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The Journal of Thoracic and Cardiovascular Surgery
15 July 2018
Editorial Board
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13

15 July 2018
Computer-aided discovery and biological characterization of human lactate dehydrogenase 5 inhibitors with anti-osteosarcoma activity
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Wei Cao, Le Fang, Siyong Teng, Hongwei Chen, Zhan Wang Human lactate dehydrogenase 5 (hLDH5) is overexpressed in various tissues of human tumors, which could be a potential therapeutic target for cancer treatment. Herein, we describe the computer-aided discovery and biological characterizations of hLDH5 inhibitors with anti-osteosarcoma activity. Biochemical assay indicated that the identified compounds 3 and 9 strongly inhibited hLDH5 function with EC50 values of 0.67 and 0.39
15 July 2018
Synthesis of carbon-11-labeled CK1 inhibitors as new potential PET radiotracers for imaging of Alzheimer’s disease
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Mingzhang Gao, Min Wang, Qi-Huang Zheng The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4
15 July 2018
‘Tethering’ fragment-based drug discovery to identify inhibitors of the essential respiratory membrane protein type II NADH dehydrogenase
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Adam Heikal, Yoshio Nakatani, Wanting Jiao, Chris Wilson, David Rennison, Marion R. Weimar, Emily J. Parker, Margaret A. Brimble, Gregory M. Cook Energy generation is a promising area of drug discovery for both bacterial pathogens and parasites. Type II NADH dehydrogenase (NDH-2), a vital respiratory membrane protein, has attracted attention as a target for the development of new antitubercular and antimalarial agents. To date, however, no potent, specific inhibitors have been identified. Here, we performed a site-directed screening technique, tethering-fragment based drug discovery, against wild-type and mutant forms of NDH-2 containing engineered active-site cysteines. Inhibitory fragments displayed IC50 values between 3 and 110
15 July 2018
lH-Pyrazolo[3,4-b]quinolin-3-amine derivatives inhibit growth of colon cancer cells via apoptosis and sub G1 cell cycle arrest
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Chandrabose Karthikeyan, Haneen Amawi, Arabela Guedes Viana, Leticia Sanglard, Noor Hussein, Maria Saddler, Charles R. Ashby, N.S. Hari Narayana Moorthy, Piyush Trivedi, Amit K. Tiwari A series of lH-pyrazolo[3,4-b]quinolin-3-amine derivatives were synthesized and evaluated for anticancer efficacy in a panel of ten cancer cell lines, including breast (MDAMB-231 and MCF-7), colon (HCT-116, HCT-15, HT-29 and LOVO), prostate (DU-145 and PC3), brain (LN-229), ovarian (A2780), and human embryonic kidney (HEK293) cells, a non-cancerous cell line. Among the eight derivatives screened, compound QTZ05 had the most potent and selective antitumor efficacy in the four colon cancer cell lines, with IC50 values ranging from 2.3 to 10.2
15 July 2018
Benzofuro[3,2-d]pyrimidines inspired from cercosporamide CaPkc1 inhibitor: Synthesis and evaluation of fluconazole susceptibility restoration
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Viet Hung Dao, Isabelle Ourliac-Garnier, Marc-Antoine Bazin, Catherine Jacquot, Blandine Baratte, Sandrine Ruchaud, St
15 July 2018
Structural basis for the selective inhibition of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) by a selenium-containing inhibitor with chloro-aminopyridine as a basic group
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Toshimasa Itoh, Nobuko Yoshimoto, Yoshinari Hirano, Keiko Yamamoto Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) is a target molecule for treating thromboembolic disorders. We previously reported that design and synthesis of compound 1 containing a selenol group and chloloaminopyridine. Compound 1 showed high inhibitory activity towards TAFIa, with a high degree of selectivity for TAFIa over carboxypeptidase N (CPN). Here we report investigation of this selectivity. To obtain co-crystal of 1/pp-CPB (a surrogate of TAFIa), we synthesized protected compound 5 as a stabilized precursor of 1. The X-ray crystal structure and docking study indicated that the Cl substituent is accommodated in the pp-CPB specific pocket whereas CPN has no identical pocket. This is important information for the design of drugs targeting TAFIa with high selectivity.

