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Journal of Medicinal Chemistry

Fatemeh Mazraati Tajabadi, Rebecca H Pouwer, Miaomiao Liu, Yousef Dashti, Marc Campitelli, Mariyam Murtaza, George D Mellick, Stephen A Wood, Ian D Jenkins, Ronald J Quinn
A chemoinformatic method was developed to extract non-flat scaffolds embedded in natural products within the Dictionary of Natural Products. The cedrane scaffold was then chosen as an example of a non-flat scaffold that directs substituents in 3D space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D and 3D libraries was synthesised on a large-scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved...
July 13, 2018: Journal of Medicinal Chemistry
Clarissa G Jakob, Anup K Upadhyay, Pamela L Donner, Emily Nicholl, Sadiya N Addo, Wei Qiu, Christopher Ling, Sujatha M Gopalakrishnan, Maricel Torrent, Steven P Cepa, Jason Shanley, Alexander R Shoemaker, Chaohong C Sun, Anil Vasudevan, Kevin R Woller, J Brad Shotwell, Bailin Shaw, Zhiguo Bian, Jessica E Hutti
IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive ,-unsaturated enone 1 makes a unique covalent linkage through active site H315...
July 13, 2018: Journal of Medicinal Chemistry
Osamu Tani, Yukie Akutsu, Shinji Ito, Takayuki Suzuki, Yukihiro Tateishi, Tomohiko Yamaguchi, Tatsuya Niimi, Ichiji Namatame, Yasunori Chiba, Hitoshi Sakashita, Tomomi Kubota, Tetsuo Yanagi, Shusaku Mizukami, Kenji Hirayama, Koji Furukawa, Kazuhiko Yamasaki
No abstract text is available yet for this article.
July 13, 2018: Journal of Medicinal Chemistry
Diana Lamaa, Hsin-Ping Lin, Lena Zig, Cyril Bauvais, Guillaume Bollot, Jérôme Bignon, Helene Levaique, Olivier Pamlard, Joëlle Dubois, Mehdi Ouaissi, Martin Souce, Athena Kasselouri, François Saller, Delphine Borgel, Chantal Jayat-Vignoles, Hazar Al-Mouhammad, Jean Feuillard, Karim Benihoud, Mouad Alami, Abdallah Hamze
Designing multi-target drugs has raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes (isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity...
July 13, 2018: Journal of Medicinal Chemistry
Shiv K Sharma, Christopher Yip, Emilio Xavier Esposito, Prateek V Sharma, Matthew P Simon, Ernesto Abel-Santos, Steven M Firestine
Clostridium difficile infections (CDI), particularly those caused by the BI/NAP1/027 epidemic strains, are challenging to treat. One method to address this disease is to prevent the development of CDI by inhibiting the germination of C. difficile spores. Previous studies have identified cholic amide m-sulfonic acid, CamSA, as an inhibitor of spore germination. However, CamSA is inactive against the hypervirulent strain R20291. To circumvent this problem, a series of cholic acid amides were synthesized and tested against R20291...
July 13, 2018: Journal of Medicinal Chemistry
Bahaa El-Dien M El-Gendy, Shaimaa Goher, Lamees Hegazy, Mohamed M H Arief, Thomas P Burris
Nuclear hormone receptors represent a large family of ligand-activated transcription factors that include steroid receptors, thyroid/retinoid receptors, and orphan receptors. Among nuclear hormone receptors, the liver X receptors have emerged as very important drug targets. These receptors regulate some of the most important metabolic functions, and they were also identified as anti-inflammatory transcription factors and regulators of the immune system. The development of drugs targeting liver X receptors continues to be a challenge, but advances in our knowledge of receptor structure and function move us forward, toward achieving this goal...
July 13, 2018: Journal of Medicinal Chemistry
Fadi Soukarieh, Paul Williams, Michael John Stocks, Miguel Camara
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multi-drug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to co-ordinate virulence gene expression, is a potential target that has been intensively investigated over the last decade...
July 12, 2018: Journal of Medicinal Chemistry
Zhongping Huang, Russell B Williams, Steven M Martin, Julie A Lawrence, Vanessa L Norman, Mark O'Neil-Johnson, Jim Harding, John E Mangette, Shuang Liu, Peter Guzzo, Courtney M Starks, Gary R Eldridge
Bifidenone is a novel natural tubulin polymerization inhibitor that exhibits antiproliferative activity against a range of human cancer cell lines, making it an attractive candidate for development. A synthetic route was previously developed to alleviate supply constraints arising from its isolation in microgram quantities from a Gabonese tree. Using that previously published route, we present here 42 analogues that were synthesized to examine the structure-activity relationship of bifidenone derivatives. In addition to in vitro cytotoxicity data, data from murine xenograft and pharmacokinetic studies were used to evaluate the analogues...
