Bioorganic and Medicinal Chemistry Letters - Aktuelle Forschungsartikel
Aktuelle Forschungsartikel: Medizinische Chemie
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Bioorganic and Medicinal Chemistry Letters - Verlag: Elsevier
Das Journal legt vorläufige experimentelle oder theoretische Forschungsergebnisse vor, die von herausragender Bedeutung und Aktualität zu allen Aspekten der Wissenschaft an der Schnittstelle von Chemie und Biologie sind und die große Fortschritte in der Medikamentenentwicklung und -entwicklung aufweisen.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Douglas J. Sheffler, Cody J. Wenthur, Joshua A. Bruner, Sheridan J.S. Carrington, Paige N. Vinson, Kiran K. Gogi, Anna L. Blobaum, Ryan D. Morrison, Mitchell Vamos, Nicholas D.P. Cosford, Shaun R. Stauffer, J. Scott Daniels, Colleen M. Niswender, P. Jeffrey Conn, Craig W. Lindsley Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) with 15-fold selectivity versus mGlu2. The mGlu3 NAM was discovered via a ‘molecular switch’ from a closely related, potent mGlu5 positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC50 value of 0.66?M and is inactive against mGlu5.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Takashi Misawa, Hisamitsu Hayashi, Makoto Makishima, Yuichi Sugiyama, Yuichi Hashimoto Bile salt export pump (BSEP) is a member of the ATP-binding cassette transmembrane transporter family and mediates biliary excretion of bile acids from hepatocytes. Several BSEP mutants, including Glu297Gly (E297G) and Asp482Gly (D482G), cause progressive familial intrahepatic cholestasis type 2. We previously found that compounds based on GW4064, a representative farnesoid X receptor (FXR) agonist, enhanced E297G BSEP transport activity. Here, we conducted a structure–activity relationship analysis of GW4064 derivatives aimed at separating E297G BSEP-function-promoting activity and FXR-agonistic activity. Among newly synthesized reversed-amide derivatives of previously reported GW4064 analogs 2a–2f, we identified 7c as a selective BSEP function enhancer.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Narsidas J. Parmar, Bhavesh R. Pansuriya, Hitesh A. Barad, Rajni Kant, Vivek K. Gupta An improved microwave assisted one-pot method for the synthesis of twelve new aryldiazenylchromeno [4,3-b] pyrrolidines via intramolecular azomethine ylide cycloaddition route is described. The method is efficient and advantageous over conventional and solvent-free thermal methods. The stereochemistry of the compounds was confirmed on the basis of various NMR experiments, and finally by single crystal X-ray diffraction data. N-Methyl or ethyl pyrrolidine based heterocycles gave good biological activities.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Ian M. Bell, Craig A. Stump, Steven N. Gallicchio, Donnette D. Staas, C. Blair Zartman, Eric L. Moore, Nova Sain, Mark Urban, Joseph G. Bruno, Amy Calamari, Amanda L. Kemmerer, Scott D. Mosser, Christine Fandozzi, Rebecca B. White, Matthew M. Zrada, Harold G. Selnick, Samuel L. Graham, Joseph P. Vacca, Stefanie A. Kane, Christopher A. Salvatore Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2?-oxo-1?,2?,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3?-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Chi-Ting Hsieh, Tusty-Jiuan Hsieh, Mohamed El-Shazly, Da-Wei Chuang, Yi-Hong Tsai, Chiao-Ting Yen, Shou-Fang Wu, Yang-Chang Wu, Fang-Rong Chang Chalcones bearing electron donating or electron withdrawing substitutions were prepared and their glucose uptake activity was evaluated. Chalcone derivatives were synthesized in one step protocol with high purity and yield. Chalcones with chloro, bromo, iodo and hydroxy substitutions at position 2 on A-ring exhibited the highest activity with glucose medium concentration (210 to 236mg/dl) compared to pioglitazone and rosiglitazone (230 and 263mg/dl, respectively). Also chalcones with iodo substitution at position 3 on A-ring were comparably active (?238mg/dl). The structure–activity relationship of the tested chalcones was studied and the findings were supported statistically
