Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design structure-activity relationship and anti-tumor activity study

摘要

Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compound >11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of >11y led to a new series of benzamide based HDAC inhibitors. Most of the compounds exhibited high HDACs inhibitory potency. Compound >11a (with 4-methoxybenzoyl as N-substituent in the cap and 4-(aminomethyl) benzoyl as the linker group) exhibited selectivity against HDAC1 to some extent, and showed potent antiproliferative activity against several tumor cell lines. In vivo studies revealed that compound >11a displayed potent oral antitumor activity in both hematological tumor cell U937 xenograft model and solid tumor cell HCT116 xenograft model with no obvious toxicity. Further modification of benzamide >3, >11a and >19 afforded new thienyl and phenyl compounds (>50a, >50b, >63a, >63b and >63c) with dramatic HDAC1 and HDAC2 dual selectivity, and the fluorine containing compound >56, with moderate HDAC3 selectivity.