Synthesis and evaluation of a novel class Hsp90 inhibitors containing 1-phenylpiperazine scaffold

  • Bioorg Med Chem Lett. 2014 Mar 15;24(6):1557-61. doi: 10.1016/j.bmcl.2014.01.070.
Jian-Min Jia  1 ,  Fang Liu  1 ,  Xiao-Li Xu  1 ,  Xiao-Ke Guo  1 ,  Fen Jiang  1 ,  Bahidja Cherfaoui  1 ,  Hao-Peng Sun  2 ,  Qi-Dong You  3
Affiliations
  • 1. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
  • 3. Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: [email protected].
PMID: 24582477 DOI: 10.1016/j.bmcl.2014.01.070
Abstract

Previously, we identified 1-(2-(4-bromophenoxy)ethoxy)-3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-2-ol (1) as a novel HSP90 Inhibitor with moderate activity through virtual screening. In this study, we report the optimization process of 1. A series of analogues containing the 1-phenylpiperazine core scaffold were synthesized and evaluated. The structure-activity relationships (SAR) for these compounds was also discussed for further molecular design. This effort afforded the most active inhibitor 13f with improved activity in not only target-based level, but also cell-based level compared with the original hit 1.

Keywords
Hsp90 inhibitors; Structure-based drug design; Structure–activity relationships.