Design, synthesis and biological evaluation of novel HDACs inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds.

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDACs inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds. Compound B3 exhibits potent inhibitory activity against HDAC1 and HDAC6 with IC50 values of 5.2 nM and 4.4 nM, respectively. It exhibited potent anti-proliferative effects against three tumour cell lines (IC50 = 0.13, 0.37, and 1.11 µM, MV-4-11, K562, and WSU-DLCL-2 respectively) with 2-6 fold improvement comparing to SAHA. Mechanistic studies on WSU-DLCL-2 cell reveal that B3 exhibits anticancer effects through induction of G0/G1 phase arrest and promotion of apoptosis. The result warrants further investigation of this series of compounds for the treatment of hematological malignancy.