title: Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase.
abstract: Mimetics of the C-terminal CAAX tetrapeptide of Ras protein were designed replacing internal dipeptide AA with 4-amino-2-phenylbenzoic acid and cysteine (C) with 2-amino-4-thiazolyl-, 2-mercapto-4-thiazolyl-, 2-mercapto-4-imidazolyl- and 2-methylmercapto-4-thiazolyl-acetic or propionic acid. The compound in which C is replaced by 2-amino-4-thiazolylacetic acid inhibited FTase activity in the low nanomolar range and showed antiproliferative effect on rat aortic smooth muscle cells interfering with Ras farnesylation. On the basis of these results, 2-aminothiazole can be considered as an alternative to heterocycles, such as pyridine and imidazole, normally used in FTase inhibitors designed as non-thiol CAAX mimetics.
authors.affiliation: Dipartimento di Scienze Farmaceutiche Pietro Pratesi, Università di Milano, via Mangiagalli 25, I-20133 Milano, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Bolchi
authors.forename: Marco
authors.initials: M
authors.lastname: Pallavicini
authors.forename: Sergio K
authors.initials: SK
authors.lastname: Bernini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Chiodini
authors.forename: Alberto
authors.initials: A
authors.lastname: Corsini
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferri
authors.forename: Laura
authors.initials: L
authors.lastname: Fumagalli
authors.forename: Valentina
authors.initials: V
authors.lastname: Straniero
authors.forename: Ermanno
authors.initials: E
authors.lastname: Valoti
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D057786:Peptidomimetics; D013844:Thiazoles; C029899:imidazole; D051231:Farnesyltranstransferase