
O
Lys101
Val179
Pro236
Hydrogen bond
Val106
Glu138
N
N
Solvent/protein interface
Entrance channel
Compound 10b3 (EC50 = 0.047 (wild-type) and 4.6 lM (mutant)) with dual structuralconformations was designed via molecular hybridization, and could occupy the protein/solvent interface and the entrance channel of HIV-1 NNIBP simultaneously.
Design, synthesis and biological evaluation of a-substituted isonipecotic acid benzothiazole analogues aspotent bacterial type II topoisomerase inhibitors
pp 6598–6603
Lorraine C. Axford*, Piyush K. Agarwal, Kelly H. Anderson, Laura N. Andrau, John Atherall,Stephanie Barker, James M. Bennett, Michael Blair, Ian Collins, Lloyd G. Czaplewski,David T. Davies, Carlie T. Gannon, Dushyant Kumar, Paul Lancett, Alastair Logan,Christopher J. Lunniss, Dale R. Mitchell, Daniel A. Offermann, James T. Palmer,Nicholas Palmer, Gary R.W. Pitt, Stéphanie Pommier, Daniel Price, B. Narasinga Rao,Rashmi Saxena, Tarun Shukla, Amit K. Singh, Mahipal Singh, Anil Srivastava,Christopher Steele, Neil R. Stokes, Helena B. Thomaides-Brears, Edward M. Tyndall,David Watson, David J. Haydon
Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc pp 6604–6609
Benjamin P. Fauber*, Gladys de Leon Boenig, Brenda Burton, Céline Eidenschenk, Christine Everett, Alberto Gobbi,Sarah G. Hymowitz, Adam R. Johnson, Marya Liimatta, Peter Lockey, Maxine Norman, Wenjun Ouyang, Olivier René,Harvey Wong
Synthesis and characterization of polyacids from palm acid oil and sunflower oil via addition reaction pp 6616–6619
Ehsan Zeimaran*, Mohammed Rafiq Abdul Kadir, Hussin Mohd Nor, Tunku Kamarul, Ivan Djordjevic
Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs) pp 6620–6624
Swati P. Mercer*, Anthony J. Roecker, Susan Garson, Duane R. Reiss, C. Meacham Harrell, Kathy L. Murphy, Joseph G. Bruno,Rodney A. Bednar, Wei Lemaire, Donghui Cui, Tamara D. Cabalu, Cuyue Tang, Thomayant Prueksaritanont,George D. Hartman, Steven D. Young, Christopher J. Winrow, John J. Renger, Paul J. Coleman
1
Me
Me
N
O
HN
O
O
N18
N
N
Cl
Cl O
HNOMe
OMe
N
O
HN
N
A D
Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for thetreatment of secondary hyperparathyroidism
pp 6625–6628
Paul M. Wehn, Paul E. Harrington*, Timothy J. Carlson, James Davis, Pierre Deprez, Christopher H. Fotsch, Mark P. Grillo,Jenny Ying-Lin Lu, Sean Morony, Kanaka Pattabiraman, Steve F. Poon, Jeff D. Reagan, David J. St. Jean Jr., Taoues Temal,Minghan Wang, Yuhua Yang, Charles Henley III III, Sarah E. Lively
HN N
O
N
N
O
S
SO2NH2
Cl18hCaSR EC50 = 10 nMRat CL = 0.32 L/h/kgF
F
1hCaSR EC50 = 16 nMRat CL = 3.8 L/h/kg
HN N
O
N
N
O
Ph
Ph S
NHSO2Me
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6505
Synthesis and methemoglobinemia-inducing properties of analogues of para-aminopropiophenonedesigned as humane rodenticides
pp 6629–6635
David Rennison*, Daniel Conole, Malcolm D. Tingle, Junpeng Yang, Charles T. Eason, Margaret A. Brimble*
H2N
X R
H2N 2 (PAPP)
O
X = C=O, N=OMe, S=O, SO2, SO2NH, SO2NMe
R = alkyl, aryl, alkyl(aryl), alkyl(heteroaryl), Cl, CN
Key: parent aryl amine core (blue); modification to 'fine-tune' electronic (red) and lipophilic/structural properties (green)
p21-Activated kinase 5: A pleiotropic kinase pp 6636–6639
PAK5 has been identified downstream of the Rho GTPases Cdc42 and Rac. There are multiplepotential regulators of intracellular activity involved in the signaling pathways.
