Non-thiol farnesyltransferase inhibitors: evaluation of different AA(X)-peptidomimetic substructures in combination with arylic cysteine replacements.
In the course of our studies on non-thiol farnesyltransferase inhibitors based on the 2, 5-diaminobenzophenone AAX-peptidomimetic substructure, we have developed the (4-nitrophenyl)butyryl (R(1)), the (2-naphthyl)acryloyl (R(2)), the 4-nitrocinnamoyl (R(3)), and the 5-(4-nitrophenyl)furylacryloyl (R(4)) groups as useful cysteine replacements. In this study, we combined these four groups with other AA(X)-peptidomimetic substructures (5-10: R = H) reported in the literature. The 5-(4-nitrophenyl)furylacryloyl moiety (R(4)) turned out to be the most useful non-thiol cysteine replacement yielding in all cases the most active inhibitors. By combination of this 5-(4-nitrophenyl) furylacryloyl moiety (R(4)) with the structurally simple AAX-peptidomimetics 4-aminobenzophenone (5) and 4-aminodiphenylsulfone (6) potent, readily accessible non-thiol farnesyltransferase inhibitors were obtained (IC(50) = 12 nMand 10 nM).
Sakowski
Jacek
J
Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Germany.
Böhm
Markus
M
Sattler
Isabel
I
Schlitzer
Martin
M
D000179:Acrylates / Q000737:chemistry; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D003545:Cysteine / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D018716:Molecular Mimicry
D000179:Acrylates; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D003545:Cysteine