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15 July 2018
Synthesis of C-ring-modified blebbistatin derivatives and evaluation of their myosin II ATPase inhibitory potency
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Bart I. Roman, Sigrid Verhasselt, Christophe W. Mangodt, Olivier De Wever, Christian V. Stevens (S)-Blebbistatin is a micromolar myosin II ATPase inhibitor that is extensively used in research. In search of analogs with improved potency, we have synthesized for the first time C-ring modified analogs. We introduced hydroxymethyl or allyloxymethyl functionalities in search of additional favorable interactions and a more optimal filling of the binding pocket. Unfortunately, the resulting compounds did not significantly inhibit the ATPase activity of rabbit skeletal-muscle myosin II. This and earlier reports suggest that rational design of potent myosin II inhibitors based on the architecture of the blebbistatin binding pocket is an ineffective strategy.

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15 July 2018
Hexahydrobenzophenanthridine alkaloids from Corydalis bungeana Turcz. and their anti-inflammatory activity
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Chang Gao, Yue Du, Xin Wang, Huikun Cao, Bin Lin, Youping Liu, Xin Di As part of a bioprospecting program aimed at the discovery of anti-inflammatory agents from the Corydalis bungeana Turcz. (C. bungeana), five new hexahydrobenzophenanthridine alkaloids, corycaline A-E (15), along with four known alkaloids, were isolated from the whole plant of C. bungeana. Their structures including absolute configurations were elucidated on the basis of extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. The inhibitory activities of the nine compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 mouse macrophage cells were determined; all tested compounds except 2 and 7 exhibited significant inhibitory effects with IC50 values in the range of 1.00–2.79
15 July 2018
Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17
15 July 2018
Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Shu Li, Gongming Li, Xiaohong Yang, Qian Meng, Shuo Yuan, Yun He, Dequn Sun Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC50
15 July 2018
Development of autotaxin inhibitors: A series of zinc binding triazoles
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Christopher G. Thomson, Darren Le Grand, Mark Dowling, Cara E. Brocklehurst, Colin Chinn, Lucy Elphick, Michael Faller, Mark Freeman, Vikki Furminger, Cornelia Gasser, Ahmed Hamadi, Elizabeth Hardaker, Victoria Head, Johan C. Hill, Diana I. Janus, David Pearce, Anne-Sophie Poulaud, Emily Stanley, Lilya Sviridenko A series of inhibitors of Autotaxin (ATX) has been developed using the binding mode of known inhibitor, PF-8380, as a template. Replacement of the benzoxazolone with a triazole zinc-binding motif reduced crystallinity and improved solubility relative to PF-8380. Modification of the linker region removed hERG activity and led to compound 12 – a selective, high affinity, orally-bioavailable inhibitor of ATX. Compound 12 concentration-dependently inhibits autotaxin and formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic experiments.

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15 July 2018
Isoxazole-tethered diarylheptanoid analogs: Discovery of a new drug-like PAR2 antagonist
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Debnath Bhuniya, Sandeep Bhosale, Satyanarayana B. Reddy, Sudharshan N. Reddy A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3-syn-diol and 1,3-anti-diol chemophoric moieties, e.g. 4ad and 5ac respectively, have been designed and synthesized starting from d-glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve™ as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca2+]i release assay, 4a and 5a, when tested at 30
15 July 2018
New TRAP1 and Hsp90 chaperone inhibitors with cationic components: Preliminary studies on mitochondrial targeting
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): R. Rondanin, G. Lettini, P. Oliva, R. Baruchello, C. Costantini, C. Trapella, D. Simoni, T. Bernardi, L. Sisinni, M. Pietrafesa, G. Ponterini, M.P. Costi, T. Vignudelli, R. Luciani, D.S. Matassa, F. Esposito, M. Landriscina TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.