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Haijun Chen, Tamara Tsalkova, Fang C. Mei, Yaohua Hu, Xiaodong Cheng, Jia Zhou Exchange proteins directly activated by cAMP (Epac) are a family of guanine nucleotide exchange factors that regulate a wide variety of intracellular processes in response to second messenger cAMP. To explore the structural determinants for Epac antagonist properties of high throughput screening (HTS) hit ESI-08, pyrimidine 1, a series of 5-cyano-6-oxo-1,6-dihydro-pyrimidine analogues have been synthesized and evaluated for their activities for Epac inhibition. Structure–activity relationship (SAR) analysis led to the identification of three more potent Epac antagonists (6b, 6g, and 6h). These inhibitors may serve as valuable pharmacological probes for further elucidation of the physiological functions and mechanisms of Epac regulation. Our SAR results and molecular docking studies have also revealed that further optimization of the moieties at the C-6 position of pyrimidine scaffold may allow us to discover more potent Epac-specific antagonists.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Tiancheng Liu, Jessie R. Nedrow-Byers, Mark R. Hopkins, Lisa Y. Wu, Jeonghoon Lee, Peter T.A. Reilly, Clifford E. Berkman Prostate-specific membrane antigen (PSMA), a type II membrane glycoprotein, its high expression is associated with prostate cancer progression, and has been becoming an active target for imaging or therapeutic applications for prostate cancer. On the other hand, streptavidin–biotin system has been successfully employed in pretargeting therapy towards multiple cancers. Herein, we describe the synthesis of bifunctional ligands (biotin-CTT54, biotin-PEG4-CTT54, and biotin-PEG12-CTT54) possessing two functional motifs separated by a length-varied polyethylene glycol (PEG) spacer: one (CTT54) binds tumor-marker PSMA and the other (biotin) binds streptavidin or avidin. All three compounds exhibited high potencies (IC50 values: 1.21, 2.53, and 10nM, respectively) and irreversibility; but only biotin-PEG12-CTT54 demonstrated specifically labeling PSMA-positive prostate cancer cells in a two-step pretargeting procedure. Additionally, the pre-formulated complex between biotin-PEG12-CTT54 and Cy5-streptavidin displayed the improved inhibitory potency (IC50=1.86nM) and irreversibility against PSMA and rapid uptake of streptavidin conjugate into PSMA-positive prostate cancer cells through PSMA-associated internalization. Together, all these results supported a proof-concept that combination of streptavidin and PSMA’s biotinylated inhibitor may lead to development of a novel strategy of tumor-targeting imaging or drug delivery towards prostate cancer.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Byung Jun Ryu, Mi-Kyung Hwang, Mikyung Park, Kyunghee Lee, Seong Hwan Kim The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a wide variety of cancer cells. Recently, cancer cell resistance to TRAIL-mediated apoptosis has become a challenging issue in the development of TRAIL-based anti-cancer therapies. In this study, we found that 1-(5-chloro-2-methyl-phenyl)-3-[4-(5-trifluoromethyl-pyrazol-1-yl)-phenyl]-thiourea (AW00178) was able to sensitize TRAIL-resistant human lung cancer H1299 cells to TRAIL-mediated apoptosis. Treatment with AW00178, either alone or in combination with TRAIL, induced the expression of CHOP, a protein related to TRAIL sensitivity, and reduced the expression of survivin, an anti-apoptotic protein involved in TRAIL resistance. Additionally, AW00178, alone or in combination with TRAIL, induced the activation of c-Jun and inactivation of Akt. A pharmacologic inhibition study revealed that c-Jun activation and Akt inactivation were strongly related to CHOP induction and survivin down-regulation, respectively. In summary, these results suggested that AW00178 mediated sensitization to TRAIL-mediated apoptosis in H1299 cells by increasing sensitivity and decreasing resistance to TRAIL via the induction of c-Jun-dependent CHOP expression and the reduction of Akt-dependent survivin expression, respectively.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Gretchen M. Schroeder, Donna Wei, Patrizia Banfi, Zhen-Wei Cai, Jonathan Lippy, Maria Menichincheri, Michele Modugno, Joseph Naglich, Becky Penhallow, Heidi L. Perez, John Sack, Robert J. Schmidt, Andrew Tebben, Chunhong Yan, Liping Zhang, Arturo Galvani, Louis J. Lombardo, Robert M. Borzilleri 5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Florence Lebon, Cécile Pégurier, Marie Ledecq, Benoit Mathieu, Nathalie Bosman, Anne Frycia, Sébastien Lengelé, Kashinath Dhurke, Ananda Kumar Kanduluru, Stéphane Meunier, Alain Wagner, Christian Wolff, Laurent Provins A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Ho-Lien Huang, Chun-Nan Yeh, Kang-Wei Chang, Jenn-Tzong Chen, Kun-Ju Lin, Li-Wu Chiang, Kee-Ching Jeng, Wei-Ting Wang, Ken-Hong Lim, Caleb Gonshen Chen, Kun-I Lin, Ying-Cheng Huang, Wuu-Jyh Lin, Tzu-Chen Yen, Chung-Shan Yu [18F]Flurobutyl ethacrynic amide ([18F]FBuEA) was prepared from the precursor tosylate N-Boc-N-[4-(toluenesulfonyloxy)butyl]ethacrynic amide with a radiochemical yield of 3%, a specific activity of 48GBq/?mol and radiochemical purity of 98%. Chemical conjugation of [18F]FBuEA with glutathione (GSH) via a self-coupling reaction and enzymatic conjugation under catalysis of glutathiontransferase alpha (GST-?) and ? provided about 41% yields of radiochemical conjugated product [18F]FBuEA–GSH, 85% and 5–16%, respectively. The catalytic selectivity of this tracer toward GST-alpha was addressed. Positron emission tomography (PET) imaging of [18F]FBuEA in normal rats showed that a homogeneous pattern of radioactivity was distributed in the liver, suggesting a catalytic role of GST. By contrast, PET images of [18F]FBuEA in rats with thioacetamide-induced cholangiocarcinoma displayed a heterogeneous pattern of radioactive accumulation with cold spots in tumor lesions. PET imaging with [18F]FBuEA could be used for early diagnosis of hepatic tumor with a low GST activity as well as liver function.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Beate Wollinsky, Lena Ludwig, Alexandra Hamacher, Xia Yu, Matthias U. Kassack, Shu-Ming Li Fourteen tryptophan-containing cyclic dipeptides 1a–14a, including all four stereoisomers of cyclo-Trp-Pro and cyclo-Trp-Ala, were converted to their C2-regularly prenylated derivatives 1b–14b in the presence of dimethylallyl diphosphate by using the purified recombinant FtmPT1 as catalyst. The enzyme products were isolated on HPLC in preparative scales and their structures were elucidated by NMR and MS analyses.The cytotoxic effects of the prenylated products and their substrates were tested with human leukemia K562 and ovarian cancer A2780 sens and A2780 CisR cell lines. Preliminary results have been clearly shown that prenylation at C2 led to a significant increase of the cytotoxicity of the tested cyclic dipeptides in all the 14 cases. The second amino acid and the stereochemistry of tryptophan moiety of the cyclic dipeptides showed less influence on the cytotoxicity of the tested compounds.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Gopi Kumar Mittapalli, Danielle Vellucci, Jun Yang, Marion Toussaint, Shaun P. Brothers, Claes Wahlestedt, Edward Roberts Highly potent and selective small molecule neuropeptide Y Y2 receptor antagonists are reported. The systematic SAR exploration of a hit molecule N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide, identified from HTS, led to the discovery of highly potent NPY Y2 antagonists 16 (CYM 9484) and 54 (CYM 9552) with IC50 values of 19nM and 12nM respectively.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Chiao-Ting Yen, Kyoko Nakagawa-Goto, Tsong-Long Hwang, Susan L. Morris-Natschke, Kenneth F. Bastow, Yang-Chang Wu, Kuo-Hsiung Lee Prenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four human cancer cell lines (KB, KBvin, A549, and DU-145) and anti-inflammatory activity toward superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, prenylxanthones 7–13 were generally less active than pyranoxanthones 14–21 in both anticancer and anti-inflammatory assays. Furthermore, two angular 3,3-dimethypyranoxanthones (16 and 20) showed the greatest and selective activity against the KBvin multidrug resistant (MDR) cell line with IC50 values of 0.9 and 0.8?g/mL, respectively. An angular 3-methyl-3-prenylpyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than phenylmethylsulfonyl fluoride (PMSF), the positive control.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Koneni V. Sashidhara, Abdhesh Kumar, Ranga Prasad Dodda, Naikade Niraj Krishna, Pooja Agarwal, Kumkum Srivastava, S.K. Puri First synthesis of novel coumarin–trioxane hybrids is reported. The synthesis was achieved via condensation of ?-hydroxyhydroperoxides with coumarinic-aldehydes in presence of p-toluenesulfonic acid in good yields and the novel hybrids were evaluated for their antimalarial activity both in vitro and in vivo.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Shinya Hagihara, Shuhei Kusano, Wei-Chen Lin, Xiao-guang Chao, Tsuneaki Hori, Shuhei Imoto, Fumi Nagatsugi The development of convenient methods for controlling the protein expression is an important challenge in the postgenomic era. We applied the crosslink forming oligonucleotide (CFO) as a terminator of the ribosomal translation. In this study, we demonstrated that the improved reactivity of our CFO under physiological conditions enabled the sequence-specific introduction of a steric block for a ribosome on mRNAs. In vitro and in cell translation experiments revealed that the crosslinked mRNA can produce the truncated proteins in which the translation terminates at the desired position.