Function-regulating pharmacophores in a sulfonamide class of glucocorticoid receptor agonists pp 6640–6644
Daniel Kuzmich, Jörg Bentzien*, Raj Betageri, Darren DiSalvo, Tazmeen Fadra-Khan, Christian Harcken, Alison Kukulka,Gerald Nabozny, Richard Nelson, Edward Pack, Donald Souza, David Thomson
NH
SO O
N
Cl
NH2 Cl
N
27
GR IC50 : 1 nMCAIA ED50 : 100 mg/kg
Substituted phenyl as a steroid A-ring mimetic: Providing agonist activity to a class of arylsulfonamidenonsteroidal glucocorticoid ligands
pp 6645–6649
Darren DiSalvo*, Daniel Kuzmich, Jörg Bentzien, John Regan, Alison Kukulka, Tazmeen Fadra-Khan, Richard Nelson,Christian Harcken, David Thomson, Gerald Nabozny
6506 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521
DPMA, a deoxypodophyllotoxin derivative, induces apoptosis and anti-angiogenesis in non-small celllung cancer A549 cells
DPMA inhibited microtubule formation, induced expression of Bax, cleaved caspase-3, p53 and improve ROS levels, as well as activated cyclinB1 and cdc2.DPMA also inhibited tube formation of VEGF-induced human umbilical vein endothelial cells.
In vitro cytotoxicity on human ovarian cancer cells by T-type calcium channel blockers pp 6656–6662
Sun Jeong Jang, Heung Woo Choi, Doo Li Choi, Sehyeon Cho, Hong-Kun Rim, Hye-Eun Choi, Ki-Sun Kim, Minghua Huang,Hyewhon Rhim, Kyung-Tae Lee*, Jae Yeol Lee*
Preparation, in vitro evaluation and molecular modelling of pyridinium–quinolinium/isoquinoliniumnon-symmetrical bisquaternary cholinesterase inhibitors
pp 6663–6666
Marketa Komloova, Anna Horova, Martina Hrabinova, Daniel Jun, Martin Dolezal, Jarmila Vinsova, Kamil Kuca,Kamil Musilek*
N (A) N
2 Br
N (A) N
2 Br
Comprehending renin inhibitor’s binding affinity using structure-based approaches pp 6667–6672
Govindan Subramanian*, Shashidhar N. Rao
Data Set54 small molecule/peptidomimetic...human renin x-ray complexes
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6507
Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in miceafter peripheral administration
pp 6673–6676
Jakub Fichna*, Marzena Mazur, Daria Grzywacz, Wojciech Kamysz, Renata Perlikowska,Justyna Piekielna, Marta Sobczak, Maciej Sałaga, Geza Toth, Anna Janecka, Chunqiu Chen,Jacek Olczak
O
RO
RO
RORO
O
O
NH
NH
O
N
ON2
OH
NH2
O
2a R = Ac2b R = H
H
The effect of the skeleton structure of flavanone and flavonoid on interaction with transferrin pp 6677–6681
Cytotoxic compounds from invasive giant salvinia (Salvinia molesta) against human tumor cells pp 6682–6687
Shiyou Li*, Ping Wang, Guangrui Deng, Wei Yuan, Zushang Su
OH
OH
1
12
3 4 5 6 78
910
1112
13
14
15 17
19
20
16
1′
6′ 5′ 4′
3′
2′
7′
8′
9′
10′ 3 R1=OH, R2=β -Hor R1=α-H, R2=OH
3a R1=OCH3, R2=H
1'
2'3'4'
5' 6'
11
1''2''3''
4''5''
6''10
1
234
56
78
9O
HO
HO
HOO
O
O
O
O
HOOH
2 R1=1'''
2'''3'''
4'''
5'''
O
OH
R2=H
R1,R2H18
Bioactivity-guided fractionation of ethanol extract of giant salvinia led to the isolation of 50 compounds including 6 new compounds. The new compoundsalviniol (1) is a rare abietane diterpene with a new ferruginol–menthol coupled skeleton and both salviniside I (2) and salviniside II (3) are novelbenzofuran glucose conjugates with unique 10-membered macrodiolide structure through acylation at C-4 and C-6 of glucopyranosyl. Cytotoxicity of 50compounds against a panel of six human tumor cell lines was examined in vitro.
