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Bioorganic & Medicinal Chemistry

Jurema Schmidt, Simone Schierle, Leonie Gellrich, Astrid Kaiser, Daniel Merk
Activation of the nuclear farnesoid X receptor (FXR) which acts as cellular bile acid sensor has been validated as therapeutic strategy to counter liver disorders such as non-alcoholic steatohepatitis by the clinical efficacy of obeticholic acid. FXR antagonism, in contrast, is less well studied and potent small molecule FXR antagonists are rare. Here we report the systematic optimization of a novel class of FXR antagonists towards low nanomolar potency. The most optimized compound antagonizes baseline and agonist induced FXR activity in a full length FXR reporter gene assay and represses intrinsic expression of FXR regulated genes in hepatoma cells...
July 11, 2018: Bioorganic & Medicinal Chemistry
Misa Yamauchi, Kotomi Ueno, Toshio Furumoto, Takatoshi Wakabayashi, Masaharu Mizutani, Hirosato Takikawa, Yukihiro Sugimoto
Reductive metabolism of strigolactones (SLs) in several plants was investigated. Analysis of aquaculture filtrates of cowpea and sorghum each fed with four stereoisomers of GR24, the most widely used synthetic SL, revealed stereospecific reduction of the double bond at C-3' and C-4' in the butenolide D-ring with preference for an unnatural 2'S configuration. The cowpea metabolite converted from 2'-epi-GR24 and the sorghum metabolite converted from ent-GR24 had the methyl group at C-4' in the trans configuration with the substituent at C-2', different from the cis configuration of the synthetic H2 -GR24 reduced with Pd/C catalyst...
July 10, 2018: Bioorganic & Medicinal Chemistry
Ji Hoon Ha, Soo Nam Park
Dicaffeoylquinic acid (DCQA), which contain 2 caffeic acids and a quinic acid, is 6 isomeric compounds (1,3-, 1,4-, 1,5-, 3,4-, 3,5-, and 4,5-DCQA). In this study, the mechanism underlying the inhibitory effect of DCQA isomers on melanogenesis in B16F1 murine melanoma cells stimulated by melanocyte stimulating hormone (α-MSH) was evaluated. DCQA isomers showed inhibitory effects on melanogenesis in α-MSH-stimulated B16F1 cells. Furthermore, the anti-melanogenesis activities of 1,5-DCQA and 4,5-DCQA were 61% and 84%, respectively, which were greater than that of arbutin (35%)...
July 9, 2018: Bioorganic & Medicinal Chemistry
Hannah J Winfield, Michael M Cahill, Kevin D O'Shea, Larry T Pierce, Thomas Robert, Sandrine Ruchaud, Stéphane Bach, Pascal Marchand, Florence O McCarthy
Synthesis and biological evaluation of a series of novel indole derivatives as anticancer agents is described. A bisindolylmaleimide template has been derived as a versatile pharmacophore with which to pursue chemical diversification. Starting from maleimide, the introduction of an oxygen to the headgroup (hydroxymaleimide) was initially investigated and the bioactivity assessed by screening of kinase inhibitory activity, identifying substituent derived selectivity. Extension of the hydroxymaleimide template to incorporate substitution of the indole nitrogens was next completed and assessed again by kinase inhibition identifying unique selectivity patterns with respect to GSK-3 and CDK kinases...
July 9, 2018: Bioorganic & Medicinal Chemistry
Andrew P Hinck
The increasing availability of detailed structural information on many biological systems provides an avenue for manipulation of these structures, either for probing mechanism or for developing novel therapeutic agents for treating disease. This has been accompanied by the advent of several powerful new methods, such as the ability to incorporate non-natural amino acids or perform fragment screening, increasing the capacity to leverage this new structural information to aid in these pursuits. The abundance of structural information also provides new opportunities for protein engineering, which may become more and more relevant as treatment of diseases using gene therapy approaches become increasingly common...
July 7, 2018: Bioorganic & Medicinal Chemistry
Andrea Angeli, Marianne Kuuslahti, Seppo Parkkila, Claudiu T Supuran
The activation of a α-class carbonic anhydrase (CAs, EC from Trypanosoma cruzi (TcCA) was investigated with the best known classes of activators, the amino acids and aromatic/heterocyclic amines. The best TcCA activators were l-/d-DOPA and 4-amino-l-phenylalanine, which had activation constants in the range of 0.38-0.83 µM. Low micromolar activators were also l-/d-Trp, l-/d-Tyr, l-Gln, histamine and serotonin (KA s of 1.79-4.92 µM), whereas l-/d-His, l-/d-Phe and l-Asp were less effective activators (KA s of 6...
July 7, 2018: Bioorganic & Medicinal Chemistry
Kun Li, Kun Yang, Lifang Zheng, Yuanyuan Li, Qi Wang, Ruili Lin, Dian He
2-Chloro-3-alkyl-1,4-naphthoquinone derivatives were synthesized and tested as the anti-acute myeloid leukaemia agents. The compound 9b (2-chloro-3-ethyl-5,6,7-trimethoxy-1,4-naphthoquinone) was the most potent toward HL-60 leukaemia cells. In mechanistic study for 9b, the protein levels of mtDNA-specific DNA polymerase γ (poly-γ) and mtDNA transcription factor A (mt-TFA) were decreased after the 24 h treatment, showing the occurrence of mtDNA damage. And 9b triggered cell cycle arrest at S phase accompanied by a secondary block in G2/M phase which had a direct link to the process of mtDNA damage...
July 7, 2018: Bioorganic & Medicinal Chemistry
Kenzo Yamatsugu, Masahiro Furuta, Siqi Xi, Yoshifumi Amamoto, Jiaan Liu, Shigehiro A Kawashima, Motomu Kanai
Lysine acylation of proteins is a crucial chemical reaction, both as a post-translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents...
July 7, 2018: Bioorganic & Medicinal Chemistry
Changyuan Wang, Si Li, Qiang Meng, Xiuli Sun, Hua Li, Xiaohong Shu, Huijun Sun, Kexin Liu, Zhihao Liu, Xiaodong Ma
A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC50 of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth...
July 6, 2018: Bioorganic & Medicinal Chemistry
Vincent Murray, Jon K Chen, Dong Yang, Ben Shen
Bleomycin (BLM) is a cancer chemotherapeutic agent that cleaves cellular DNA at specific sequences. Using next-generation Illumina sequencing, the genome-wide sequence specificity of DNA cleavage by two BLM analogues, 6'-deoxy-BLM Z and zorbamycin (ZBM), was determined in human HeLa cells and compared with BLM. Over 200 million double-strand breaks were examined for each sample, and the 50,000 highest intensity cleavage sites were analysed. It was found that the DNA sequence specificity of the BLM analogues in human cells was different to BLM, especially at the cleavage site (position "0") and the "+1" position...
July 5, 2018: Bioorganic & Medicinal Chemistry
Jinyu Liu, Xiaoyan Su, Huachong Li, Li Fan, Yuanyuan Li, Xuemei Tang, Jufang Yan, Xin Chen, Feifei Chen, Jie Liu, Dacheng Yang
In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105...
July 5, 2018: Bioorganic & Medicinal Chemistry
Ehsan Ullah Mughal, Asif Javid, Amina Sadiq, Shahzad Murtaza, Muhammad Naveed Zafar, Bilal Ahmad Khan, Sajjad Hussain Sumrra, Muhammad Nawaz Tahir, Kanwal, Khalid Mohammed Khan
No abstract text is available yet for this article.
July 5, 2018: Bioorganic & Medicinal Chemistry
Satoshi Kanamori, Hiroaki Ishida, Keiko Yamamoto, Toshimasa Itoh
β-Oxidation of most fatty acids occurs in the mitochondria. However, β-oxidation for ω-3 polyunsaturated fatty acids (PUFAs) is distinct from abundant fatty acids and occurs in the peroxisomes. Since little is known about peroxisomal β-oxidation, here we report the synthesis of proposed intermediates of ω-3 PUFA β-oxidation steps in free fatty acid form having a conjugated double bond, a β-hydroxyl group, a β-olefin and a β-carbonyl group. These fatty acids can serve as authentic samples for biological experiments...
July 4, 2018: Bioorganic & Medicinal Chemistry
Stavroula Balomenou, Dimitris Koutsioulis, Anastasia Tomatsidou, Mary Tzanodaskalaki, Kyriacos Petratos, Vassilis Bouriotis
Peptidoglycan N-acetylglucosamine (GlcNAc) deacetylases (PGNGdacs) from bacterial pathogens are validated targets for the development of novel antimicrobial agents. In this study we examined the in vitro inhibition of hydroxamate ligand N-hydroxy-4-(naphthalene-1-yl)benzamide (NHNB), a selective inhibitor of histone deacetylases-8 (HDAC8), against two PGNGdacs namely BC1974 and BC1960 from B. cereus, highly homologous to BA1977 and BA1961 of B. anthracis, respectively. Kinetic analysis showed that this compound functions as a competitive inhibitor of both enzymes with apparent Ki 's of 8...
