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. Epub 2014 Feb 15.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • HCT116 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • MCF-7 Cells
  • Molecular Docking Simulation
  • Phenyl Ethers / chemical synthesis*
  • Phenyl Ethers / chemistry
  • Phenyl Ethers / pharmacology*
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Phenyl Ethers
  • Piperazines
  • phenylpiperazine