title: Antineoplastic agents. 599. Total synthesis of dolastatin 16.
abstract: The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis. Regrettably, the synthetic dolastatin 16 (1), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (1) or to a chemically undetected component isolated with the natural product.
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: George R
authors.initials: GR
authors.lastname: Pettit
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Smith
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Arce
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Flahive
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Collin R
authors.initials: CR
authors.lastname: Anderson
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Chapuis
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Xu
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Groy
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Belcher
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 871604, Tempe, Arizona 85287-1604, United States.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Macdonald
mesh_terms: D000812:Anhydrides / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D009579:Nitrobenzoates / Q000737:chemistry; D019906:Nuclear Magnetic Resonance, Biomolecular; D014407:Tumor Cells, Cultured
chemical_list: C526944:2-methyl-6-nitrobenzoic anhydride; D000812:Anhydrides; D000970:Antineoplastic Agents; D047630:Depsipeptides; D009579:Nitrobenzoates; C108201:dolastatin 16