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Bioorganic & Medicinal Chemistry

Qin Wang, Katherine J Franz
BSIH ((E)-N'-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)isonicotinohydrazide) is a prodrug version of the metal chelator SIH ((E)-N'-(2-hydroxybenzylidene)isonicotinohydrazide) in which a boronate group prevents metal chelation until reaction with hydrogen peroxide releases SIH, which is then available for sequestering iron(III) and inhibiting iron-catalyzed oxidative damage. While BSIH has shown promise for conditionally targeting iron sequestration in cells under oxidative stress, the yield of SIH is limited by the fact that BSIH exists in cell culture media as an equilibrium mixture with its hydrolysis products isoniazid and 2-formylphenyl boronic acid...
November 5, 2018: Bioorganic & Medicinal Chemistry
Xuehua Zheng, Zan Jiang, Xiaolin Li, Chen Zhang, Zhe Li, Yinuo Wu, Xinhua Wang, Chao Zhang, Hai-Bin Luo, Jun Xu, Deyan Wu
AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 μM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions...
November 3, 2018: Bioorganic & Medicinal Chemistry
Liming Chang, Mengwu Xiao, Linlin Yang, Shuai Wang, Sai-Qi Wang, Andreas Bender, Aixi Hu, Zhe-Sheng Chen, Bin Yu, Hong-Min Liu
Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance...
November 3, 2018: Bioorganic & Medicinal Chemistry
Steven P Tanis, Jerry R Colca, Timothy T Parker, Gerald D Artman, Scott D Larsen, William G McDonald, Robert C Gadwood, Rolf F Kletzien, James B Zeller, Pil H Lee, Wade J Adams
No abstract text is available yet for this article.
November 2, 2018: Bioorganic & Medicinal Chemistry
Jinming Guan, Leanne Barnard, Jeanne Cresson, Annabelle Hoegl, Justin H Chang, Erick Strauss, Karine Auclair
Pantothenate kinase (PanK) catalyzes the transformation of pantothenate to 4'-phosphopantothenate, the first committed step in coenzyme A biosynthesis. While numerous pantothenate antimetabolites and PanK inhibitors have been reported for bacterial type I and type II PanKs, only a few weak inhibitors are known for bacterial type III PanK enzymes. Here, a series of pantothenate analogues were synthesized using convenient synthetic methodology. The compounds were exploited as small organic probes to compare the ligand preferences of the three different types of bacterial PanK...
November 2, 2018: Bioorganic & Medicinal Chemistry
Rosimeire Borges Moreira Lacerda, Thamires Rodrigues Freitas, Mário Machado Martins, Thaise Lara Teixeira, Cláudio Vieira da Silva, Pamela Aparecida Candido, Ronaldo Junio de Oliveira, Claudio Viegas Júnior, Vanderlan da Silva Bolzani, Amanda Danuello, Marcos Pivatto
Leishmaniasis is one of the most important neglected tropical diseases (NTDs) that are especially common among low-income populations in developing regions of Africa, Asia, and the Americas. Many natural products, particularly alkaloids, have been reported to have inhibitory activity against arginase, the key enzyme in the pathology caused by Leishmania sp. In this way, piperidine alkaloids (-)-cassine (1), (-)-spectaline (2), (-)-3-O-acetylcassine (3), and (-)-3-O-acetylspectaline (4) were isolated from Senna spectabilis flowers...
November 2, 2018: Bioorganic & Medicinal Chemistry
Elisabetta Barresi, Chiara Giacomelli, Simona Daniele, Ilaria Tonazzini, Marco Robello, Silvia Salerno, Ilaria Piano, Barbara Cosimelli, Giovanni Greco, Federico Da Settimo, Claudia Martini, Maria Letizia Trincavelli, Sabrina Taliani
The expression levels and the subcellular localization of adenosine receptors (ARs) are affected in several pathological conditions as a consequence of changes in adenosine release and metabolism. In this respect, labelled probes able to monitor the AR expression could be a useful tool to investigate different pathological conditions. Herein, novel ligands for ARs, bearing the fluorescent 7-nitrobenzofurazan (NBD) group linked to the N1 (1,2) or N10 (3,4) nitrogen of a triazinobenzimidazole scaffold, were synthesized...
November 1, 2018: Bioorganic & Medicinal Chemistry
Gang Xing, Li Pan, Ce Yi, Xiaoran Li, Xinyue Ge, Ying Zhao, Yichuang Liu, Jinyan Li, Anthony Woo, Bin Lin, Yuyang Zhang, Maosheng Cheng
A series of novel β2 -adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β2 -adrenoceptor agonistic effects and high β2 /β1 -selectivity with EC50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation...
