title: Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships.
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.
authors.affiliation: Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045-7582, USA.
authors.forename: Gary E L
authors.initials: GE
authors.lastname: Brandt
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Schmidt
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D036701:Limonins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D018841:HSP90 Heat-Shock Proteins; D036701:Limonins; C106014:gedunin