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15 July 2018
Structure activity relationships of anthranilic acid-based compounds on cellular and in vivo mitogen activated protein kinase-5 signaling pathways
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Suravi Chakrabarty, Darlene A. Monlish, Mohit Gupta, Thomas D. Wright, Van T. Hoang, Mitchel Fedak, Ishveen Chopra, Patrick T. Flaherty, Jeffry Madura, Shankar Mannepelli, Matthew E. Burow, Jane E. Cavanaugh

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15 July 2018
Adamantyl thioureas as soluble epoxide hydrolase inhibitors
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Vladimir Burmistrov, Christophe Morisseau, Dmitry Pitushkin, Dmitry Karlov, Robert R. Fayzullin, Gennady M. Butov, Bruce D. Hammock A series of inhibitors of the soluble epoxide hydrolase (sEH) containing one or two thiourea groups has been developed. Inhibition potency of the described compounds ranges from 50
15 July 2018
Synthesis, characterization and cytotoxicity studies of 1,2,3-triazoles and 1,2,4-triazolo [1,5-a] pyrimidines in human breast cancer cells
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Maryam Gilandoust, Kachigere B. Harsha, Chakrabhavi Dhananjaya Mohan, Ainiah Rushdiana Raquib, Shobith Rangappa, Vijay Pandey, Peter E. Lobie, Basappa, Kanchugarakoppal S. Rangappa Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is essential for physiological functions of tissues and neovasculature. VEGFR signaling is associated with the progression of pathological angiogenesis in various types of malignancies, making it an attractive therapeutic target in cancer treatment. In the present work, we report the synthesis of 1,4-disubstituted 1,2,3-triazoles and 1,2,4-triazolo[1, 5-a]pyrimidine derivatives via copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and screened for their anticancer activity against MCF7 cells. We identified 1-(2
15 July 2018
Chemical space screening around Phe3 in opioid peptides: Modulating µ versus
15 July 2018
Structure-activity relationship of uridine-based nucleoside phosphoramidate prodrugs for inhibition of dengue virus RNA-dependent RNA polymerase
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Gang Wang, Siew Pheng Lim, Yen-Liang Chen, J
15 July 2018
Synthesis of novel hetero ring fused pyridine derivatives; Their anticancer activity, CoMFA and CoMSIA studies
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): G. Santhosh Kumar, Y. Poornachandra, Shravan Kumar Gunda, K. Ratnakar Reddy, Jaheer Mohmed, Kamal Shaik, C. Ganesh Kumar, B. Narsaiah A series of novel furo[2,3-b]pyridine-2-carboxamide 4ah/pyrido[3
15 July 2018
Pyrrolinone derivatives as a new class of P2X3 receptor antagonists. Part 1: Initial structure-activity relationship studies of a hit from a high throughput screening
Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13 Author(s): Hiroyuki Tobinaga, Takayuki Kameyama, Miho Oohara, Naotake Kobayashi, Masahide Ohdan, Natsuki Ishizuka, Masaharu Kume, Maki Tomari, Yoshikazu Tanaka, Fumiyo Takahashi, Haruki Kinoshita, Shinji Shimada, Shunji Shinohara, Hiroyuki Kai The P2X3 receptor is primarily expressed in the peripheral sensory nerves, and therefore, antagonists of this receptor may be useful for the treatment of chronic pain. Pyrrolinone derivatives have been identified as a novel class of P2X3 receptor antagonists. A lead structure with moderate activity was discovered through a high-throughput screening assay. A structure-activity study led to the discovery of several P2X3 receptor antagonists. Compound 34 showed potent and specific antagonistic activity and analgesic efficacy.

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15 July 2018
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Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13

15 July 2018
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Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13

1 July 2018
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Publication date: 15 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 13

1 July 2018
Editorial Board
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12

1 July 2018
1,2,3,4,6-Penta-O-galloyl-
1 July 2018
The discovery and preclinical evaluation of BMS-707035, a potent HIV-1 integrase strand transfer inhibitor
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): B. Narasimhulu Naidu, Michael A. Walker, Margaret E. Sorenson, Yasutsugu Ueda, John D. Matiskella, Timothy P. Connolly, Ira B. Dicker, Zeyu Lin, Sagarika Bollini, Brian J. Terry, Helen Higley, Ming Zheng, Dawn D. Parker, Dedong Wu, Stephen Adams, Mark R. Krystal, Nicholas A. Meanwell BMS-707035 is an HIV-1 integrase strand transfer inhibitor (INSTI) discovered by systematic optimization of N-methylpyrimidinone carboxamides guided by structure-activity relationships (SARs) and the single crystal X-ray structure of compound 10. It was rationalized that the unexpectedly advantageous profiles of N-methylpyrimidinone carboxamides with a saturated C2-substitutent may be due, in part, to the geometric relationship between the C2-substituent and the pyrimidinone core. The single crystal X-ray structure of 10 provided support for this reasoning and guided the design of a spirocyclic series 12 which led to discovery of the morpholino-fused pyrimidinone series 13. Several carboxamides derived from this bicyclic scaffold displayed improved antiviral activity and pharmacokinetic profiles when compared with corresponding spirocyclic analogs. Based on the excellent antiviral activity, preclinical profiles and acceptable in vitro and in vivo toxicity profiles, 13a (BMS-707035) was selected for advancement into phase I clinical trials.