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Jonathan S. Foot, Mandar Deodhar, Craig I. Turner, Ping Yin, Ellen M. van Dam, Diego G. Silva, Aldo Olivieri, Andrew Holt, Ian A. McDonald A new class of 3-fluoroallyl amine-based SSAO/VAP-1 inhibitors is reported. These compounds have excellent selectivity over diamine oxidase, MAO-A and MAO-B. Synthesis and SAR studies leading to compound 28 (PXS-4159A) are reported. The pharmacokinetic profile of 28 in the rat, together with activity in a murine model of lung inflammation are also disclosed.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Samuel D. Banister, Louis M. Rendina, Michael Kassiou A series of N-substituted 7-azabicyclo[2.2.1]heptanes (12–17 and 22–25) and similarly substituted pyrrolidines (32–36 and 41–44) were synthesized as sterically-reduced, achiral analogs of adamantane- and trishomocubane-derived ? ligands. In vitro competition binding assays against ? receptors revealed that arylalkyl N-substituents conferred selectivity for the ?2 subtype, while alicyclic or polycarbocyclic substituents imparted high affinity for both subtypes. The ?2 binding and subtype selectivities of N-arylalkyl-7-azanorbornanes was generally greater than the analogously-substituted pyrrolidines, indicating that steric bulk and conformational restriction around the nitrogen atom are likely important for subtype discrimination.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Heidi L. Perez, Patrizia Banfi, Jay Bertrand, Zhen-Wei Cai, James W. Grebinski, Kyoung Kim, Jonathan Lippy, Michele Modugno, Joseph Naglich, Robert J. Schmidt, Andrew Tebben, Paola Vianello, Donna D. Wei, Liping Zhang, Arturo Galvani, Louis J. Lombardo, Robert M. Borzilleri A series of phenylacylsulfonamides has been prepared as antagonists of Bcl-2/Bcl-xL. In addition to potent binding affinities for both Bcl-2 and Bcl-xL, these compounds were shown to induce classical markers of apoptosis in isolated mitochondria. Overall weak cellular potency was improved by the incorporation of polar functionality resulting in compounds with moderate antiproliferative activity.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 William McCoull, Matthew S. Addie, Alan M. Birch, Susan Birtles, Linda K. Buckett, Roger J. Butlin, Suzanne S. Bowker, Scott Boyd, Stephen Chapman, Robert D.M. Davies, Craig S. Donald, Clive P. Green, Chloe Jenner, Paul D. Kemmitt, Andrew G. Leach, Graeme C. Moody, Pablo Morentin Gutierrez, Nicholas J. Newcombe, Thorsten Nowak, Martin J. Packer, Alleyn T. Plowright, John Revill, Paul Schofield, Chris Sheldon, Steve Stokes, Andrew V. Turnbull, Steven J.Y. Wang, David P. Whalley, J. Matthew Wood A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Mengyang Xue, Wanyi Guan, Yang Zou, Junqiang Fang, Xian-wei Liu, Peng George Wang, Fengshan Wang Nucleotide sugars are essential glycosyl donors for Leloir-type glycosyltransferases. The UDP-N-acetylgalactosamine pyrophosphorylase (UDP-GalNAc PP; AGX1) from Homo sapiens catalyzes the synthesis of UDP-N-acetylgalactosamine from N-acetylgalactosamine 1-phosphate and UTP. In this Letter, we systematically studied nucleotide substrate specificity of AGX1 during its uridyltransfer reaction, and described the capability of AGX1 to catalyze dUTP and dTTP to their corresponding nucleotide sugars for the first time. Furthermore, using such a eukaryotic enzyme, we synthesized dUDP-GalNAc and dTDP-GalNAc in multiple mg scale in vitro efficiently and rapidly.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Vladimir Sukalovic, Djurdjica Ignjatovic, Gordana Tovilovic, Deana Andric, Kaveh Shakib, Sladjana Kostic-Rajacic, Vukic Soskic It is suggested that the ratio of dopamine D2 to 5-hydroxytryptamine 5-HT1A activity is an important parameter that determines the efficiency of antipsychotic drugs. Here we present the synthesis of N-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-2-aryl-2-yl-acetamides and 1-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-3-aryl-2-yl-ureas and their structure–activity relationship studies on dopamine D2 and 5-hydrohytryptamine 5-HT1A receptors. It was shown that ligand selectivity and affinity strongly depends on their topology and the presence of a pyridyl group in the head of molecules. Molecular modeling studies using homology modeling and docking simulation revealed a rational explanation for the ligand behavior. The observed binding modes and receptor–ligand interactions provided us with a clue for optimizing the optimal selectivity towards 5-HT1A receptors.