title: Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors.
abstract: Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.
authors.affiliation: Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com <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: Weibo
authors.initials: W
authors.lastname: Wang
authors.forename: Nan-Horng
authors.initials: NH
authors.lastname: Lin
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Wen-zhen
authors.initials: WZ
authors.lastname: Gu
authors.forename: Jerry
authors.initials: J
authors.lastname: Cohen
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Charles
authors.initials: C
authors.lastname: Hutchins
authors.forename: David
authors.initials: D
authors.lastname: Frost
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D015363:Quinolones / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D006912:Hydroxyquinolines; D007211:Indoles; D015363:Quinolones; C010064:carbostyril; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase