Design, Synthesis, and Antiproliferative Activity of Selective Histone Deacetylases 6 Inhibitors Containing a Tetrahydropyridopyrimidine Scaffold.

The development of selective histone deacetylase 6 inhibitors (sHDAC6is) is being recognized as a therapeutic approach for cancers. In this paper, we designed a series of novel tetrahydropyridopyrimidine derivatives as sHDAC6 inhibitors. The most potent compound, 8-(2, 4-bis(3-methoxyphenyl)-5, 8-dihydropyrido [3, 4-]pyrimidin-7(6)-yl)--hydroxy-8-oxooctanamide (), inhibited HDAC6 with IC of 6.4 nM, and showed > 48-fold selectivity over other subtypes. In Western blot assay, elevated the levels of acetylated -tubulin in a dose-dependent manner. In vitro, inhibited RPMI-8226, HL60, and HCT116 tumor cells with IC of 2.8, 3.20, and 3.25 μM, respectively. Moreover, showed good antiproliferative activity against a panel of tumor cells.