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Dearg S. Brown, John G. Cumming, Paul Bethel, Jonathan Finlayson, Stefan Gerhardt, Ian Nash, Richard A. Pauptit, Kurt G. Pike, Alan Reid, Wendy Snelson, Steve Swallow, Caroline Thompson A novel, potent and selective quinazolinone series of inhibitors of p38? MAP kinase has been identified. Modifications designed to address the issues of poor aqueous solubility and high plasma protein binding as well as embedded aniline functionalities resulted in the identification of a clinical candidate N-cyclopropyl-4-methyl-3-[6-(4-methylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZD6703). Optimisation was guided by understanding of the binding modes from X-ray crystallographic studies which showed a switch from DFG ‘out’ to DFG ‘in’ as the inhibitor size was reduced to improve overall properties.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Guanghui Deng, Qinghua Meng, Qian Liu, Xuesong Xu, Qiongfeng Xu, Feng Ren, Taylor B. Guo, Hongtao Lu, Jia-Ning Xiang, John D. Elliott, Xichen Lin A novel series of benzoxazole-derived S1P1 agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P1 agonist (over S1P3) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Virginie Suchaud, Fabrice Bailly, Cédric Lion, Enzo Tramontano, Francesca Esposito, Angela Corona, Frauke Christ, Zeger Debyser, Philippe Cotelle We report herein the synthesis of a series of 3-hydroxyquinolin-2(1H)-one derivatives. Esters and amide groups were introduced at position 4 of the basis scaffold and some modulations of the benzenic moiety were performed. Most compounds presented selective inhibitory properties in the 10–20?M range against HIV-1 reverse transcriptase associated ribonuclease H activity, without affecting the integrase and reverse transcriptase DNA polymerase activities. Unfortunately all tested compounds exhibited high cellular cytotoxicity in cell culture which limited their applications as antiviral agents.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Ky-Youb Nam, Nam Song Choi, Cheol Kyu Han, Soon Kil Ahn Chalcones have an affinity for many receptors, enzymes, and transcription factors as flavonoid analogues. Their most studied pharmacological action is that of vasodilatation due to inhibition of phosphodiesterase 5A1 (PDE5A1). To this end, we have established a recursive partitioning model with 3 chemical descriptors for the prediction of compounds that can inhibit PDE5A1. This model was able to predict active compounds with an accuracy of 82.8%. Compound 4 was found to be a potent and selective inhibitor, with a relatively low IC50 value. The binding mechanism of this compound was also investigated through molecular docking studies.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Zhongyong Wei, Hua Yang, Ziping Liu, Maxime Tremblay, Shawn Johnstone, Sara Béha, Shi Yi Yue, Sanjay Srivastava, Miroslaw J. Tomaszewski, William Brown, Christopher Walpole, Stéphane St-Onge, Etienne Lessard, Anne-Julie Archambault, Thierry Groblewski, Daniel Pagé Cannabinoid CB1 receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB1/hCB2 dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Ana Bela Santana, Susana D. Lucas, Lídia M. Gonçalves, Henrique F. Correia, Teresa A.F. Cardote, Rita C. Guedes, Jim Iley, Rui Moreira The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Wen-Hua Chen, Jia Zhou, Yong-Min Wang Three tetrameric sterol–spermine conjugates were shown to be capable of mediating chloride transport across 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC)-based liposomal membranes via an anion-exchange mechanism. Of the three conjugates, the one that was derived from deoxycholic acid showed the highest activity. Such anion transporting properties may provide molecular basis for the antibacterial activities of these sterol–spermine tetramers. In other words, they function as antibiotics, most probably via the formation of anion-selective pores or channels.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Siyuan Li, Xianqiang Sun, Hongli Zhao, Yun Tang, Minbo Lan By using of structure-based virtual screening, 13 novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were discovered from 197,116 compounds in the SPECS database here. Among them, 8 compounds significantly inhibited EGFR kinase activity with IC50 values lower than 10?M. 3-{[1-(3-Chloro-4-fluorophenyl)-3,5-dioxo-4-pyrazolidinylidene]methyl}phenyl 2-thiophenecarboxylate (13), particularly, was the most potent inhibitor possessing the IC50 value of 3.5?M. The docking studies also provide some useful information that the docking models of the 13 compounds are beneficial to find a new path for designing novel EGFR inhibitors.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Rong Jiang, Xinyi Song, Purva Bali, Anthony Smith, Claudia Ruiz Bayona, Li Lin, Michael D. Cameron, Patricia H. McDonald, Paul J. Kenny, Theodore M. Kamenecka A series of orexin receptor antagonists was synthesized based on a substituted piperidine scaffold. Through traditional medicinal chemistry structure–activity relationships (SAR), installation of various groups at the 3–6-positions of the piperidine led to modest enhancement in receptor selectivity. Compounds were profiled in vivo for plasma and brain levels in order to identify candidates suitable for efficacy in a model of drug addiction.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Yan Li, Lianzhi Li, Xuewei Pu, Guolin Ma, Erqiong Wang, Jinming Kong, Zhipeng Liu, Yangzhong Liu A novel ratiometric fluorescent peptidyl chemosensor (Dansyl-Cys-Pro-Gly-Cys-Trp-NH2, D-P5) for metal ions detection has been synthesized via Fmoc solid-phase peptide synthesis. The chemosensor exhibited a high selectivity for Cd2+ over other metal ions including competitive transition and Group I and II metal ions in neutral pH. The fluorescence emission intensity of D-P5 was significantly enhanced in the presence of Cd2+ by fluorescent resonance energy transfer (FRET) and chelation enhanced fluorescence (CHEF) effects. The binding stoichiometry, detection limit, binding affinity, reversibility and pH sensitivity of the sensor for Cd2+ were investigated.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Jeffrey M. Axten, Jesús R. Medina, Charles W. Blackledge, Céline Duquenne, Seth W. Grant, Mark A. Bobko, Tony Peng, William H. Miller, Theresa Pinckney, Timothy F. Gallagher, Swarupa Kulkarni, Thomas Lewandowski, Glenn S. Van Aller, Rimma Zonis, Paris Ward, Nino Campobasso A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Angeline C.-H. Lee, Pondy Murugappan Ramanujulu, Anders Poulsen, Meredith Williams, Stéphanie Blanchard, Diana M. Ma, Zahid Bonday, Kay Lin Goh, Kee Chuan Goh, Miah Kiat Goh, Jeanette Wood, Brian W. Dymock Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 John G. Cumming, Justin F. Bower, David Waterson, Alan Faull, Philip J. Poyser, Paul Turner, Benjamin McDermott, Andrew D. Campbell, Julian Hudson, Michael James, Jon Winter, Christine Wood A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Jean-Yves Le Brazidec, Angela Pasis, Betty Tam, Christina Boykin, Deping Wang, Douglas J. Marcotte, Gisela Claassen, Jer-Hong Chong, Jianhua Chao, Junhua Fan, Khanh Nguyen, Laura Silvian, Leona Ling, Lin Zhang, Michael Choi, Min Teng, Nuzhat Pathan, Shuo Zhao, Tony Li, Art Taveras This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Mi-Sun Yu, June Lee, Jin Moo Lee, Younggyu Kim, Young-Won Chin, Jun-Goo Jee, Young-Sam Keum, Yong-Joo Jeong Severe acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there are no natural or synthetic compounds currently available that can inhibit SARS-CoV. We examined the inhibitory effects of 64 purified natural compounds against the activity of SARS helicase, nsP13, and the hepatitis C virus (HCV) helicase, NS3h, by conducting fluorescence resonance energy transfer (FRET)-based double-strand (ds) DNA unwinding assay or by using a colorimetry-based ATP hydrolysis assay. While none of the compounds, examined in our study inhibited the DNA unwinding activity or ATPase activity of human HCV helicase protein, we found that myricetin and scutellarein potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity, but not the unwinding activity, nsP13. In addition, we observed that myricetin and scutellarein did not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Our study demonstrates for the first time that selected naturally-occurring flavonoids, including myricetin and scultellarein might serve as SARS-CoV chemical inhibitors.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Jongkook Lee, Sun-Young Han, Heejung Jung, Jeon Yang, Jie-Won Choi, Chong Hack Chae, Chi Hoon Park, Sang Un Choi, Kwangho Lee, Jae Du Ha, Chong Ock Lee, Jae Wook Ryu, Hyoung Rae Kim, Jong Sung Koh, Sung Yun Cho A series of hydroxybenzoxazole derivatives was synthesized, and their c-Met kinase inhibitory activity was evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent benzoxazole scaffold, with particular focus on the hydroxyl substituent of the benzoxazole moiety.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Christopher W. Davies, Joseph Chaney, Gregory Korbel, Dagmar Ringe, Gregory A. Petsko, Hidde Ploegh, Chittaranjan Das UCHL1 is a 223 amino acid member of the UCH family of deubiquitinating enzymes (DUBs), found abundantly and exclusively expressed in neurons and the testis in normal tissues. Two naturally occurring variants of UCHL1 are directly involved in Parkinson’s disease (PD). Not only has UCHL1 been linked to PD, but it has oncogenic properties, having been found abnormally expressed in lung, pancreatic, and colorectal cancers. Although inhibitors of UCHL1 have been described previously the co-crystal structure of the enzyme bound to any inhibitor has not been reported. Herein, we report the X-ray structure of UCHL1 co-crystallized with a peptide-based fluoromethylketone inhibitor, Z-VAE(OMe)-FMK (VAEFMK) at 2.35Å resolution. The co-crystal structure reveals that the inhibitor binds in the active-site cleft, irreversibly modifying the active-site cysteine; however, the catalytic histidine is still misaligned as seen in the native structure, suggesting that the inhibitor binds to an inactive form of the enzyme. Our structure also reveals that the inhibitor approaches the active-site cleft from the opposite side of the crossover loop as compared to the direction of approach of ubiquitin’s C-terminal tail, thereby occupying the P1? (leaving group) site, a binding site perhaps used by the unknown C-terminal extension of ubiquitin in the actual in vivo substrate(s) of UCHL1. This structure provides a view of molecular contacts at the active-site cleft between the inhibitor and the enzyme as well as furnishing structural information needed to facilitate further design of inhibitors targeted to UCHL1 with high selectivity and potency.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Melissa C. Grenier, Robert W. Davis, Kelsey L. Wilson-Henjum, Jade E. LaDow, Jacob W. Black, Kevin L. Caran, Kyle Seifert, Kevin P.C. Minbiole Dialkyl 4,4?-bipyridinium compounds are widely employed for their useful redox properties, and are commonly known as viologens due to their intense coloration upon reduction. Despite their prevalence and amphiphilic nature, the antibacterial activity of these compounds remains largely unreported. We have thus prepared a series of mono- and bis-alkylated analogs of 4,4?-bipyridine to investigate structure–activity relationships in their inhibition of a battery of Gram positive and Gram negative bacteria. The prepared cationic compounds were conventional (one cationic head, one non-polar tail), bicephalic (two heads, one tail), or gemini (two heads, two tails) in their amphiphilic structure. Additionally, an isomeric series of six bis-alkylated compounds ranging from symmetric (PQ-11,11) to highly asymmetric (PQ-20,2) were prepared. Four themes of bioactivity emerged: (1) the most bioactive compounds were gemini in structure; (2) 22 carbons in the alkyl chains, with little to modest asymmetry, led to optimal activity; (3) bicephalic compounds were generally comparable to conventional amphiphiles, though only about 12 carbons in the alkyl chains were solubilized in water by each cationic nitrogen; (4) the effects of counterion identity were not evident between chlorides and bromides; however, the presence of the iodide counterion inhibited dissolution in all compounds tested. Three isomeric compounds with little to no asymmetry in tail length, PQ-11,11, PQ-12,10, and PQ-14,8, prepared as the bromide salts, showed comparable and highly potent activity, with MIC levels around 2?M against 3 of 4 bacteria tested. The simple (one- to two-step) syntheses of potent antimicrobials portend well for future optimization.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Christine Jespersen, Elisabetta Soragni, C. James Chou, Paramjit S. Arora, Peter B. Dervan, Joel M. Gottesfeld We have shown that a specific pyrrole–imidazole polyamide–DNA alkylator (chlorambucil) conjugate, 1R-Chl, alters the growth characteristics of various cancer cell lines in culture, and causes these cells to arrest in the G2/M stage of the cell cycle, without apparent cytotoxicity. This molecule has also shown efficacy in several mouse xenograft models, preventing tumor growth. Previous microarray studies have suggested that members of the histone H4 gene family, H4c and H4j/k, are the primary targets of this molecule, leading to reduced histone mRNA synthesis and growth arrest in cancer cells. In the present study, we examine the effects of 1R-Chl on transcription of other members of the H4 gene family, with the result that mRNA transcription of most genomic copies of H4 are down-regulated by 1R-Chl in a human pancreatic cancer cell line (MIA PaCa-2), but not in a cell line of non-cancerous origin (HEK293 cells). The basis for this differential effect is likely an open chromatin conformation within the H4 genes in cancer cells. Chromatin immunoprecipitation experiments show increased histone acetylation on the histone H4 genes in cancer cells, compared to HEK293 cells, explaining the differential activity of this molecule in cancer versus non-cancer cells.