Efficient Synthesis and Bioevaluation of Novel Dual Tubulin/Histone Deacetylase 3 Inhibitors as Potential Anticancer Agents

Novel
dual HDAC3/tubulin inhibitors were designed and efficiently
synthesized by combining the pharmacophores of SMART (tubulin inhibitor)
and MS-275 (HDAC inhibitor), among which compound 15c was found to be the most potent and balanced HDAC3/tubulin dual
inhibitor with high HDAC3 activity (IC50 = 30 nM) and selectivity
(SI > 1000) as well as excellent antiproliferative potency against
various cancer cell lines, including an HDAC-resistant gastric cancer
cell line (YCC3/7) with IC50 values in the range of 30–144
nM. Compound 15c inhibited B16-F10 cancer cell migration
and colony formation. In addition, 15c demonstrated significant in vivo antitumor efficacy in a B16-F10 melanoma tumor model
with a better TGI (70.00%, 10 mg/kg) than that of the combination
of MS-275 and SMART. Finally, 15c presented a safe cardiotoxicity
profile and did not cause nephro-/hepatotoxicity. Collectively, this
work shows that compound 15c represents a novel tubulin/HDAC3
dual-targeting agent deserving further investigation as a potential
anticancer agent.