Design, synthesis and antiproliferative activity of ACY-1215 analogs as potent selective histone deacetylases 6 inhibitors

Histone deacetylase 6 (HDAC6) plays an important role in cancer treatment, and the development of selective HDAC6 inhibitors (sHDAC6is) attracts more and more attention in recent years. In this research, a series of ACY-1215 analogs based on diphenylpyrimidine scaffold were designed and synthesized. Among these, the most potent compound 7-((4, 6-diphenylpyrimidin-2-yl)amino)-N-hydroxyheptanamide (11a) inhibited HDAC6 with IC50 of 3.8 nM and showed 26~fold selectivity over HDAC1, better than those of ACY-1215. In cellular assay, these diphenylpyrimidines exhibited promising antiproliferative activities against different tumor cell lines. Altogether, this work highlighted the therapeutic potential of diphenylpyrimidine-inspired sHDAC6 inhibitors and provides a valuable lead compound for the discovery of novel antitumor agents.