Design and Synthesis of Dual-Action Inhibitors Targeting Histone Deacetylases and 3‑Hydroxy-3-methylglutaryl Coenzyme A Reductase for Cancer Treatment

• Published in: Journal of medicinal chemistry 2013-05, Vol.56 (9), p.3645-3655
• Main Authors: Chen, Jhih-Bin, Chern, Ting-Rong, Wei, Tzu-Tang, Chen, Ching-Chow, Lin, Jung-Hsin, Fang, Jim-Min
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry Techniques, Synthetic; Drug Design; Histone Deacetylase Inhibitors - chemical synthesis; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - chemistry; Histone Deacetylases - metabolism; Humans; Hydroxymethylglutaryl CoA Reductases - chemistry; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemical synthesis; Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Models, Molecular; Protein Conformation
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400179b

A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells.