Design, Synthesis and Biological Evaluation of Histone Deacetylase Inhibitors Based on Pyrrolo[2,3-d]pyrimidine and Pyrrolo[2,3-b]pyridine Scaffolds.

ABSTRACT

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDAC inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds. Compound B3 {(E)-3-(4-(((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide} exhibits potent inhibitory activity against HDACs 1, 2, 3, 6, and 8 with IC50 values of 5.2, 6.0, 8.8, 4.4, and 173.0 nM, respectively. It exhibited potent antiproliferative effects against three tumour cell lines (IC50 values of 0.13, 0.37, and 1.11 µM, against MV-4-11, K562, and WSU-DLCL-2 cells, respectively) with two- to sixfold improvement relative to suberoylanilide hydroxamic acid (SAHA). Mechanistic studies on WSU-DLCL-2 cells revealed that B3 exhibits anticancer effects through the induction of G0 /G1 -phase arrest and promotion of apoptosis. The results of this study warrant further investigation of this compound series for the treatment of hematological malignancy.