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

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.
AuthorsPeter Wipf, Daniel J Minion, Robert J Halter, Margareta I Berggren, Caroline B Ho, Gary G Chiang, Lynn Kirkpatrick, Robert Abraham, Garth Powis
JournalOrganic & biomolecular chemistry (Org Biomol Chem) Vol. 2 Issue 13 Pg. 1911-20 (Jul 07 2004) ISSN: 1477-0520 [Print] England
PMID15227545 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Androstadienes
  • Androstenes
  • Bacteriocins
  • Phosphatidylinositols
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • viridin
  • Wortmannin
Topics
  • Alkylation
  • Androstadienes (chemistry, pharmacology)
  • Androstenes (chemical synthesis, chemistry, pharmacology, toxicity)
  • Bacteriocins (chemical synthesis, chemistry, pharmacology, toxicity)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Phosphatidylinositols (chemistry, metabolism)
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
  • Substrate Specificity
  • Wortmannin

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