November 1, 2018: Bioorganic & Medicinal Chemistry
Taiki Itoh, Kei Tamura, Hiroki Ueda, Tomohiro Tanaka, Kyouhei Sato, Reiko Kuroda, Shin Aoki
Boron neutron capture therapy (BNCT) is one of the radiotherapies that involves the use of boron-containing compounds for the treatment of cancer. Boron-10 (10 B) containing compounds that can accumulate in tumor tissue are expected to be suitable agents for BNCT. We report herein on the design and synthesis of some new BNCT agents based on a d-glucose scaffold, since glycoconjugation has been recognized as a useful strategy for the specific targeting of tumors. To introduce a boryl group into a d-glucose scaffold, we focused on the hydroboration of d-glucal derivatives, which have a double bond between the C1 and C2 positions...
October 30, 2018: Bioorganic & Medicinal Chemistry
Koji Matsuoka, Kiyotaka Nishikawa, Yusuke Goshu, Tetsuo Koyama, Ken Hatano, Takahiko Matsushita, Miho Watanabe-Takahashi, Yasuhiro Natori, Daiyo Terunuma
Synthetic assembly of sugar moieties and amino acids in order to create "sugar-amino acid hybrid polymers" was accomplished by means of simple radical polymerization of carbohydrate monomers having an amino acid-modified polymerizable aglycon. Amines derived from globotriaoside and lactoside as glycoepitopes were condensed with known carbobenzyloxy derivatives, including Z-Gly, Z-l-Ala and Z-β-Ala, which had appropriate spacer ability and a chiral center to afford fully protected sugar-amino acid hybrid compounds in good yields...
October 30, 2018: Bioorganic & Medicinal Chemistry
Rawny Galdino Gouveia, Amélia Galdino Ribeiro, Miguel Ângelo Santos Pinheiro Segundo, Jamerson Ferreira de Oliveira, Maria do Carmo Alves de Lima, Túlio Ricardo Couto de Lima Souza, Sinara Mônica Vitalino de Almeida, Ricardo Olímpio de Moura
Nine new spiroacridine derivatives were synthetized by introducing cyano-N-acylhydrazone group between the acridine and phenyl-substituted rings followed by spontaneous cyclization. The new compounds were assayed for their DNA binding properties, human topoisomerase IIα inhibition and bovine serum albumin (BSA) interaction. Besides, docking analysis were performed in order to better understanding the biomolecule-compounds interactions. All compounds interacted with BSA which was demonstrated by the fluorescence suppression constant of 104  M-1 ...
October 29, 2018: Bioorganic & Medicinal Chemistry
Changxing Qi, Weixi Gao, Danyingzi Guan, Jianping Wang, Mengting Liu, Chunmei Chen, Hucheng Zhu, Yuan Zhou, Yongji Lai, Zhengxi Hu, Qun Zhou, Yonghui Zhang
Chemical study on the extract of a marine-derived fungus Aspergillus terreus yielded twelve butenolide derivatives, including three new compounds, namely asperlides A-C (1-3) and nine known butenolides (4-12). The structures of 1-3 were confirmed by comprehensive spectroscopic analysis, including HRESIMS, NMR spectroscopy, and calculated electronic circular dichroism (ECD). The cytotoxicity of the compounds was evaluated using PANC-1, HCC1806, HepG2, BEAS-2B and HT-29 cancer cells. The results showed that (+)-3',3'-di-(dimethylallyl)-butyrolactone II (4) and versicolactone B (6) exhibited the most potent cytotoxin of PANC-1 cell line, with the IC50 values of 5...
October 29, 2018: Bioorganic & Medicinal Chemistry
Claudia Carpentier, Xavier Barbeau, Jabrane Azelmat, Katy Vaillancourt, Daniel Grenier, Patrick Lagüe, Normand Voyer
Herein we report the anti-inflammatory activity of lobaric acid and pseudodepsidones isolated from the nordic lichen Stereocaulon paschale. Lobaric acid (1) and three compounds (2, 7 and 9) were found to inhibit the NF-κB activation and the secretion of pro-inflammatory cytokines (IL-1β and TNF-α) in LPS-stimulated macrophages. Inhibition and docking simulation experiments provided evidence that lobaric acid and pseudodepsidones bind to PPAR-γ between helix H3 and the beta sheet, similarly to partial PPAR-γ agonists...
October 28, 2018: Bioorganic & Medicinal Chemistry
Qingqing Zhou, Tristan A Reekie, Ramzi H Abbassi, Dinesh Indurthi Venkata, Josep S Font, Renae M Ryan, Lenka Munoz, Michael Kassiou
Dual-specificity tyrosine phosphorylation-related kinase 1A (DYRK1A) is a dual-specificity protein kinase that catalyses phosphorylation and autophosphorylation. Higher DYRK1A expression correlates with cancer, in particular glioblastoma present within the brain. We report here the synthesis and biological evaluation of new heterocyclic diphenolic derivatives designed as novel DYRK1A inhibitors. The generation of these heterocycles such as benzimidazole, imidazole, naphthyridine, pyrazole-pyridines, bipyridine, and triazolopyrazines was made based on the structural modification of the lead DANDY and tested for their ability to inhibit DYRK1A...