New cytotoxic benzosuberene analogs. Synthesis, molecular modeling and biological evaluation pp 6688–6694
Zecheng Chen, Andreas Maderna*, Sai Chetan K. Sukuru, Melissa Wagenaar, Christopher J. O’Donnell, My-Hanh Lam,Sylvia Musto, Frank Loganzo
MeOOH
MeO
MeOOMe
R
MeOOH
MeO
MeOOMe
MeOOH
MeO
MeOOMe
O
4 - 6 nM 9 - 16 nM
987
654
32
1
A B
C
44 - 1000 nM
IC50 Tumor Cell Proliferation Assays
6508 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521
An assay for human telomeric G-quadruplex DNA binding drugs pp 6695–6699
Derrick Watkins, Nihar Ranjan, Sunil Kumar, Changjun Gong, Dev P. Arya*
Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylasein the brain
pp 6700–6705
Young Jun Seo, Lisa Muench, Alicia Reid, Jinzhu Chen,Yeona Kang, Jacob M. Hooker*, Nora D. Volkow,Joanna S. Fowler, Sung Won Kim*
Brain uptake of HDAC inhibitor and substrates
HN
OH
O
3O
O
HN
NHO 2
O
*
*HN N
HO2
OF*
inhibitor substrate substrateBrain uptake of HDAC inhibitor and substrates.
Anion inhibition studies of a b-carbonic anhydrase from Clostridium perfringens pp 6706–6710
Daniela Vullo, R. Siva Sai Kumar, Andrea Scozzafava, Clemente Capasso, James G. Ferry, Claudiu T. Supuran*
Design and synthesis of novel 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine derivatives as selective G-protein-coupled receptor kinase-2 and -5 inhibitors
pp 6711–6716
Sung Yun Cho, Byung Ho Lee, Heejung Jung, Chang Soo Yun, Jae Du Ha, Hyoung Rae Kim, Chong Hak Chae, Jeong Hyun Lee,Ho Won Seo, Kwang-Seok Oh*
N
H2N
O
N
N N
NH
N
1o: GRK2 IC50 = 0.46 μMGRK5 IC50 = 0.059 μM
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6509
Truncated and constrained helical analogs of antimicrobial esculentin-2EM pp 6717–6720
Thanh Kim Pham, Do-Hee Kim, Bong-Jin Lee, Young-Woo Kim*
Synthesis and biological evaluation of nimesulide based new class of triazole derivatives as potentialPDE4B inhibitors against cancer cells
6i: IC50 of 2.55 nM for AChE, 2.80 nM for BuChE;hydrogen peroxide scavenging activity: 83.7% at 20 μM;Peroxynitrite scavenging activity:1.26 equivalent of ebselen
Scorpion toxins for the reversal of BoNT-induced paralysis pp 6743–6746
Colin A. Lowery, Michael Adler, Andrew Borrell, Kim D. Janda*
TIINVKCTSPKQCLPPCKAQFGQSAGAKCMNGKCKCYPH
S S
S S
SS
Margatoxin
pQFTDVDCSVSKECWSVCKDLFGVDRGKCMGKKCRCYQ
S S
S SS S
Iberiotoxin
pQFTNVSCTTSKECWSVCQRLHNTSRGKCMNKKCRCYS
S S
SSSS
Charybdotoxin
Discovery of benzo[d]imidazo[5,1-b]thiazole as a new class of phosphodiesterase 10A inhibitors pp 6747–6754
Abhisek Banerjee, Lakshminarayana Narayana, Firoj A. Raje, Dnyandeo V. Pisal, Pradip A. Kadam, Srinivas Gullapalli,Hemant Kumar, Sandeep V. More, Malini Bajpai, Ramachandra Rao Sangana, Satyawan Jadhav, Girish S. Gudi,Neelima Khairatkar-Joshi, Ravi R.T. Merugu, Sreedhara R. Voleti, Laxmikant A. Gharat*
N
S
N
ON
O
9e
PDE10A IC50: 7.45±3.56 nM
PDE selectivity > 500 fold
Rat B/P ratio: 1.82
Rat PK Cmax: 720 ng/mL; AUC0-24h: 2827 ng.h/mL
MK-801 induced model of Psychosis in rats: ED50: 1.44 mg/kg (i.p.)
