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Synthesis, biological evaluation, and molecular docking analysis of novel linker-less benzamide based potent and selective HDAC3 inhibitors.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2021 Sep; Vol. 114, pp. 105050. Date of Electronic Publication: 2021 Jun 04. - Publication Year :
- 2021
-
Abstract
- A series of novel linker-less benzamides with different aryl and heteroaryl cap groups have been designed, synthesized, and screened as potent histone deacetylase (HDAC) inhibitors with promising anticancer activity. Two lead compounds 5e and 5f were found as potent and highly selective HDAC3 inhibitors over other Class-I HDACs and HDAC6. Compound 5e bearing a 6-quinolinyl moiety as the cap group was found to be a highly potent HDAC3 inhibitor (IC <subscript>50</subscript>  = 560 nM) and displayed 46-fold selectivity for HDAC3 over HDAC2, and 33-fold selectivity for HDAC3 over HDAC1. The synthesized compounds possess antiproliferative activities against different cancer cell lines and significantly less cytotoxic to normal cells. Molecular Docking studies of compounds 5e and 5f reveal a similar binding mode of interactions as CI994 at the HDAC3 active site. These observations agreed with the in vitro HDAC3 inhibitory activities. Significant enhancement of the endogenous acetylation level on H3K9 and H4K12 was found when B16F10 cells were treated with compounds 5e and 5f in a dose-dependent manner. The compounds induced apoptotic cell death in Annexin-V/FITC-PI assay and caused cell cycle arrest at G2/M phase of cell cycle in B16F10 cells. These compounds may serve as potential HDAC3 inhibitory anticancer therapeutics.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Benzamides chemical synthesis
Benzamides chemistry
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors chemistry
Humans
Mice
Molecular Structure
Structure-Activity Relationship
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Benzamides pharmacology
Histone Deacetylase Inhibitors pharmacology
Histone Deacetylases metabolism
Molecular Docking Simulation
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 114
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34120025
- Full Text :
- https://doi.org/10.1016/j.bioorg.2021.105050