Non-thiol farnesyltransferase inhibitors: the concept of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors.
Replacement of the thiol in a benzophenone-based CAAX-peptidomimetic farnesyltransferase inhibitor by a carboxylic acid moiety resulted in a marked drop in inhibitory potency. Transformation of these carboxylic acid derivatives into bisubstrate analogues by addition of a lipophilic alkyl chain, which should be able to occupy considerable portions of the farnesyl binding region in the farnesyltransferase's active site, resulted in a regain of the inhibitory activity. These bisubstrate analogues represent new lead structures for non-thiol farnesyltransferase inhibitors.
Schlitzer
M
M
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, D-35032, Marburg, Germany. schlitze@mailer.uni-marburg.de
Sattler
I
I
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001577:Benzophenones / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D013057:Spectrum Analysis; D013379:Substrate Specificity; D013438:Sulfhydryl Compounds / Q000737:chemistry
D001577:Benzophenones; D004791:Enzyme Inhibitors; D013438:Sulfhydryl Compounds; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase