Synthesis of N-Substituted Benzamide Derivatives and their Evaluation as Antitumor Agents.

Abstract

BACKGROUND\nHistone deacetylases inhibitors (HDACIs) with different chemical structures have been reported to play an important role in the treatment of cancer.\n\n\nOBJECTIVE\nThe study aims to modify the structure of Entinostat (MS-275) to discover new compounds with improved anti-proliferative activities and perform SAR studies of this class of bioactive compounds.\n\n\nMETHODS\nFourteen N-substituted benzamide derivatives were synthesized and their anti-proliferative activities were tested with four cancer cell lines (MCF-7, A549, K562 and MDA-MB-231) by MTT assay.\n\n\nRESULTS\nCompared with MS-275, six compounds exhibited comparable or even better anti-proliferative activities against specific/certain cancer cell lines.\n\n\nCONCLUSION\nThe preliminary SARs showed that (ⅰ) the 2-substituent of the penyl ring in the R group and heteroatoms of amide which can chelate with zinc ions is critical to the anti-proliferative activity and (ⅱ) chlorine atom or nitro-group on the same benzene ring will largely decrease their anti-proliferative activity. Molecular docking study illustrated the interaction (binding affinity) between the synthesized compounds and HDAC2 is similar to that of MS-275.