Synthesis and biological evaluation of 3,5-disubstituted-4-alkynylisoxozales as a novel class of HSP90 inhibitors

Bioorg Med Chem Lett. 2015 Aug 15;25(16):3129-34. doi: 10.1016/j.bmcl.2015.06.009. Epub 2015 Jun 15.

Abstract

A series of 3,5-disubstitute-4-alkynylisoxazole derivatives were designed and synthesized through palladium(II)-copper(I) catalyzed Sonogashira cross-coupling reaction of an alkynyl moiety and an isoxazole scaffold as novel HSP90 inhibitors. The resultant compounds displayed moderate to potent binding affinity to HSP90 proteins, and also demonstrated good cell growth inhibitory activity against various cancer cell lines (A549, K562, MCF-7, DU145 and Hela). Some compounds (18d, 18e, 19a, 19d, 20c and 20q) show similar or better binding affinity towards HSP90α and HSP90β comparing to NVP-AUY922. In addition, compounds 18e, 19a and 20q exhibited potent inhibitory activity against various human cancer cell lines.

Keywords: 3,5-Disubstitute-4-alkynylisoxazole; HSP90; HSP90 inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Binding Sites
  • Catalysis
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Copper / chemistry
  • Drug Screening Assays, Antitumor
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacology
  • Isoxazoles / toxicity
  • Molecular Docking Simulation
  • Palladium / chemistry
  • Resorcinols / toxicity
  • Structure-Activity Relationship

Substances

  • 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
  • HSP90 Heat-Shock Proteins
  • Isoxazoles
  • Resorcinols
  • Palladium
  • Copper