title: Synthesis and biological evaluation of 2-indolyloxazolines as a new class of tubulin polymerization inhibitors. Discovery of A-289099 as an orally active antitumor agent.
abstract: A series of indole containing oxazolines has been discovered as a result of structural modifications of the lead compound A-105972. The compounds exert their anticancer activity through inhibition of tubulin polymerization by binding at the colchicine site. A-289099 was identified as an orally active antimitotic agent active against various cancer cell lines including those that express the MDR phenotype. The anticancer activity, pharmacokinetics, and an efficient and enantioselective synthesis of A-289099 are described.
authors.affiliation: Cancer Research, Abbott Laboratories, 60064-6101, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Keith W
authors.initials: KW
authors.lastname: Woods
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Gwaltney
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Barr
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Laura
authors.initials: L
authors.lastname: Gehrke
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Credo
authors.forename: Yu Hua
authors.initials: YH
authors.lastname: Hui
authors.forename: Jang
authors.initials: J
authors.lastname: Lee
authors.forename: Robert B
authors.initials: RB
authors.lastname: Warner
authors.forename: Peter
authors.initials: P
authors.lastname: Kovar
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nukkala
authors.forename: Nicolette A
authors.initials: NA
authors.lastname: Zielinski
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Michael
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Ki H
authors.initials: KH
authors.lastname: Kim
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: David
authors.initials: D
authors.lastname: Frost
authors.forename: Shi-Chung
authors.initials: SC
authors.lastname: Ng
authors.forename: Saul
authors.initials: S
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D010080:Oxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011108:Polymers / Q000138:chemical synthesis; D051381:Rats; D013237:Stereoisomerism; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D010080:Oxazoles; D011108:Polymers; D014404:Tubulin; C456410:A 289099