2. Academic Validation
  3. Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents

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

  • Eur J Med Chem. 2017 May 26:132:42-62. doi: 10.1016/j.ejmech.2017.03.024.
Tooba Abdizadeh 1,  Mohammad Reza Kalani 2,  Khalil Abnous 3,  Zahra Tayarani-Najaran 4,  Bibi Zahra Khashyarmanesh 5,  Rahman Abdizadeh 6,  Razieh Ghodsi 7,  Farzin Hadizadeh 8
Affiliations

Affiliations

  • 1 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 2 School of Cell and Molecular Biology, University of Illinois at Urbana-Champaign, Urbana, United States; Department of Molecular Medicine, Golestan University of Medical Sciences, Golestan, Iran.
  • 3 Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 4 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 6 Department of Medical Parasitology and Mycology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran.
  • 7 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: ghodsir@mums.ac.ir.
  • 8 Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: hadizadehf@mums.ac.ir.
PMID: 28340413 DOI: 10.1016/j.ejmech.2017.03.024
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.

Keywords

2-AminoBenzamide; Coumarin; Docking; Histone deacetylase inhibitors; Molecular dynamics.

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