| Summary: | Twenty newly synthesized derivatives of [6]-shogaol (<b>4</b>) were tested for inhibitory activity against histone deacetylases. All derivatives showed moderate to good histone deacetylase inhibition at 100 µM with a slightly lower potency than the lead compound. Most potent inhibitors among the derivatives were the pyrazole products, <b>5j</b> and <b>5k,</b> and the Michael adduct with pyridine <b>4c</b> and benzothiazole <b>4d,</b> with IC<sub>50</sub> values of 51, 65, 61 and 60 µM, respectively. They were further evaluated for isoform selectivity via a molecular docking study. Compound <b>4d</b> showed the best selectivity towards HDAC3, whereas compound <b>5k</b> showed the best selectivity towards HDAC2. The potential derivatives were tested on five cancer cell lines, including human cervical cancer (HeLa), human colon cancer (HCT116), human breast adenocarcinoma cancer (MCF-7), and cholangiocarcinoma (KKU100 and KKU-M213B) cells with MTT-based assay. The most active histone deacetylase inhibitor <b>5j</b> exhibited the best antiproliferative activity against HeLa, HCT116, and MCF-7, with IC<sub>50</sub> values of 8.09, 9.65 and 11.57 µM, respectively, and a selective binding to HDAC1 based on molecular docking experiments. The results suggest that these compounds can be putative candidates for the development of anticancer drugs via inhibiting HDACs.
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