title: Antineoplastic Agents. 603. Quinstatins: Exceptional Cancer Cell Growth Inhibitors.
abstract: Discovery of the exceptionally powerful anticancer drug dolastatin 10 (1), contained in the sea hare Dolabella auricularia, opened a new frontier needed for improving human cancer treatment. Subsequently, major advances have been achieved based on results of structurally modifying this unusual natural peptide while maintaining the remarkable anticancer activity necessary for preparation of successful monoclonal antibody drug conjugates (ADC). Among the first several hundred SAR products based on dolastatin 10 our group synthesized and termed auristatins was auristatin E (2a). An anticancer activity-equivalent, desmethylaurisatin E (2b), linked to a CD30 monoclonal antibody is the very successful anticancer drug Adcetris, now approved for use in 65 countries. In the present investigation, we discovered a new subset of auristatins designated quinstatins derived from dolastatin 10 by replacing the C-terminal Doe unit with a carefully designed quinoline, which led to low or subnanomolar levels of cancer cell growth inhibition required for construction of chemically unique ADC drugs. The synthesis of quinstatins 2-8 is presented along with their cancer cell line biological data.
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.identifier: 0000-0001-8706-8929
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: Noeleen
authors.initials: N
authors.lastname: Melody
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
mesh_terms: D062365:Aminobenzoates; D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000079963:Brentuximab Vedotin; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D049851:Gastropoda / Q000737:chemistry; D006801:Humans; D018796:Immunoconjugates; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology
chemical_list: D062365:Aminobenzoates; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047630:Depsipeptides; D018796:Immunoconjugates; D009842:Oligopeptides; C543533:auristatin; D000079963:Brentuximab Vedotin; C064570:dolastatin 10