title: On the interactivity of complex synthesis and tumor pharmacology in the drug discovery process: total synthesis and comparative in vivo evaluations of the 15-aza epothilones.
abstract: The total syntheses of 12,13,15-desoxy-15(S)-aza-epothilone B (aza-dEpoB; dEpoB-lactam) and 12,13,15-desoxy-15(R)-aza-epothilone B (15-epi-aza-dEpoB; 15-epi-dEpoB-lactam) have been accomplished via a highly convergent strategy. We have also successfully oxidized 12,13,15-desoxy-15(S)-aza-epothilone B to aza-epothilone B (aza-EpoB; EpoB-lactam). Aza-epothilone B has been advanced to phase I clinical trials by the Bristol-Myers Squibb group. Our synthesis is efficient and was amenable to the production of significant quantities of these lactams. Using our fully synthetically derived lactams, in vitro and in vivo studies were conducted in comparison with advanced clinical candidates, 12,13-desoxyepothilone B and 12,13-desoxyepothilone F, also derived by total synthesis.
authors.affiliation: Laboratories for Bioorganic Chemistry, Preclinical Pharmacology, and the Preparative Synthesis Core Facility, The Sloan-Kettering Institute for Cancer, Research, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Stachel
authors.forename: C B
authors.initials: CB
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Spassova
authors.forename: M D
authors.initials: MD
authors.lastname: Chappell
authors.forename: W G
authors.initials: WG
authors.lastname: Bornmann
authors.forename: S J
authors.initials: SJ
authors.lastname: Danishefsky
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: Y
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D013057:Spectrum Analysis; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D004852:Epoxy Compounds; D013844:Thiazoles; C093788:epothilone B