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1 July 2018
Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Ning Li, Li-Jun Wang, Bo Jiang, Shu-Ju Guo, Xiang-Qian Li, Xue-Chun Chen, Jiao Luo, Chao Li, Yi Wang, Da-Yong Shi A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC50 values of 64.47
1 July 2018
A small diversity library of
1 July 2018
Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Matthew W. Martin, Jennifer Y. Lee, David R. Lancia, Pui Yee Ng, Bingsong Han, Jennifer R. Thomason, Maureen S. Lynes, C. Gary Marshall, Chiara Conti, Alan Collis, Monica Alvarez Morales, Kshama Doshi, Aleksandra Rudnitskaya, Lili Yao, Xiaozhang Zheng N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.

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1 July 2018
Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Yulong Xu, Xicheng Yang, Yiyi Chen, Hao Chen, Huijiao Sun, Wei Li, Qiong Xie, Linqian Yu, Liming Shao A series of structurally novel proteasome inhibitors 112 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50
1 July 2018
N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Achim Schlapbach, Laszlo Revesz, Carole Pissot Soldermann, Thomas Zoller, Catherine H. R
1 July 2018
Design and synthesis of a series of bioavailable fatty acid synthase (FASN) KR domain inhibitors for cancer therapy
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Tianbao Lu, Carsten Schubert, Maxwell D. Cummings, Gilles Bignan, Peter J. Connolly, Karine Smans, Donald Ludovici, Michael H. Parker, Christophe Meyer, Christian Rocaboy, Richard Alexander, Bruce Grasberger, Sabine De Breucker, Norbert Esser, Erwin Fraiponts, Ron Gilissen, Boudewijn Janssens, Danielle Peeters, Luc Van Nuffel, Peter Vermeulen, James Bischoff, Lieven Meerpoel We designed and synthesized a new series of fatty acid synthase (FASN) inhibitors with potential utility for the treatment of cancer. Extensive SAR studies led to highly active FASN inhibitors with good cellular activity and oral bioavailability, exemplified by compound 34. Compound 34 is a potent inhibitor of human FASN (IC50
1 July 2018
Synthesis and antiviral evaluation of novel peptidomimetics as norovirus protease inhibitors
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Franck Amblard, Shaoman Zhou, Peng Liu, Jack Yoon, Bryan Cox, Kendall Muzzarelli, Benjamin D. Kuiper, Ladislau C. Kovari, Raymond F. Schinazi A series of tripeptidyl transition state inhibitors with new P1 and warhead moieties were synthesized and evaluated in a GI-1 norovirus replicon system and against GII-4 and GI-1 norovirus proteases. Compound 19, containing a 6-membered ring at the P1 position and a reactive aldehyde warhead exhibited sub-micromolar replicon inhibition. Retaining the same peptidyl scaffold, several reactive warheads were tested for protease inhibition and norovirus replicon inhibition. Of the six that were synthesized and tested, compounds 42, 43, and 45 potently inhibited the protease in biochemical assay and GI-1 norovirus replicon in the nanomolar range.

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1 July 2018
Effective gene silencing activity of prodrug-type 2
1 July 2018
The discovery of VU0486846: steep SAR from a series of M1 PAMs based on a novel benzomorpholine core
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Jeanette L. Bertron, Hyekyung P. Cho, Pedro M. Garcia-Barrantes, Joseph D. Panarese, James M. Salovich, Kellie D. Nance, Darren W. Engers, Jerri M. Rook, Anna L. Blobaum, Colleen M. Niswender, Shaun R. Stauffer, P. Jeffrey Conn, Craig W. Lindsley This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).

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1 July 2018
Design, synthesis and evaluation of photoactivatable derivatives of microtubule (MT)-active [1,2,4]triazolo[1,5-a]pyrimidines
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Killian Oukoloff, Jane Kovalevich, Anne-Sophie Cornec, Yuemang Yao, Zachary A. Owyang, Michael James, John Q. Trojanowski, Virginia M.-Y. Lee, Amos B. Smith, Kurt R. Brunden, Carlo Ballatore The [1,2,4]triazolo[1,5-a]pyrimidines comprise a promising class of non-naturally occurring microtubule (MT)-active compounds. Prior studies revealed that different triazolopyrimidine substitutions can yield molecules that either promote MT stabilization or disrupt MT integrity. These differences can have important ramifications in the therapeutic applications of triazolopyrimidines and suggest that different analogues may exhibit different binding modes within the same site or possibly interact with tubulin/MTs at alternative binding sites. To help discern these possibilities, a series of photoactivatable triazolopyrimidine congeners was designed, synthesized and evaluated in cellular assays with the goal of identifying candidate probes for photoaffinity labeling experiments. These studies led to the identification of different derivatives that incorporate a diazirine ring in the amine substituent at position 7 of the triazolopyrimidine heterocycle, resulting in molecules that either promote stabilization of MTs or disrupt MT integrity. These photoactivatable candidate probes hold promise to investigate the mode of action of MT-active triazolopyrimidines.

