Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors

Qun Li; Keith W Woods; Weibo Wang; Nan-Horng Lin; Akiyo Claiborne; Wen-zhen Gu; Jerry Cohen; Vincent S Stoll; Charles Hutchins; David Frost; Saul H Rosenberg; Hing L Sham

doi:10.1016/j.bmcl.2005.02.062

Design, synthesis, and activity of achiral analogs of 2-quinolones and indoles as non-thiol farnesyltransferase inhibitors

Bioorg Med Chem Lett. 2005 Apr 15;15(8):2033-9. doi: 10.1016/j.bmcl.2005.02.062.

Authors

Qun Li¹, Keith W Woods, Weibo Wang, Nan-Horng Lin, Akiyo Claiborne, Wen-zhen Gu, Jerry Cohen, Vincent S Stoll, Charles Hutchins, David Frost, Saul H Rosenberg, Hing L Sham

Affiliation

¹ Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. qun.li@abbott.com <qun.li@abbott.com>

PMID: 15808463
DOI: 10.1016/j.bmcl.2005.02.062

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.

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Animals
Cattle
Drug Design*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Farnesyltranstransferase
Hydroxyquinolines / chemical synthesis*
Hydroxyquinolines / pharmacology
Indoles / chemical synthesis*
Indoles / pharmacology
Mice
NIH 3T3 Cells
Quinolones / chemical synthesis*
Quinolones / pharmacology
Stereoisomerism

Substances

Enzyme Inhibitors
Hydroxyquinolines
Indoles
Quinolones
carbostyril
Alkyl and Aryl Transferases
Farnesyltranstransferase