Gedunin, a novel Hsp90 inhibitor: Semisynthesis of derivatives and preliminary structure-activity relationships

Gary E.L. Brandt, Matthew D. Schmidt, Thomas E. Prisinzano, Brian S.J. Blagg

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

Gedunin (1), a tetranortriterpenoid isolated from the Indian neem tree (Azadirachta indica), was recently shown to manifest anticancer activity via inhibition of the 90 kDa heat shock protein (Hsp90) folding machinery and to induce the degradation of Hsp90-dependent client proteins similar to other Hsp90 inhibitors. The mechanism of action by which gedunin induces client protein degradation remains undetermined, however, prior studies have demonstrated that it does not bind competitively versus ATP. In an effort to further probe the mechanism of action, 19 semisynthetic derivatives of gedunin were prepared and their antiproliferative activity against MCF-7 and SkBr3 breast cancer cells determined. Although no compound was found to exhibit antiproliferative activity more effective than the natural product, functionalities critical for antiproliferative activity have been identified.

Original languageEnglish
Pages (from-to)6495-6502
Number of pages8
JournalJournal of Medicinal Chemistry
Volume51
Issue number20
DOIs
StatePublished - Oct 23 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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