Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors.
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.
Li
Qun
Q
Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com <qun.li@abbott.com>
Woods
Keith W
KW
Wang
Weibo
W
Lin
Nan-Horng
NH
Claiborne
Akiyo
A
Gu
Wen-zhen
WZ
Cohen
Jerry
J
Stoll
Vincent S
VS
Hutchins
Charles
C
Frost
David
D
Rosenberg
Saul H
SH
Sham
Hing L
HL
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
D004791:Enzyme Inhibitors; D006912:Hydroxyquinolines; D007211:Indoles; D015363:Quinolones; C010064:carbostyril; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase