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.

Oxidation/Alkylation of Amino Acids with α-Bromo Carbonyls Catalyzed by Copper and Quick Access to HDAC Inhibitor

“…To further showcase the synthetic potential of this oxidation/alkylation reaction in architectures of diverse HDAC inhibitors, a novel SAHA phenylalanine-containing analogue (SPACA) was synthesized in total 6 steps (Scheme ). The synthesis consulted the original procedure and in our version, it started from monomethyl suberate, which was converted to the protected monohydroxamates 30 .…”

Cu-Catalyzed α-Alkylation of Glycine Derivatives for C(sp3)–H/C(sp3)–H Bond Selective Functionalization

“…Next, the in vitro antitumor activities of representative products toward MV-4–11 (human myeloid mononuclear leukemia cells) and WSU-DLCL-2 (human diffuse large B lymphoma cells) tumor cell lines were investigated . Compounds 65 and 68 having potent inhibitory effects at 20 μM were selected for further evaluation to determine their IC 50 values against two tumor cell lines using SAHA as the positive control (Table ).…”