Design, synthesis, and activity of 4-quinolone and pyridone compounds as nonthiol-containing farnesyltransferase inhibitors

Qun Li; Akiyo Claiborne; Tongmei Li; Lisa Hasvold; Vincent S Stoll; Steven Muchmore; Clarissa G Jakob; Wendy Gu; Jerry Cohen; Charles Hutchins; David Frost; Saul H Rosenberg; Hing L Sham

doi:10.1016/j.bmcl.2004.08.012

Design, synthesis, and activity of 4-quinolone and pyridone compounds as nonthiol-containing farnesyltransferase inhibitors

Bioorg Med Chem Lett. 2004 Nov 1;14(21):5367-70. doi: 10.1016/j.bmcl.2004.08.012.

Authors

Qun Li¹, Akiyo Claiborne, Tongmei Li, Lisa Hasvold, Vincent S Stoll, Steven Muchmore, Clarissa G Jakob, Wendy Gu, Jerry Cohen, Charles Hutchins, David Frost, Saul H Rosenberg, Hing L Sham

Affiliation

¹ Cancer Research, GPRD, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. [email protected]

PMID: 15454228
DOI: 10.1016/j.bmcl.2004.08.012

Abstract

As a part of our efforts to identify potent inhibitors of farnesyltransferase (FTase), modification of the structure of tipifarnib through structure-based design was undertaken by replacing the 2-quinolones with 4-quinolones and pyridones, and subsequent relocation of the D-ring to the N-methyl group on the imidazole ring. This study has yielded a novel series of potent and selective FTase inhibitors. The X-ray structure of tipifarnib (1) in complex with FTase was described.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

4-Quinolones / chemical synthesis*
4-Quinolones / chemistry
Alkyl and Aryl Transferases / antagonists & inhibitors*
Alkyl and Aryl Transferases / chemistry*
Crystallography, X-Ray
Farnesyltranstransferase
Models, Molecular
Pyridones / chemical synthesis*
Pyridones / chemistry
Quinolones / chemistry
Structure-Activity Relationship

Substances

4-Quinolones
Pyridones
Quinolones
Alkyl and Aryl Transferases
Farnesyltranstransferase
tipifarnib