July 4, 2018: Bioorganic & Medicinal Chemistry
Wei-Wei Ni, Qi Liu, Shen-Zhen Ren, Wei-Yi Li, Li-Li Yi, Heng Jing, Li-Xin Sheng, Qin Wan, Ping-Fu Zhong, Hai-Lian Fang, Hui Ouyang, Zhu-Ping Xiao, Hai-Liang Zhu
Two series of ω-phenoxy contained acylhydroxamic acids as novel urease inhibitors were designed and synthesized. Biological activity evaluations revealed that ω-phenoxypropinoylhydroxamic acids were more active than phenoxyacetohydroxamic acids. Out of these compounds, 3-(3,4-dichlorophenoxy)propionylhydroxamic acid c24 showed significant potency against urease in both cell free extract (IC50  = 0.061 ± 0.003 μM) and intact cell (IC50  = 0.89 ± 0.05 μM), being over 450- and 120-fold more potent than the clinically prescribed urease inhibitor AHA, repectively...
July 4, 2018: Bioorganic & Medicinal Chemistry
Fabrice Gallou
No abstract text is available yet for this article.
July 3, 2018: Bioorganic & Medicinal Chemistry
Suresh Paudel, Ningning Sun, Daulat Bikram Khadka, Goon Yoon, Kyeong-Man Kim, Seung Hoon Cheon
Rational drug design method has been used to generate 4-arylpiperazine carboxamides in an effort to develop safer, more potent and effective monoamine neurotransmitters reuptake inhibitors. Out of twenty-seven synthesized compounds, compound 9 displayed potent monoamine neurotransmitter reuptake inhibitory activity against HEK cells transfected with hSERT or hNET. A Surflex-Dock docking model of 9 was also studied.
July 2, 2018: Bioorganic & Medicinal Chemistry
Yiming Xu, Dewang Jing, Rui Chen, Haroon Ur Rashid, Jun Jiang, Xu Liu, Lisheng Wang, Peng Xie
Based on our previous study and the binding mode of camptothecin with Topo I, a series of novel sophoridine imine derivatives containing conjugated planar structure were designed, synthesized and tested for their in vitro anticancer activity. The results showed that most of the derivatives displayed potent activity. In particular, compounds 10b exhibited excellent anti-proliferative activities with IC50 5.7 µM and 8.5 µM against HepG-2 and HeLa cell lines, respectively. Molecular docking studies revealed that the introduction of conjugated planar structure could form π-π stacking interaction with DNA, leading to the improvement of biological activity...
July 2, 2018: Bioorganic & Medicinal Chemistry
Koshi Machida, Daisuke Arai, Ryosuke Katsumata, Satoshi Otsuka, Jun K Yamashita, Tao Ye, Shoubin Tang, Nobuhiro Fusetani, Yoichi Nakao
Sameuramide A (1), a new cyclic depsipeptide encompassing one each of alanine, N-methyl alanine, N-methyl dehydroalanine, N,O-dimethyl threonine, phenyllactic acid, three β-hydroxy leucines, and two propionates, was isolated from a didemnid ascidian collected at the northern part of Japan. The planar structure was established based on the interpretation of MS and NMR data. The absolute configuration of the subunits was determined by the advanced Marfey's method and the chiral LC-MS analysis. Compound 1 exhibited the activity of maintaining colony formation of murine embryonic stem (mES) cells without leukemia inhibitory factor (LIF)...
June 30, 2018: Bioorganic & Medicinal Chemistry
Lorena Navarro, Gloria Rosell, Silvia Sánchez, Núria Boixareu, Klaus Pors, Ramon Pouplana, Josep M Campanera, M Dolors Pujol
A novel group of aryl methyl sulfones based on nonsteroidal anti-inflammatory compounds exhibiting a methyl sulfone instead of the acetic or propionic acid group was designed, synthesized and evaluated in vitro for inhibition against the human cyclooxygenase of COX-1 and COX-2 isoenzymes and in vivo for anti-inflammatory activity using the carrageenan induced rat paw edema model in rats. Also, in vitro chemosensitivity and in vivo analgesic and intestinal side effects were determined for defining the therapeutic and safety profile...
June 30, 2018: Bioorganic & Medicinal Chemistry
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