title: Synthesis and biological activities of novel 17-aminogeldanamycin derivatives.
abstract: Geldanamycin interferes with the action of heat shock protein 90 (Hsp90) by binding to the N-terminal ATP binding site and inhibiting an essential ATPase activity. In a program directed toward finding potent, water soluble inhibitors of Hsp90, we prepared a library of over sixty 17-alkylamino-17-demethoxygeldanamycin analogs, and compared their affinity for Hsp90, ability to inhibit growth of SKBr3 mammalian cells, and in selected cases, water solubility. Over 20 analogs showed cell growth inhibition potencies similar to that of 17-allylamino-17-demethoxygeldanamycin (17-AAG), the front-runner geldanamycin analog that is currently in multiple clinical trials. Many of these analogs showed water solubility properties that were desirable for formulation. One of the most potent and water-soluble analogs in the series was 17-(2-dimethylaminoethyl)amino-17-demethoxygeldanamycin (17-DMAG), which was independently prepared by the NCI and will soon enter clinical trials. Importantly, the binding affinity of these analogs to the molecular target Hsp90 does not correlate well with their cytotoxicity in SKBr3 cells.
authors.affiliation: Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, CA 94545, USA. tian@kosan.com
authors.forename: Zong-Qiang
authors.initials: ZQ
authors.lastname: Tian
authors.forename: Yaoquan
authors.initials: Y
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Wang
authors.forename: Steven D
authors.initials: SD
authors.lastname: Dong
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Carreras
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Zhou
authors.forename: Giulio
authors.initials: G
authors.lastname: Rastelli
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Santi
authors.forename: David C
authors.initials: DC
authors.lastname: Myles
mesh_terms: D000595:Amino Acid Sequence; D016227:Benzoquinones; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D008969:Molecular Sequence Data; D011809:Quinones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D011994:Recombinant Proteins; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D014867:Water; C001277:geldanamycin