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1 July 2018
In vitro activity of salicylamide derivatives against vancomycin-resistant enterococci
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Sarka Pospisilova, Hana Michnova, Tereza Kauerova, Karel Pauk, Peter Kollar, Jarmila Vinsova, Ales Imramovsky, Alois Cizek, Josef Jampilek A series of 13 salicylamide derivatives was assessed for antibacterial activity against three isolates of vancomycin-resistant Enterococcus faecalis (VRE) and Enterococcus faecalis ATCC 29212 as a quality standard. The minimum inhibitory concentration was determined by the broth microdilution method with subsequent subcultivation of aliquots to assess minimum bactericidal concentration. The growth kinetics was established by the time-kill assay. Ampicillin, ciprofloxacin, tetracycline and vancomycin were used as the reference antibacterial drugs. Three of the investigated compounds showed strong bacteriostatic activity against VRE (0.199–25
1 July 2018
Insight into the recognition mechanism of DNA cytosine-5 methyltransferases (DNMTs) by incorporation of acyclic 5-fluorocytosine (FC) nucleosides into DNA
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Shohei Utsumi, Kousuke Sato, Satoshi Ichikawa DNA cytosine-5 methyltransferase (DNMT) catalyzes methylation at the C5 position of cytosine in the CpG sequence in double stranded DNA to give 5-methylCpG (mCpG) in the epigenetic regulation step in human cells. The entire reaction mechanism of DNMT is divided into six steps, which are scanning, recognition, flipping, loop locking, methylation, and releasing. The methylation and releasing mechanism are well-investigated; however, few reports are known about other reaction steps. To obtain insight into the reaction mechanism, we planned the incorporation of acyclic nucleosides, which make it easy to flip out the target nucleobase, into oligodeoxynucleotides (ODNs) and investigated the interaction between the ODN and DNMT. Here, we describe the design and synthesis of ODNs containing new acyclic 5-fluorocytosine nucleosides and their physiological and biological properties, including their interactions with DNMT. We found that the ODNs containing the acyclic 5-fluorocytosine nucleoside showed higher flexibility than those that contain 5-fluoro-2
1 July 2018
Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Siem Jakob Veenstra, Heinrich Rueeger, Markus Voegtle, Rainer Lueoend, Philipp Holzer, Konstanze Hurth, Marina Tintelnot-Blomley, Mathias Frederiksen, Jean-Michel Rondeau, Laura Jacobson, Matthias Staufenbiel, Ulf Neumann, Rainer Machauer New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing A
1 July 2018
Synthesis and biological evaluation of 6-hydroxyl C-aryl glucoside derivatives as novel sodium glucose co-transporter 2 (SGLT2) inhibitors
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Xiaoyu Zhao, Bin Sun, Hongbo Zheng, Jun Liu, Lilin Qian, Xiaoning Wang, Hongxiang Lou The sodium glucose co-transporter 2 (SGLT2) was considered as an important target for the treatment of type 2 diabetes mellitus in recent years. This report describes the design and synthesis of a series of novel SGLT2 inhibitors (11a17a) as well as their dehydrate dihydrofuran derivatives (11b17b), which were prepared by Mitsunobu reaction. Their SGLT2 inhibitory activity was also evaluated, and 16a and 17a were found to be the most potent compounds with IC50 values of 0.63 and 0.81
1 July 2018
Kakeromamide A, a new cyclic pentapeptide inducing astrocyte differentiation isolated from the marine cyanobacterium Moorea bouillonii
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Fumiaki Nakamura, Hiroshi Maejima, Midori Kawamura, Daisuke Arai, Tatsufumi Okino, Meng Zhao, Tao Ye, Jungyeol Lee, Young-Tae Chang, Nobuhiro Fusetani, Yoichi Nakao Kakeromamide A (1), a new cyclic pentapeptide encompassing a thiazole ring moiety and a
1 July 2018
Anti-allergic inflammatory components from Sanguisorba officinalis L.
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Xiang Dong Su, Rui Hong Guo, Hong Xu Li, Jin Yeul Ma, Young Ran Kim, Young Ho Kim, Seo Young Yang Sanguisorba officinalis L. was well known as a traditional herbal medicine to treat inflammation and allergic skin diseases. The aim of this research was to indentify compounds with anti-allergic inflammatory property. Twenty-five compounds (125) were isolated from S. officinalis including two new compounds (1 and 8), and their chemical structures were identified by NMR and ESIMS analysis. Consequently, the anti-allergic inflammatory activities of these isolates were investigated by inhibiting
1 July 2018
Valproic acid induces three novel cytotoxic secondary metabolites in Diaporthe sp., an endophytic fungus from Datura inoxia Mill.
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Vishal Sharma, Venugopal Singamaneni, Nisha Sharma, Amit Kumar, Divya Arora, Manoj Kushwaha, Shashi Bhushan, Sundeep Jaglan, Prasoon Gupta Addition of the valproic acid (histone deacetylases inhibitor) to a culture of an endophytic fungus Diaporthe sp. harbored from Datura inoxia significantly altered its secondary metabolic profile and resulted in the isolation of three novel compounds, identified as xylarolide A (1), diportharine A (2) and xylarolide B (3) along with one known compound xylarolide (4). The structures of all the compounds (14) were determined by detailed analysis of 1D and 2D NMR spectroscopic data. The relative configurations of compounds 13 were determined with the help of NOESY data and comparison of optical rotations with similar compounds with established stereochemistry. All the isolated compounds were screened for antibacterial, antioxidant and cytotoxic activities. Xylarolide A (1) and xylarolide (4) displayed significant growth inhibition of MIAPaCa-2 with an IC50 of 20 and 32
1 July 2018
Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6)
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Keisuke Motoyama, Tsutomu Nagata, Jun Kobayashi, Akifumi Nakamura, Naoki Miyoshi, Miho Kazui, Ken Sakurai, Tomoko Sakakura In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11
1 July 2018
Corrigendum to “Design, solvent free synthesis, and antimicrobial evaluation of 1,4 dihydropyridines” [Bioorg. Med. Chem. Lett. 22 (2012) 6016–6023]
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12 Author(s): Rajack Abdul, Taraka Ramji Moturu, J. Jeson babu, K. Aruna Lakshmi
1 July 2018
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Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12

1 July 2018
Graphical abstract TOC
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12

Available online 19 June 2018
Graphical abstract TOC
Publication date: 1 July 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 12


ROCK Inhibitors 3: Design, Synthesis and Structure-Activity Relationships of 7-Azaindole-Based Rho kinase (ROCK) Inhibitors
Publication date: Available online 19 June 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Upul K. Bandarage, Jingrong Cao, Jon H. Come, John J. Court, Huai Gao, Marc D. Jacobs, Craig Marhefka, Suganthi Nanthakumar, Jeremy Green Rho kinase (ROCK) inhibitors are potential therapeutic agents for the treatment of a variety of disorders including hypertension, glaucoma and erectile dysfunction. Here we disclose a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Substitution of the 3-position of 7-azaindole led to compounds such as 37, which possess excellent ROCK inhibitory potency and high selectivity against the closely related kinase PKA.

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