October 28, 2018: Bioorganic & Medicinal Chemistry
Roman S Pavelyev, Oksana V Bondar, Thi N T Nguyen, Alisa A Ziganshina, Mohammad Al Farroukh, Rawdah Karwt, Gulnaz D Alekbaeva, Mikhail V Pugachev, Zilya R Yamaleeva, Olga N Kataeva, Konstantin V Balakin, Yurii G Shtyrlin
Two series of novel pyridoxine-based azaheterocyclic analogs of feruloyl methane (Dehydrozingerone, DZG) were synthesized, and their biological activity against a panel of tumor and normal cell lines was evaluated in vitro. The most active compounds possessed expressed cytotoxic activity, which was comparable to cytotoxic activity of doxorubicin and significantly higher than that of DZG, and a remarkable selectivity for the studied cancer cell lines as compared to the normal cells. The leading compound and DZG initiated arrest of the cell cycle in the G2/M phase, preventing normal division and further transition of daughter cells to the G0/G1 phase...
October 27, 2018: Bioorganic & Medicinal Chemistry
Leon Jacobs, Carmen de Kock, Dale Taylor, Stephen C Pelly, Margaret A L Blackie
Research has indicated that N-myristoyl transferase, an enzyme that catalyzes the addition of a myristate group to the N-terminal glycine residues of proteins, is involved in the myristoylation of more than 100 proteins. Genetic knockdown of the enzyme proved detrimental for the viability of the parasite P. knowlesi. A crystal structure of P. vivax N-myristoyl transferase (pvNMT), containing a 3-methyl benzofuran ligand has made it possible to assess key amino acid residue-ligand interactions. We synthesized five libraries of 6,5-fused heterocycles to establish the importance of the heterocycles as core scaffolds, as well as introduced various aromatic amides and esters to determine which carbonylic group affects the potency of each heterocyclic antiplasmodial agent...
October 27, 2018: Bioorganic & Medicinal Chemistry
Larissa Sens, Ana Caroline Arruda de Souza, Lucas Antonio Pacheco, Angela Camila Orbem Menegatti, Mattia Mori, Alessandra Mascarello, Ricardo José Nunes, Hernán Terenzi
Mycobacterium tuberculosis secretes two protein tyrosine phosphatases as virulence factors, PtpA and PtpB. Inhibition studies of these enzymes have shown significant attenuation of the M. tuberculosis growth in vivo. As PtpA mediates many effects on the regulation of host signaling ensuring the intracellular survival of the bacterium we report, for the first time, thiosemicarbazones as potential novel class of PtpA inhibitors. Several compounds were synthesized and biologically evaluated, revealing interesting results...
October 27, 2018: Bioorganic & Medicinal Chemistry
Teri J Slack, Wanqing Li, Dashuang Shi, John B McArthur, Gengxiang Zhao, Yanhong Li, An Xiao, Zahra Khedri, Hai Yu, Yang Liu, Xi Chen
Sialidases or neuraminidases are enzymes that catalyze the cleavage of terminal sialic acids from oligosaccharides and glycoconjugates. They play important roles in bacterial and viral infection and have been attractive targets for drug development. Structure-based drug design has led to potent inhibitors against neuraminidases of influenza A viruses that have been used successfully as approved therapeutics. However, selective and effective inhibitors against bacterial and human sialidases are still being actively pursued...
October 27, 2018: Bioorganic & Medicinal Chemistry
Doretta Cuffaro, Caterina Camodeca, Felicia D'Andrea, Eugenia Piragine, Lara Testai, Vincenzo Calderone, Elisabetta Orlandini, Elisa Nuti, Armando Rossello
MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives to characterize the structure-activity relationship (SAR) within this class of glycoconjugate inhibitors...
October 26, 2018: Bioorganic & Medicinal Chemistry
Junsuke Hayashi, Yosuke Ochi, Yasuyuki Morita, Katsuma Soubou, Yuhei Ohtomo, Misa Nishigaki, Yuko Tochiyama, Osamu Nakagawa, Shun-Ichi Wada, Hidehito Urata
We previously reported that reducing-environment-responsive prodrug-type small interfering RNA (siRNA) bearing 2'-O-methyldithiomethyl (2'-O-MDTM) uridine exhibits efficient knockdown activity and nuclease resistance. In this report, we describe the preparation of 2'-O-MDTM oligonucleotides modified not only at uridine but also at adenosine, guanosine and cytidine residues by post-synthetic modification. Precursor oligonucleotides bearing 2'-O-(2,4,6-trimethoxybenzylthiomethyl) (2'-O-TMBTM) adenosine, guanosine, and cytidine were reacted with dimethyl(methylthio)sulfonium tetrafluoroborate to form 2'-O-MDTM oligonucleotides in the same manner as the oligonucleotide bearing 2'-O-TMBTM uridine...
October 26, 2018: Bioorganic & Medicinal Chemistry
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