title: Antineoplastic agents 365. Dolastatin 10 SAR probes.
abstract: The remarkable anticancer drug dolastatin 10 (1a) from the Indian Ocean sea hare Dolabella auricularia is currently undergoing phase I clinical trials. Thirty-eight new structural modifications of this unusual peptide have been synthesized and evaluated against a variety of human and murine cancer cell lines, and for their ability to inhibit tubulin polymerization and vinblastine and GTP binding to tubulin. Dolastatin 10 and one structural modification was found to have antifungal activity, while one other structural modification of the parent compound exhibited antibacterial activity. Some of the new peptides approximated the antineoplastic potency of dolastatin 10, especially those based on replacement of the Doe unit with Met, Phe or an appropriately substituted phenylethylamide.
authors.affiliation: Department of Chemistry, Arizona State University, Tempe, AZ 85287-2404, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Pettit
authors.forename: J K
authors.initials: JK
authors.lastname: Srirangam
authors.forename: J
authors.initials: J
authors.lastname: Barkoczy
authors.forename: M D
authors.initials: MD
authors.lastname: Williams
authors.forename: M R
authors.initials: MR
authors.lastname: Boyd
authors.forename: E
authors.initials: E
authors.lastname: Hamel
authors.forename: R K
authors.initials: RK
authors.lastname: Pettit
authors.forename: F
authors.initials: F
authors.lastname: Hogan
authors.forename: R
authors.initials: R
authors.lastname: Bai
authors.forename: J C
authors.initials: JC
authors.lastname: Chapuis
authors.forename: S C
authors.initials: SC
authors.lastname: McAllister
authors.forename: J M
authors.initials: JM
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects; D047630:Depsipeptides; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D016982:Micrococcus luteus / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D000970:Antineoplastic Agents; D047630:Depsipeptides; D009842:Oligopeptides; D014404:Tubulin; C064570:dolastatin 10