title: Synthesis and structure-activity relationship of vicenistatin, a cytotoxic 20-membered macrolactam glycoside.
abstract: We have developed two syntheses of vicenistatin and its analogues. Our first-generation strategy included the rapid and sequential assembly of the macrocyclic lactam by using an intermolecular Horner-Wadsworth-Emmons reaction between the C3-C13 fragment and the C1-C2, C14-C19 fragment, followed by an intramolecular Stille coupling reaction. The second-generation strategy utilized a ring-closing metathesis of a hexaene intermediate to generate the desired 20-membered macrolactam. This second-generation strategy made it possible to prepare synthetic analogues of vicenistatin, including the C20- and/or C23-demethyl analogues. Evaluation of the cytotoxic effect of these analogues indicated the importance of the fixed conformation of aglycon for determining the biological activity of the vicenistatins.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-9578, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Fukuda
authors.forename: Yuko
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Shiina
authors.initials: S
authors.lastname: Nakamura
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Ohno
authors.forename: Tadashi
authors.initials: T
authors.lastname: Eguchi
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Iwabuchi
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.forename: Naoki
authors.initials: N
authors.lastname: Kanoh
mesh_terms: D000617:Aminoglycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D000970:Antineoplastic Agents; D006027:Glycosides; D007769:Lactams; D018942:Macrolides; C082785:vicenistatin