Synthesis and biological evaluation of synthetic viridins derived from C(20)-heteroalkylation of the steroidal PI-3-kinase inhibitor wortmannin

Org Biomol Chem. 2004 Jul 7;2(13):1911-20. doi: 10.1039/b405431h. Epub 2004 Jun 14.

Abstract

A series of viridin analogs was prepared from wortmannin by nucleophilic ring opening at C(20) and evaluated against the signaling kinases PI-3-kinase and mTOR. Several subnanomolar enzyme inhibitors with orders of magnitude selectivity for PI-3-kinase and strong cytotoxic activity against four cancer cell lines were identified. Among the ten most promising derivatives, six demonstrated lower liver toxicity and greater promise for inhibition of tumor cell growth than the lead structure wortmannin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylation
  • Androstadienes / chemistry*
  • Androstadienes / pharmacology
  • Androstenes / chemical synthesis*
  • Androstenes / chemistry
  • Androstenes / pharmacology*
  • Androstenes / toxicity
  • Bacteriocins / chemical synthesis*
  • Bacteriocins / chemistry
  • Bacteriocins / pharmacology*
  • Bacteriocins / toxicity
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Phosphatidylinositols / chemistry
  • Phosphatidylinositols / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Substrate Specificity
  • Wortmannin

Substances

  • Androstadienes
  • Androstenes
  • Bacteriocins
  • Phosphatidylinositols
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • viridin
  • Wortmannin