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Jiae Kim, Ligong Wang, Yongfeng Li, Kimberlynne D. Becnel, Kathleen M. Frey, Scott J. Garforth, Vinayaka R. Prasad, Raymond F. Schinazi, Dennis C. Liotta, Karen S. Anderson Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RTWT. The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RTWT. The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RTK65R. These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Vikrantsinh M. Gohil, Keyur G. Brahmbhatt, Philippe M. Loiseau, Kamlesh K. Bhutani ?-carbolines from various natural and synthetic sources have been known to show diverse biological activities. As a part of our current ongoing project to search for potent natural product-derived anti-leishmanial compounds, we have synthesized a series of substituted 1-aryl-?-carboline derivatives. A total of 22 compounds were synthesized and tested in vitro against Leishmania donovani, out of which 6 compounds (4, 5, 10, 11, 19 and 22) showed notably more activity than the standard miltefosine (IC50 12.07±0.82?M), with compound 4 being the most potent (IC50 2.16±0.26?M).
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Alan Talevi, Andrea V. Enrique, Luis E. Bruno-Blanch A virtual screening campaign based on application of a topological discriminant function capable of identifying novel anticonvulsant agents indicated several widely-used artificial sweeteners as potential anticonvulsant candidates. Acesulfame potassium, cyclamate and saccharin were tested in the Maximal Electroshock Seizure model (mice, ip), showing moderate anticonvulsant activity. We hypothesized a probable structural link between the receptor responsible of sweet taste and anticonvulsant molecular targets. Bioinformatic tools confirmed a highly significant sequence-similarity between taste-related protein T1R3 and several metabotropic glutamate receptors from different species, including glutamate receptors upregulated in epileptogenesis and certain types of epilepsy.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Gary E. Keck, Yam B. Poudel, Arnab Rudra, Jeffrey C. Stephens, Noemi Kedei, Nancy E. Lewin, Peter M. Blumberg The role of the C8gem-dimethyl group in the A-ring of bryostatin 1 has been examined through chemical synthesis and biological evaluation of a new analogue. Assays for biological function using U937, K562, and MV4-11 cells as well as the profiles for downregulation of PKC isozymes revealed that the presence of this group is not a critical determinant for the unique pattern of biological activity of bryostatin.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Nalin L. Subasinghe, Mark J. Wall, Michael P. Winters, Ning Qin, Mary Lou Lubin, Michael F.A. Finley, Michael R. Brandt, Michael P. Neeper, Craig R. Schneider, Raymond W. Colburn, Christopher M. Flores, Zhihua Sui Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ?-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Yu Kushida, Kenjiro Hanaoka, Toru Komatsu, Takuya Terai, Tasuku Ueno, Kengo Yoshida, Masanobu Uchiyama, Tetsuo Nagano We have developed a novel red fluorescent dye, 2Me SiR600 (?em=613nm), in which the O atom of Rhodamine Green at the 10 position of the xanthene moiety is replaced with a Si atom, as a scaffold for probes to detect protease activity with extremely high S/N ratio. As proof of concept, we designed and synthesized probes for caspase-3 activity (Z-DEVD-SiR600) and leucine aminopeptidase activity (Leu-SiR600). Caspase-3-mediated cleavage of Z-DEVD-SiR600 resulted in a large bathochromic shift (93nm) of the absorption maximum and a 432-fold fluorescence enhancement.
Publication year: 2012 Source:Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 12 Christiane M. Bode, Alessandro A. Boezio, Brian K. Albrecht, Steven F. Bellon, Loren Berry, Martin A. Broome, Deborah Choquette, Isabelle Dussault, Richard T. Lewis, Min-Hwa Jasmine Lin, Karen Rex, Douglas A. Whittington, Yajing Yang, Jean-Christophe Harmange Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.
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Posted on 27 May 2012 | 1:18 am
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