HDAC4 Inhibitors with Cyclic Linker and Non-hydroxamate Zinc Binding Group: Design, Synthesis, HDAC Screening and in vitro Cytotoxicity evaluation

摘要

Recent evidences highlight the usefulness of small molecule (Histone deacetylase 4) HDAC4 inhibitors in the several preclinical paradigms. Major toxicity and mutagenicity issues associated with hydroxamate HDAC inhibitors, stimulated us to develop potent non-hydroxamate inhibitors. In the present work a novel series of thiazolidinedione (TZD) derivatives with pyridine as cyclic linker and TZD ring as zinc binding group was designed and screened in a panel of isoenzymes of HDACs, wherein the most potent compounds exhibiting HDAC4 IC_(50) - values < 5 μM were 5v, 5w, 5y and 5z (IC_(50) =4.2 ± 1 μM, 0.75 ± 0.03 μM, 4.9 ± 0.5 and 2.3 ± 0.5 μM, respectively). The docking studies displayed the unique binding mode of this series of compound at active site of HDAC4, wherein TZD ring was indicated as zinc binding group. Further, 5w and 5y were found as the most potent antiproliferative agent in lymphoblastic leukemia (CCRF-CEM) and breast cancer MDA-MB-231 cells. Compound 5y was found to induce the apoptosis and DNA fragmentation of CEM cells. The western blotting analysis of 5y also showed the presence of cleaved caspases supporting their apoptotic nature. Further, Class IIa (HDAC4) selectivity of 5y was also supported by western blotting observations, wherein 5y caused the accumulation of acetylated H3 but not of acetylated Tubulin. Thus, our findings endorse the further investigation of this series of compounds for their potential as targeted cancer therapeutic agents.