New, non-quinone fluorogeldanamycin derivatives strongly inhibit Hsp90

Chembiochem. 2015 Jan 19;16(2):302-11. doi: 10.1002/cbic.201402375. Epub 2015 Jan 8.

Abstract

Streptomyces hygroscopicus is a natural producer of geldanamycin. Mutasynthetic supplementation of an AHBA-blocked mutant with all possible monofluoro 3-aminobenzoic acids provided new fluorogeldanamycins. These showed strong antiproliferative activity and inhibitory effects on human heat shock protein Hsp90. Binding to Hsp90 in the low nanomolar range was determined from molecular modelling, AFM analysis and by calorimetric studies.

Keywords: Hsp90; fluorinated compounds; geldanamycin; inhibitors; mutasynthesis; single molecule force spectroscopy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Benzoquinones / chemistry*
  • Calorimetry / methods
  • Cell Line, Tumor / drug effects
  • Cell Proliferation / drug effects
  • Fluorobenzenes / metabolism
  • Fluorobenzenes / pharmacology
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / chemistry*
  • Magnetic Resonance Spectroscopy
  • Microscopy, Atomic Force
  • Models, Molecular
  • Quinones / chemistry
  • Streptomyces / genetics
  • Streptomyces / metabolism*
  • meta-Aminobenzoates / metabolism
  • meta-Aminobenzoates / pharmacology

Substances

  • Antineoplastic Agents
  • Benzoquinones
  • Fluorobenzenes
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Quinones
  • meta-Aminobenzoates
  • geldanamycin