Design, synthesis, and biological evaluation of N-hydroxycinnamamide/salicylic acid hybrids as histone deacetylase inhibitors

Abstract Novel histone deacetylase (HDAC) inhibitors 9a – l were designed and synthesized by coupling the carboxyl group of salicylic acid (SA) with N- hydroxycinnamamides through various alkylol amines, and their in vitro biological activities were evaluated. The N -hydroxycinnamamide/SA hybrids 9b – f and 9h showed good to moderate anti-tumor activities. Notably, compound 9e had a greater potency, comparable to vorinostat (SAHA), in human colon carcinoma cells, which was probably, or at least partially, attributable to the positive effects of the chain length noted in alkylol amines. Furthermore, the HDAC inhibitory activities of 9e against Hela cell nuclear were also similar to that of vorinostat (SAHA), while the tested compounds 9c – f did not exhibit any isoform selectivity in the inhibition of HDACs. In addition, compound 9e could selectively inhibit tumor cells, but not inhibit non-tumor cell proliferation in vitro . Our findings suggest that the N- hydroxycinnamamide/SA hybrids may hold significant promise as therapeutic agents for the intervention of human cancers.