Design, synthesis and biological evaluation of novel coumarin-based benzamides as potent histone deacetylase inhibitors and anticancer agents.
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 IC50in 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 IC50value 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.
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Tooba
T
Abdizadeh
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.
Mohammad Reza
MR
Kalani
Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Khalil
K
Abnous
Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Zahra
Z
Tayarani-Najaran
Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Bibi Zahra
BZ
Khashyarmanesh
Department of Medical Parasitology and Mycology, Faculty of Medicine, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Rahman
R
Abdizadeh
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.
Razieh
R
Ghodsi
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.
Farzin
F
Hadizadeh
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001549:Benzamides; D003374:Coumarins; D056572:Histone Deacetylase Inhibitors; C030123:coumarin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1
2-AminoBenzamide; Coumarin; Docking; Histone deacetylase inhibitors; Molecular dynamics