Design, Synthesis and Biological Evaluation of Nitro Oxide Donating N-Hydroxycinnamamide Derivatives as Histone Deacetylase Inhibitors

Novel nitro oxide (NO)-donating N-hydroxycinnamamide derivatives 12a-j were designed and synthesized by coupling the carboxyl group of N-hydroxycinnamamides with phenylsulfonylfuroxan through various diols or alkylol amines, and their in vitro biological activities were evaluated. It was discovered that most of target compounds showed good histone deacetylases (HDACs) inhibition and anti-tumor activities, particularly for 12j, which had great HDACs inhibitory activities (IC(50)s=0.15-0.26 mu m) and antiproliferative effects (IC(50)s=3.21-7.12 mu m) comparable to suberoylanilide hydroxamic acid (SAHA) (IC(50)s=0.16-1.41 mu m for HDACs, IC(50)s=3.15-7.45 mu m for cancer cell inhibition). Furthermore, compound 12j with strong antitumor activities produced high levels of NO (up to 8.0 mu m of nitrites/nitrates) in colon cancer cells, and its antiproliferative activity was nearly half-diminished by hemoglobin (10 mu m), an NO scavenger. These results suggest that the strong antiproliferative activity of 12j could be attributed to the additive effects of high levels of NO production and inhibition of HDAC in the cancer cells.