CAR model of psychosis in rats: ED50: 1.60 mg/kg (i.p.)
Synthesis and antitumor activity evaluation of maleopimaric acid N-aryl imide atropisomers pp 6755–6758
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6511
Salen and tetrahydrosalen derivatives act as effective inhibitors of the tumor-associated carbonicanhydrase XII—A new scaffold for designing isoform-selective inhibitors
pp 6759–6763
Simone Carradori*, Celeste De Monte, Melissa D’Ascenzio, Daniela Secci, Gulsah Celik, Mariangela Ceruso, Daniela Vullo,Andrea Scozzafava, Claudiu T. Supuran*
Ki hCA XII = 37 nMRATIO Ki hCA II/Ki hCA XII = 95
Zn2+
HNNH
OH HO
Synthesis and initial biological evaluation of substituted 1-phenylamino-2-thio-4,5-dimethyl-1H-imidazole derivatives
Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquineanalogues
pp 6769–6772
Bianca C. Pérez, Iva Fernandes, Nuno Mateus, Cátia Teixeira, Paula Gomes*
4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable Stearoyl-CoA desaturase-1(SCD1) inhibitors. Part 1: Urea-based analogs
pp 6773–6776
Shyh-Ming Yang*, Yuting Tang, Rui Zhang, Huajun Lu, Gee-Hong Kuo, Michael D. Gaul, Yaxin Li, George Ho,James G. Conway, Yin Liang, James M. Lenhard, Keith T. Demarest, William V. Murray
N
N
FO
HN
S
NMe
N
N
FO
HN
S
N
OH4d, rSCD1: 26 nM
A431: 21 nM5n, rSCD1: 14 nM
A431: 1 nM
6512 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521
The discovery of novel N-(2-pyrimidinylamino) benzamide derivatives as potent hedgehog signalingpathway inhibitors
pp 6777–6783
Minhang Xin*, Jun Wen, Feng Tang, Chongxing Tu, Han Shen, Xinge Zhao
N
N
NH
NH
O
OCF3
6a
Hedgehog signaling inhibitory activityIC50=1.3nMHedgehog signaling pathway inhibitors are emerging as new therapeutic intervention against cancer. A novel series of N-(2-
pyrimidinylamino) benzamide derivatives as hedgehog signaling pathway inhibitors were designed and synthesized. Mostcompounds presented significant inhibitory effect on hedgehog signaling pathway, among which 21 compounds exhibited morepotent than vismodegib. Furthermore, compound 6a showed moderate pharmacokinetic properties in vivo, representing apromising lead compound for further exploration.
Synthesis of novel 7-substituted pyrido[20,30:4,5]furo[3,2-d]pyrimidin-4-amines and their N-arylanalogues and evaluation of their inhibitory activity against Ser/Thr kinases
Discovery of a potent respiratory syncytial virus RNA polymerase inhibitor pp 6789–6793
Hui Xiong, Melinda Foulk, Lisa Aschenbrenner, Jun Fan, Choi-Lai Tiong-Yip, Kenneth D. Johnson, Demetri Moustakas,Paul R. Fleming, Dean G. Brown, Minli Zhang, Douglas Ferguson, Dedong Wu, Qin Yu*
The new phosphorothioate and phosphorodithioate analogues of 2-methoxy-lysophosphatidylcholine were synthesized employing oxathiaphospholaneand dithiaphospholane chemistry.
