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Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Research Article

Novel Hydroxamic Acids Incorporating 1-((1H-1,2,3-Triazol-4-yl)methyl)- 3-substituted-2-oxoindolines: Synthesis, Biological Evaluation and SAR Analysis

Author(s): Do T.M. Dung, Nguyen V. Huan, Do M. Cam, Dao C. Hieu, Pham-The Hai, Le-Thi-Thu Huong, Jisung Kim, Jeong E. Choi, Jong S. Kang, Sang-Bae Han* and Nguyen-Hai Nam*

Volume 14, Issue 8, 2018

Page: [831 - 850] Pages: 20

DOI: 10.2174/1573406414666180528111749

Price: $65


Background: Histone deacetylases (HDAC) enzymes are emerging as potential targets for cancer treatments. In this study, several series of novel hydroxamic acids incorporating 1-((1H- 1,2,3-triazol-4-yl)methyl)-3-substituted-2-oxoindolines were explored.

Methods: The compounds were designed using Autodock Vina program, then synthesized and evaluated in vitro and in silico for their inhibitory activity against HDACs. The cytotoxicity was measured by SRB method. The enzyme inhibitory effects of the compounds were evaluated by the fluorescent assay.

Results: Biological evaluation showed that these hydroxamic acids were generally cytotoxic against four human cancer cell lines (SW620, colon; PC-3, prostate; AsPC-1, pancreas; NCI-H23, lung). Several compounds, e.g. 7g, 11c, and 11g, displayed up to 10-fold more potent than SAHA (suberoylanilide hydroxamic acid, vorinostat) in term of cytotoxicity. The synthesized compounds were also comparably potent to SAHA in inhibiting HDAC2. In particular, compound 11c displayed potential inhibitory effects against HDAC1, HDAC2, HDAC6, and HDAC8 with comparable or slightly higher potency than SAHA. Docking results on four class I and IIB isoenzymes indicated that these compounds tightly bound to HDACs at the active site with binding affinities much higher than that of SAHA. Finally, chemo-informatics approaches were employed to assess the pharmacokinetic and toxicity profiles of 7g and 11c. We identified degradation via phase II metabolism and toxicity two of the most serious problems that need further optimization.

Conclusion: Taking altogether our findings are encouraging and current hydroxamate derivatives are worth being considered as potential HDAC inhibitors and could be useful for further research on the development of new anti-cancer agents.

Keywords: Histone deacetylase (HDAC) inhibitors, hydroxamic acids, 2-oxoindoline, triazole, molecular docking, ADMET profiling.

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