Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents

Abdizadeh, T. and Kalani, M.R. and Abnous, K. and Tayarani-Najaran, Z. and Khashyarmanesh, B.Z. and Abdizadeh, R. and Ghodsi, R. and Hadizadeh, F. (2017) Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents. European Journal of Medicinal Chemistry, 132. pp. 42-62.

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Abstract

Histone deacetylases (HDACs) are attractive therapeutic targets for the treatment of cancer and other diseases. It has four classes (I-IV), among them especially class I isozyme are involved in promoting tumor cells proliferation, angiogenesis, differentiation, invasion and metastasis and also viable targets for cancer therapeutics. A novel series of coumarin-based benzamides was designed and synthesized as HDAC inhibitors. The cytotoxic activity of the synthesized compounds (8a-u) was evaluated against six human cancer cell lines including HCT116, A2780, MCF7, PC3, HL60 and A549 and a single normal cell line (Huvec). We evaluated their inhibitory activities against pan HDAC and HDAC1 isoform. Four compounds (8f, 8q, 8r and 8u) showed significant cytotoxicity with IC50 in the range of 0.53–57.59 μM on cancer cells and potent pan-HDAC inhibitory activity (consists of HDAC isoenzymes) (IC50 = 0.80–14.81 μM) and HDAC1 inhibitory activity (IC50 = 0.47–0.87 μM and also, had no effect on Huvec (human normal cell line) viability (IC50 > 100 μM). Among them, 8u displayed a higher potency for HDAC1 inhibition with IC50 value of 0.47 ± 0.02 μM near equal to the reference drug Entinostat (IC50 = 0.41 ± 0.06 μM). Molecular docking studies and Molecular dynamics simulation of compound 8a displayed possible mode of interaction between this compound and HDAC1enzyme

Item Type: Article
Additional Information: cited By 0
Uncontrolled Keywords: 2-AminoBenzamide, Coumarin, Docking, Histone deacetylase inhibitors, Molecular dynamics
Subjects: QZ pathology-Neoplasms
QV pharmacology
Divisions: Faculty of Medicine > Basic Sciences Academic Groups > Department of Parasitology and Mycology
Depositing User: zahra bagheri .
Date Deposited: 20 Jun 2017 04:15
Last Modified: 28 Jun 2017 08:40
URI: http://eprints.skums.ac.ir/id/eprint/142

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