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6513
Sulfur incorporation generally improves Ricin inhibition in pterin-appended glycine-phenylalaninedipeptide mimics
pp 6799–6804
Paul A. Wiget, Lawrence A. Manzano, Jeff M. Pruet, Grace Gao, Ryota Saito, Arthur F. Monzingo, Karl R. Jasheway,Jon D. Robertus, Eric V. Anslyn*
HN
N N
N
H2N
O
O
n+m=3Y = O or S
n NH
YmH
NHN
n
Y
mHN
N N
N
H2N
O
O
HN
"Inside" amide "Outside" amide
HN
N N
N
H2N
O
O
HN
NH
O CO2H
remove
amideinversion
edge-to-faceelectroniceffects
R R
S
amidetransposition
Design, synthesis and evaluation of 6-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl)phenanthridine analogues as antimycobacterial agents
Among the series two compounds 7f, 7j (MIC = 3.125 lg/mL) exhibited good activity and compound 8a (MIC = 1.56 lg/mL) exhibited very good activityagainst Mycobacterium tuberculosis H37Rv.
A ratiometric fluorescent detection of Zn(II) in aqueous solutions using pyrene-appended histidine pp 6811–6815
Réjean Ruel*, Alexandre L’Heureux, Carl Thibeault, Philippe Lapointe, Alain Martel, Jennifer X. Qiao, Ji Hua, Laura A. Price,Qimin Wu, Ming Chang, Joanna Zheng, Christine S. Huang, Ruth R. Wexler, Robert Rehfuss, Patrick Y.S. Lam
N
HN
O
HN
OOCF3
N
4a
P2Y1 K i = 16 nMPA IC50 = 2.4 μM [ADP = 2.5 μM]
Novel Mps1 kinase inhibitors: From purine to pyrrolopyrimidine and quinazoline leads pp 6829–6833
Matthew G. Bursavich*, David Dastrup, Mark Shenderovich, Kraig M. Yager, Daniel M. Cimbora, Brandi Williams,D. Vijay Kumar
N
N
NH
NO
OMe
R1
N
NN
NH
HN
NH
N
OMe
O
N
N
NH
N
OMe
ONR1
Design, synthesis and cytotoxicity of novel 30-N-alkoxycarbonyl docetaxel analogs pp 6834–6837
An interesting by-product 9a was identified with very potent cytotoxicity. The structure of 9a was carefully characterized by 1D and 2D NMR and further confirmed by means ofsynthesis. The preliminary SAR study demonstrated that analogs with (R)-configuration were slightly more potent than analogs with (S)-configuration, and a,a-gem-dimethylanalogs 16g–i exhibited more potent cytotoxicity.
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6515
Synthesis and antiprotozoal activity of nitazoxanide–N-methylbenzimidazole hybrids pp 6838–6841
Olivia Soria-Arteche, Alicia Hernández-Campos, Lilián Yépez-Mulia, Pedro Josué Trejo-Soto, Francisco Hernández-Luis,Jorge Gres-Molina, Luis A. Maldonado, Rafael Castillo*
Anti-tubercular agents. Part 8: Synthesis, antibacterial and antitubercular activity of 5-nitrofuran based1,2,3-triazoles
pp 6842–6846
Ahmed Kamal*, Syed Mohammed Ali Hussaini, Shaikh Faazil, Y. Poornachandra, G. Narender Reddy, C. Ganesh Kumar,Vikrant Singh Rajput, Chitra Rani, Rashmi Sharma, Inshad Ali Khan, N. Jagadeesh Babu
SN
N
O O
NH
NO
O2NO
O2N
HN
O
NNN
Cl
F
MIC(H37Rv) = 1 µg/ml MIC(H37Rv) = 0.25 µg/ml
Synthesis of 20-O-(thymin-1-yl)methyluridine and its incorporation into secondary nucleic acidstructures
pp 6847–6850
Pawan Kumar, Charlotte S. Madsen, Poul Nielsen*
N
NH
O
OO
OH
HO
OH
N
NH
O
OO
O
O
O
N
NH
O
O
PO
O
A double-headed nucleotide monomer with an additional thymine attached to the 20-O-position of uridine via an methylene linker is introduced and found to stabilize some secondarynucleic acid structures.
Polycation-assisted DNA detection by reduction triggered fluorescence amplification probe pp 6851–6853
Cytidine derivatives as IspF inhibitors of Burkolderia pseudomallei pp 6860–6863
Zheng Zhang, Sriram Jakkaraju, Joy Blain, Kenneth Gogol, Lei Zhao, Robert C. Hartley, Courtney A. Karlsson, Bart L. Staker,Thomas E. Edwards, Lance J. Stewart, Peter J. Myler, Michael Clare, Darren W. Begley, James R. Horn, Timothy J. Hagen*
NH
HO OH
O N
O N NH2
R
O
Antiproliferative activities and SAR studies of substituted anthraquinones and 1,4-naphthoquinones pp 6864–6867
Deepak Bhasin, Jonathan P. Etter, Somsundaram N. Chettiar, May Mok, Pui-Kai Li*
O
OR1 R3
R2
R41
2
5
8
30,40-Bis-difluoromethoxycinnamoylanthranilate (FT061): An orally-active antifibrotic agent that reducesalbuminuria in a rat model of progressive diabetic nephropathy
pp 6868–6873
Spencer J. Williams*, Steven C. Zammit, Alison J. Cox, David M. Shackleford, Julia Morizzi, Yuan Zhang, Andrew K. Powell,Richard E. Gilbert, Henry Krum, Darren J. Kelly*
O
NH CO2H
F2CHO
F2CHO
Inhibits TGF-β stimulated collagen biosynthesisImproved bioavailability versus tranilastReduces albuminuria in streptozotocin-treated hypertensive rat
FT061
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6517
Design, synthesis, and evaluation of curcumin-derived arylheptanoids for glioblastoma andneuroblastoma cytotoxicity
pp 6874–6878
Catherine A. Campos, Joseph B. Gianino, Barbara J. Bailey, Mary E. Baluyut, Constanze Wiek, Helmut Hanenberg,Harlan E. Shannon, Karen E. Pollok*, Brandon L. Ashfeld*
Anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors with sub-micromolar potencyin the cell-based replicon assay
pp 6879–6885
Timothy A. Stammers*, René Coulombe, Martin Duplessis, Gulrez Fazal, Alexandre Gagnon, Michel Garneau, Sylvie Goulet,Araz Jakalian, Steven LaPlante, Jean Rancourt, Bounkham Thavonekham, Dominik Wernic, George Kukolj, Pierre L. Beaulieu
IC50 0.22 μMEC50 > 30 μμM
1
IC50 0.078 μMEC50 0.095 μM
46
CF3
O
N
O
O HO
N
O
OOS
NH
O
O H
Design, synthesis and in vitro anticancer evaluation of 4,6-diamino-1,3,5-triazine-2-carbohydrazides and-carboxamides
pp 6886–6889
Hend Kothayer, Abdalla A. Elshanawani, Mansour E. Abu Kull, Osama I. El-Sabbagh, Malathy P.V. Shekhar, Andrea Brancale,Arwyn T. Jones, Andrew D. Westwell*
Identification of clinical candidates from the benzazepine class of histamine H3 receptor antagonists pp 6890–6896
David M. Wilson*, James Apps, Nicholas Bailey, Mark J. Bamford, Isabel J. Beresford, Kim Brackenborough, Michael A. Briggs,Stephen Brough, Andrew R. Calver, Barry Crook, Rebecca K. Davis, Robert P. Davis, Susannah Davis, David K. Dean,Leanne Harris, Teresa Heslop, Vicky Holland, Phillip Jeffrey, Terrance A. Panchal, Christopher A. Parr, Nigel Quashie,Joanne Schogger, Sanjeet S. Sehmi, Tania O. Stean, Jon G.A. Steadman, Brenda Trail, Jeffrey Wald, Angela Worby,Andrew K. Takle, Jason Witherington, Andrew D. Medhurst
6518 Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521
The discovery of the benzazepine class of histamine H3 receptor antagonists pp 6897–6901
David M. Wilson*, James Apps, Nicholas Bailey, Mark J. Bamford, Isabel J. Beresford, Michael A. Briggs, Andrew R. Calver,Barry Crook, Robert P. Davis, Susannah Davis, David K. Dean, Leanne Harris, Tom D. Heightman, Terry Panchal,Christopher A. Parr, Nigel Quashie, Jon G.A. Steadman, Joanne Schogger, Sanjeet S. Sehmi, Tania O. Stean, Andrew K. Takle,Brenda K. Trail, Trevor White, Jason Witherington, Angela Worby, Andrew D. Medhurst
Structure–activity relationship studies of thalidomide analogs with a taxol-like mode of action pp 6902–6904
Bulbul Pandit, Zhigen Hu, Somsundaram N. Chettiar, Jennifer Zink, Zili Xiao, Jonathan P. Etter, Deepak Bhasin, Pui-Kai Li*
N
O
O
HO
5HPP-33
(S)-4-Trimethylsilyl-3-butyn-2-ol as an auxiliary for stereocontrolled synthesis of salinosporamideanalogs with modifications at positions C2 and C5
pp 6905–6910
Landy K. Blasdel, DongEun Lee, Binyuan Sun, Andrew G. Myers*
Synthetic a-(aminomethyl)-c-butyrolactones and their anti-pancreatic cancer activities pp 6911–6914
P. Veeraraghavan Ramachandran*, Daniel R. Nicponski, Hari N.G. Nair, Matthew A. Helppi, Pravin D. Gagare,C. Max Schmidt, Michele T. Yip-Schneider
O O
Ph
Ph
NR2
O O
Ph
Ph
NR2
O O
Ph
Ph
O O
Ph
Ph
O
OMe
HNR2
HNR2
Highly active against Panc-1, MIA PaCa-2,and BxPC-3 pancreatic cancer cell lines.
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6519
Asymmetric synthesis and effect of absolute stereochemistry of YCZ-2013, a brassinosteroid biosynthesisinhibitor
pp 6915–6919
Keimei Oh*, Kazuhiro Yamada, Yuko Yoshizawa
Chlorophenylpiperazine analogues as high affinity dopamine transporter ligands pp 6920–6922
William C. Motel, Jason R. Healy, Eddy Viard, Buddy Pouw, Kelly E. Martin, Rae R. Matsumoto, Andrew Coop*
Oxime-based inhibitors of glucose transporter 1 displaying antiproliferative effects in cancer cells pp 6923–6927
*Corresponding authorSupplementary data available via ScienceDirect
COVER
An unusual non-nucleoside inhibitor bound to HIV-1 reverse transcriptase. The inhibitor is dimeric in an NNRTI-linker-NNRTI motif. It iscomputed to extend beyond the NNRTI binding site into the entrance channel. A precedent is set for other constructs that could effectivelyincorporate two drugs in one compound [Ekkati, A. R.; Bollini, M.; Domaoal, R. A.; Spasov, K. A.; Anderson, K. A.; Jorgensen, W. L. Discovery ofdimeric inhibitors by extension into the entrance channel of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2012, 22, 1565–1568].
Available online at www.sciencedirect.com
ScienceDirect
Indexed/Abstracted in: Beilstein, Biochemistry & Biophysics Citation Index, CANCERLIT, Chemical Abstracts, ChemistryCitation Index, Current Awareness in Biological Sciences/BIOBASE, Current Contents: Life Sciences, EMBASE/Excerpta Medica,MEDLINE, PASCAL, Research Alert, Science Citation Index, SciSearch, TOXFILE. Also covered in the abstract and citationdatabase Scopus�. Full text available on ScienceDirect�
ISSN 0960-894X
Contents / Bioorg. Med. Chem. Lett. 23 (2013) 6501–6521 6521
![FLAMING CLIFFS 2 - [FLAMING CLIFFS 2] 1 TABLE OF CONTENTS | GRAPHICAL USER INTERFACE TABLE OF CONTENTS MAIN MENU .....4 ...](https://static.documents.pub/doc/80x56/5af425d67f8b9ae9488ba3f5/flaming-cliffs-2-flaming-cliffs-2-1-table-of-contents-graphical-user-interface.jpg)