July 11, 2018: Journal of Medicinal Chemistry
Travis T Denton, Pramod Srivastava, Zuping Xia, Gang Chen, Christy Watson, Alec Wynd, Philip Lazarus
Cigarette smoking causes nearly one in every five deaths in the United States. The development of a specific inhibitor of cytochrome P450 2A6 (CYP2A6), the major nicotine-metabolizing enzyme in humans, which could be prescribed for the cessation of cigarette smoking, has been undertaken. To further refine the structure activity relationship of CYP2A6, previously synthesized 3-alkynyl and 3-heteroaromatic substituted pyridine methanamines were used as lead compounds. Isosteric pyridine replacement and appendage of all available positions around the pyridine ring with a methyl group was performed to identify a modification that would increase CYP2A6 inhibition potency which led to 4g (IC50 = 0...
July 11, 2018: Journal of Medicinal Chemistry
Ryo Iwamura, Masayuki Tanaka, Eiji Okanari, Tomoko Kirihara, Noriko Odani-Kawabata, Naveed Shams, Kenji Yoneda
EP2 receptor agonists are expected to be effective ocular hypotensive agents; however, it has been suggested that agonism to other EP receptor subtypes may lead to undesirable effects. Through medicinal chemistry efforts, we identified a scaffold bearing a (pyridin-2-ylamino)acetic acid moiety as a promising EP2-selective receptor agonist. (6-((4-(Pyrazol-1-yl)benzyl)(pyridin-3-ylsulfonyl)aminomethyl)pyridin-2-ylamino)acetic acid 13ax (omidenepag, OMD) exerted potent and selective activity toward the human EP2 receptor (h-EP2)...
July 11, 2018: Journal of Medicinal Chemistry
Tengfei Bian, Kavitha Chandagirikoppal Vijendra, Yi Wang, Amy Meacham, Santanu Hati, Christopher Cogle, Haifeng Sun, Chengguo Xing
Multiple drug resistance (MDR) is one major barrier in cancer management, urging for new drugs to help treat MDR malignancies and elucidate MDR mechanisms. A series of chromene compounds (CXL series) demonstrate increased anti-proliferative activity towards MDR acute myeloid leukemia (AML) cells. Structure-activity relationship (SAR) on anti-proliferative potency has been partly characterized while the structural determinants contributing to its selectivity have not been investigated. In this study, three series of CXL compounds were synthesized and evaluated in HL60 and HL60/MX2 leukemia cells...
July 11, 2018: Journal of Medicinal Chemistry
Yuta Naro, Nicholas Ankenbruck, Meryl Thomas, Yaniv Tivon, Colleen M Connelly, Laura Gardner, Alexander Deiters
Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure-activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines...
July 11, 2018: Journal of Medicinal Chemistry
Jason R Abbott, Timothy R Hodges, R Nathan Daniels, Pratiq A Patel, J Phillip Kennedy, Jennifer E Howes, Denis T Akan, Michael C Burns, Jiqing Sai, Tammy Sobolik, Yugandhar Beesetty, Taekyu Lee, Olivia W Rossanese, Jason Phan, Alex G Waterson, Stephen W Fesik
Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds...
July 11, 2018: Journal of Medicinal Chemistry
David Carcache, Anna Vulpetti, Joerg Kallen, Henri Mattes, David Orain, Rowan Stringer, Eric Vangrevelinghe, Romain M Wolf, Klemens Kaupmann, Johannes Ottl, Janet Dawson King, Nigel G Cooke, Klemens Hoegenauer, Andreas Billich, Juergen Wagner, Christine Guntermann, Samuel Hintermann
The transcription factor RORγt is an attractive drug-target due to its role in the differentiation of IL-17 producing Th17 cells that play a critical role in the etiopathology of several autoimmune diseases. Identification of starting points for RORγt inverse agonists with good properties has been a challenge. We report the identification of a fragment hit and its conversion into a potent inverse agonist through fragment optimization, growing and merging efforts. Further analysis of the binding mode revealed that inverse agonism was achieved by an unusual mechanism...
July 10, 2018: Journal of Medicinal Chemistry
Dahlia R Weiss, Joel Karpiak, Xi-Ping Huang, Maria Flori Sassano, Jiankun Lyu, Bryan L Roth, Brian K Shoichet
To investigate large library docking's ability to find molecules with joint activity against on-targets, and selectivity versus anti-targets, the dopamine D2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H1 receptor. In a second campaign, -opioid receptor ligands were sought with selectivity versus the -opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the anti-targets, even though the molecules were selected for their putative lack of binding to the off-targets...
July 10, 2018: Journal of Medicinal Chemistry
Francesca Gado, Lorenzo Di Cesare Mannelli, Elena Lucarini, Simone Bertini, Elena Cappelli, Maria Digiacomo, Lesley A Stevenson, Marco Macchia, Tiziano Tuccinardi, Carla Ghelardini, Roger G Pertwee, Clementina Manera
The direct activation of cannabinoid receptors (CBRs) results in several beneficial effects, therefore numerous CB1 R and CB2 R ligands have been developed and tested in vitro and in vivo, but none of them reached an advanced stage of clinical development due to several side effects in particular on the CNS. Medicinal chemistry approaches are now engaged to develop allosteric modulators that might offer a novel therapeutic approach to achieve potential therapeutic benefits avoiding inherent side effects of orthosteric ligands...
July 10, 2018: Journal of Medicinal Chemistry
Jinghua Li, Runguo Tian, Chaochao Ge, Ying Chen, Xiaodan Liu, Yuxia Wang, Yacheng Yang, Wen Luo, Fujun Dai, Senzhen Wang, Shuai Chen, Songqiang Xie, Chaojie Wang
Polyamine derivatives have a promising prospect in dealing with disseminated tumor cells, a major obstacle in cancer therapy. To develop a bifunctional polyamine derivative which can serve as a fluorescent probe and an antimetastatic agent, three kinds of polyamine conjugates with benzo[cd]indol-2(1H)-one as a scaffold were designed and synthesized. Compound 5e was selected as a lead by in vitro screening. Two animal models demonstrated that 5e inhibited pulmonary metastasis and tumor growth. As a fluorescent probe, 5e might partially enter cells via a polyamine transporter and subsequently localize in the lysosome...
July 10, 2018: Journal of Medicinal Chemistry
Rocio Otero, Michiyasu Ishizawa, Nobutaka Numoto, Teikichi Ikura, Nobutoshi Ito, Hiroaki Tokiwa, Antonio Mouriño, Makoto Makishima, Sachiko Yamada
Both 25 R- and 25 S-25-adamantyl-23-yne-26,27-dinor-1α,25-dihydroxyvitamin D3 (4a and 4b) were stereoselectively synthesized by a Pd(0)-catalyzed ring closure and Suzuki-Miyaura coupling between enol-triflate 7 and alkenyl-boronic ester 8. The 25 S isomer (4b) showed high vitamin D receptor (VDR) affinity (50% of that of the natural hormone 1α,25-dihydroxyvitamin D3 , 1) and transactivation potency (kidney HEK293, 90%). In endogenous gene expression, it showed high cell-type selectivity for kidney cells (HEK293, CYP24A1 160% of 1), bone cells (MG63, osteocalcin 64%) and monocytes (U937, CAMP 96%) over intestine (SW480, CYP24A1 8%) and skin (HaCaT, CYP24A1 7%) cells...
July 10, 2018: Journal of Medicinal Chemistry
Sonali S Bharate, Serge Mignani, Ram A Vishwakarma
Small molecule natural products (NPs) have a long and successful track record of providing first-in-class drugs and pharmacophore (scaffolds) in all therapeutic areas, serving as a bridge between modern and traditional medicine. This trajectory has been remarkably successful in three key areas of modern therapeutics: cancers, infections and CNS diseases. Beginning with the discovery of morphine 200 years ago, natural products have remained primary source of new drugs/scaffolds for CNS diseases. In this perspective, we address the question; why are majority of active compounds in the CNS domain natural products? Our analysis indicates that ~84% approved drugs for CNS diseases are NPs or NP-inspired, and interestingly, 20 natural products provided more than 400 FDA approved CNS drugs...
July 10, 2018: Journal of Medicinal Chemistry
Sandra Karch, Johannes Broichhagen, Julia Schneider, Daniel Böning, Stephanie Hartmann, Benjamin Schmid, Philipp Tripal, Ralf Palmisano, Christian Alzheimer, Kai Johnsson, Tobias Huth
β-site APP-cleaving enzyme 1 (BACE1) is a major player in the pathogenesis of Alzheimer's disease. Structural and functional fluorescence microscopy offers a powerful approach to learn about the physiology and pathophysiology of this protease. Up to now, however, common labeling techniques require genetic manipulation, use large antibodies, or are not compatible with live cell imaging. Fluorescent small molecules that specifically bind to the protein of interest can overcome these limitations. Herein, we introduce SiR-BACE1, a conjugate of the BACE1 inhibitor S-39 and SiR647, as a novel fluorogenic, tag-free, and antibody-free label for BACE1...
July 10, 2018: Journal of Medicinal Chemistry
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