Design, Synthesis and Biological Evaluation of Potent Human Glyoxalase I Inhibitors

• Published in: Chemical & pharmaceutical bulletin Vol. 65; no. 5; pp. 455 - 460
• Main Authors: Jin, Tian, Zhai, Jing, Liu, Xiao, Yue, Yan, Huang, Maolin, Li, Zonghe, Ni, Caixia, Deng, Qishan, Sang, Yankui, Yao, Zhongwei, Zhang, Hong, Hu, Xiaopeng, Zheng, Zhe-Bin
• Format: Journal Article
• Language: English
• Published: TOKYO The Pharmaceutical Society of Japan 01.05.2017; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Japan Science and Technology Agency
• Subjects: Animals; Aromatic compounds; Biological Assay; Cell Line, Tumor; cell membrane permeability study; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Drug Design; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Esters - chemical synthesis; Esters - chemistry; Esters - pharmacology; Glutathione; Glutathione - chemical synthesis; Glutathione - chemistry; Glutathione - pharmacology; glyoxalase I inhibitor; Humans; inhibition constant; Inhibitors; Lactoylglutathione lyase; Lactoylglutathione Lyase - antagonists & inhibitors; Life Sciences & Biomedicine; Mice; Models, Biological; Molecular Structure; NCI-H522 cell line; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; synthesis; Tumor Burden - drug effects; Xenografts; synthesis; SYSTEM; ENZYME; inhibition constant; MECHANISM; ANALOG; glyoxalase I inhibitor; NCI-H522 cell line; ACTIVE-SITE; cell membrane permeability study; TIGHT-BINDING INHIBITORS; DISCOVERY
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c16-00800

Several glutathione derivatives bearing the S-(N-aryl-N-hydroxycarbamoyl) or S-(C-aryl-N-hydroxycarbamoyl) moieties (10, 10′, 13–15) were synthesized, characterized, and their human glyoxalase I (hGLO1) inhibitory activity was evaluated. Compound 10 was proved to be the effective hGLO1 inhibitor with a Ki value of 1.0 nM and the inhibition effect of compound 10 on hGLO1 was nearly ten-fold higher than that of the strongest inhibitor 2 (Ki=10.0 nM) which has been reported in the field of glutathione-type hGLO1 inhibitors. Its diethyl ester prodrug 10′ was able to penetrate cell membrane and had good inhibitory effect on the growth of NCI-H522 cell xenograft tumor model.