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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-<i>d</i>]pyrimidin-7(6<i>H</i>)-yl)-<i>N</i>-hydroxy-8-oxooctanamide (<b>8f</b>), inhibited HDAC6 with IC₅₀ of 6.4 nM, and showed > 48-fold selectivity over other subtypes. In Western blot assay, <b>8f</b> elevated the levels of acetylated <i>α</i>-tubulin in a dose-dependent manner. In vitro, <b>8f</b> inhibited RPMI-8226, HL60, and HCT116 tumor cells with IC₅₀ of 2.8, 3.20, and 3.25 μM, respectively. Moreover, <b>8f</b> showed good antiproliferative activity against a panel of tumor cells.