title: Complex target-oriented total synthesis in the drug discovery process: the discovery of a highly promising family of second generation epothilones.
abstract: The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.
authors.affiliation: Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Rivkin
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yoshimura
authors.forename: Ana E
authors.initials: AE
authors.lastname: Gabarda
authors.forename: Ting-Chao
authors.initials: TC
authors.lastname: Chou
authors.forename: Huajin
authors.initials: H
authors.lastname: Dong
authors.forename: William P
authors.initials: WP
authors.lastname: Tong
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
mesh_terms: D000970:Antineoplastic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D034261:Epothilones / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones