title: D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors.
abstract: Modifications of the D-piece carboxylic acid group of the hemiasterlin analog HTI-286 gave tubulin inhibitors which were potent cytotoxic agents in taxol resistant cell lines expressing P-glycoprotein. Amides derived from proline had potency comparable to HTI-286. Reduction of the carboxylic acid to ketones and alcohols or its conversion to acidic heterocycles also gave potent analogs. Synthetic modifications of the carboxylic acid could be carried out selectively using a wide range of synthetic reagents. Proline analog 3 was found to be effective in a human xenograft model in athymic mice.
authors.affiliation: Wyeth Research, Chemical and Screening Sciences, 401 North Middletown Road, Pearl River, NY 10965, USA. zaska@wyeth.com
authors.forename: Arie
authors.initials: A
authors.lastname: Zask
authors.forename: Gary
authors.initials: G
authors.lastname: Birnberg
authors.forename: Katherine
authors.initials: K
authors.lastname: Cheung
authors.forename: Joshua
authors.initials: J
authors.lastname: Kaplan
authors.forename: Chuan
authors.initials: C
authors.lastname: Niu
authors.forename: Emily
authors.initials: E
authors.lastname: Norton
authors.forename: Ayako
authors.initials: A
authors.lastname: Yamashita
authors.forename: Carl
authors.initials: C
authors.lastname: Beyer
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Lee M
authors.initials: LM
authors.lastname: Greenberger
authors.forename: Frank
authors.initials: F
authors.lastname: Loganzo
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators
chemical_list: C473896:HTI-286; D009842:Oligopeptides; D050257:Tubulin Modulators