Exploration of a novel series of isoindolinone-based hydroxamate derivatives: Design, synthesis, and evaluation of...

Histone deacetylases (HDACs) have been identified as a class of crucial epigenetic enzymes that are responsible for the removal of acetyl groups from the lysine residues in the amino-terminal tails of histones. Their overexpression is closely associated with cancer growth, progression, and acquisition of therapeutic resistance, etc. Therefore, the treatment of diverse cancers could benefit from HDACs inhibitors, especially hematologic malignancies. Herein, a series of novel hydroxamate derivatives were designed by incorporating a clover-leaf scaffold into the cap region of SAHA to explore additional binding sites and obtain more potent HDACs inhibitors. Modifications on cap region and linker led to the optimal inhibitor 31a. Preliminary evaluation of inhibitory potency against HDAC isoenzymes indicated that it could inhibit several HDAC subtypes, including HDAC1 (IC₅₀ = 2.4 nM), HDAC2 (IC₅₀ = 5.8 nM), HDAC3 (IC₅₀ = 5.2 nM), and HDAC6 (IC₅₀ = 3.3 nM). Additionally, it displayed moderate to potent in vitro antiproliferative activity against broad spectrum of cancers, especially MV4-11 cells (IC₅₀ = 0.17 μM). Flow cytometry analysis showed that it could induce remarkable cell apoptosis at the concentration of 3.0 μM. However, no cell cycle arrest was observed at the test concentration. Importantly, novel binding sites which could enhance binding affinity with HDAC1 were first confirmed in this work. In our opinion, they are worth applying in the development of HDACs inhibitors. Overall, this study provides a new structure design for HDACs inhibitors and also offers promising novel HDACs inhibitors with potential antiproliferative activity against several types of cancers.