Development of Coumarin-Based Hydroxamates as Histone Deacetylase Inhibitors with Antitumor Activities

Histone deacetylases (HDACs) have been proved to be promising targets for the treatment of cancer, and five histone deacetylase inhibitors (HDACis) have been approved on the market for the treatment of different lymphomas. In our previous work, we designed a series of novel coumarin-containing hydroxamate HDACis, among which compounds6and7displayed promising activities against tumor growth. Based on a molecular docking study, we further developed 26 additional analogues with the aim to improve activity of designed compounds. Several of these new derivatives not only showed excellent HDAC1 inhibitory effects, but also displayed significant growth inhibitory activities against four human cancer cell lines. Representative compounds,13aand13c, showed potent anti-proliferative activities against solid tumor cell lines with IC50values of 0.36–2.91 µM and low cytotoxicity against Beas-2B and L-02 normal cells. Immunoblot analysis revealed that13aand13cdose-dependently increased the acetylation of histone H3 and H4. Importantly, the two compounds displayed much better anti-metastatic effects than SAHA against the MDA-MB-231 cell line. Moreover,13aand13carrested MDA-MB-231 cells at G2/M phase and induced MDA-MB-231 cell apoptosis. Finally, the molecular docking study rationalized the high potency of compound13c.Keywords:coumarin;anti-tumor;HDAC inhibitors;structural modification;anti-proliferative