Novel (E)‐3‐(3‐Oxo‐4‐substituted‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐6‐yl)‐N‐hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis and Bioevaluation

Abstract

AbstractHerein, we report the design, synthesis and evaluation of novel (E)‐3‐(3‐oxo‐4‐substituted‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐6‐yl)‐N‐hydroxypropenamides (4 a–i, 7 a–g) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC‐3, prostate; NCI−H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a–i bearing the alkyl substituents seemed to be less potent than the benzyl‐containing compounds 7 a–g in all biological assays. Compounds 7 e–f were found to be the most active HDAC inhibitors with IC50 of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC50 values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.