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.

β -Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its scaffold. Systematic SAR studies led to the discovery of compounds 27f and 39f , which exhibited potent inhibitory activity against HDACs (HDAC1: IC 50 = 22 and 9 nM; HDAC6: 8 and 14 nM, respectively). In cellular levels, 27f and 39f significantly inhibited cell proliferation of five tumour cell lines (IC 50 : 0.79 - 4.42 µM). Preliminary mechanistic studies indicated that 27f and 39f efficiently induced cell apoptosis. Unexpectedly, compound 39f could also stimulate cell cycle arrest in G1 phase. Further in vivo study in WSU-DLCL-2 xenografted mouse model validated the antitumor activities of 27f , without significant toxicity. The results suggest the therapeutic potential of these HDACs inhibitors in lymphoma and provide valuable insight and understanding for further structural optimisation around β -elemene scaffold.

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