title: Total synthesis and biological evaluation of C16 analogs of (-)-dictyostatin.
abstract: The structure-activity relationship of the crucial C16 region of (-)-dictyostatin was established through total synthesis of analogs followed by detailed biological characterization. A versatile synthetic strategy was used to prepare milligram quantities of 16-normethyldictyostatin, 16-epi-dictyostatin, and the C16-normethyl-C15Z isomer. Along the way, a number of other E/Z isomers and epimers were prepared, and a novel lactone ring contraction to make iso-dictyostatins with 20-membered macrolactones (instead of 22-membered macrolactones) was discovered. The synthesis of 16-normethyl-15,16-dehydrodictyostatin is the first of any dictyostatin by a maximally convergent route in which three main fragments are assembled, coupled in back-to-back steps, and then processed through refunctionalization and macrolactonization. Cell-based and biochemical evaluations showed 16-normethyl-15,16-dehydrodictyostatin and 16-normethyldictyostatin to be the most potent of the new agents, only 2- and 5-fold less active than (-)-dictyostatin itself. This data and that from previously generated dictyostatin analogs are combined to produce a picture of the structure-activity relationships in this series of anticancer agents.
authors.affiliation: Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Won-Hyuk
authors.initials: WH
authors.lastname: Jung
authors.forename: Cristian
authors.initials: C
authors.lastname: Harrison
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.forename: Jean-Hugues
authors.initials: JH
authors.lastname: Fournier
authors.forename: Raghavan
authors.initials: R
authors.lastname: Balachandran
authors.forename: Brianne S
authors.initials: BS
authors.lastname: Raccor
authors.forename: Rachel P
authors.initials: RP
authors.lastname: Sikorski
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Curran
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002417:Cattle; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008870:Microtubules / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D018942:Macrolides; D014404:Tubulin; C470814:dictyostatin