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.
Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase / C. Bolchi, M. Pallavicini, S.K. Bernini, G. Chiodini, A. Corsini, N. Ferri, L. Fumagalli, V. Straniero, E. Valoti. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 21:18(2011), pp. 5408-5412.
Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase
C. Bolchi;M. Pallavicini;G. Chiodini;A. Corsini;N. Ferri;L. Fumagalli;V. Straniero;E. Valoti
2011
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.File | Dimensione | Formato | |
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