Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity

Qun Li; Tongmei Li; Keith W Woods; Wen-Zhen Gu; Jerry Cohen; Vincent S Stoll; Tomas Galicia; Charles Hutchins; David Frost; Saul H Rosenberg; Hing L Sham

doi:10.1016/j.bmcl.2005.03.049

Benzimidazolones and indoles as non-thiol farnesyltransferase inhibitors based on tipifarnib scaffold: synthesis and activity

Bioorg Med Chem Lett. 2005 Jun 2;15(11):2918-22. doi: 10.1016/j.bmcl.2005.03.049. Epub 2005 Apr 21.

Authors

Qun Li¹, Tongmei Li, Keith W Woods, Wen-Zhen Gu, Jerry Cohen, Vincent S Stoll, Tomas Galicia, 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

PMID: 15911281
DOI: 10.1016/j.bmcl.2005.03.049

Abstract

A series of analogs of tipifarnib (1) has been synthesized as inhibitors of FTase by substituting the benzimidazolones and indoles for the 2-quinolone of tipifarnib. The novel benzimidazolones are potent and selective FTase inhibitors (FTIs) with IC(50) values of the best compounds close to that of tipifarnib. The current series demonstrate good cellular activity as measured in their inhibiting the Ras processing in NIH-3T3 cells, with compounds 2c and 2f displaying EC(50) values of 18 and 22nM, respectively.

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Animals
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Farnesyltranstransferase
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Mice
NIH 3T3 Cells
Quinolones / chemistry*

Substances

Benzimidazoles
Enzyme Inhibitors
Indoles
Quinolones
benzimidazolone
Alkyl and Aryl Transferases
Farnesyltranstransferase
tipifarnib