Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase

Cristiano Bolchi; Marco Pallavicini; Sergio K. Bernini; Giuseppe Chiodini; Alberto Corsini; Nicola Ferri; Laura Fumagalli; Valentina Straniero; Ermanno Valoti

doi:10.1016/j.bmcl.2011.07.003

Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase

Cristiano Bolchi, Marco Pallavicini, Sergio K. Bernini, Giuseppe Chiodini, Alberto Corsini, Nicola Ferri, Laura Fumagalli, Valentina Straniero, Ermanno Valoti

IRCCS Multimedica

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	5408-5412
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2011.07.003
Publication status	Published - Sep 15 2011

Keywords

Antiproliferative agents
Antitumors
Farnesyltransferase
Peptidomimetic inhibitors
Prenylation inihibitors

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

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Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase. / Bolchi, Cristiano; Pallavicini, Marco; Bernini, Sergio K.; Chiodini, Giuseppe; Corsini, Alberto; Ferri, Nicola; Fumagalli, Laura; Straniero, Valentina; Valoti, Ermanno.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 21, No. 18, 15.09.2011, p. 5408-5412.

Research output: Contribution to journal › Article › peer-review

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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.",

keywords = "Antiproliferative agents, Antitumors, Farnesyltransferase, Peptidomimetic inhibitors, Prenylation inihibitors",

author = "Cristiano Bolchi and Marco Pallavicini and Bernini, {Sergio K.} and Giuseppe Chiodini and Alberto Corsini and Nicola Ferri and Laura Fumagalli and Valentina Straniero and Ermanno Valoti",

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AU - Bernini, Sergio K.

AU - Chiodini, Giuseppe

AU - Corsini, Alberto

AU - Ferri, Nicola

AU - Fumagalli, Laura

AU - Straniero, Valentina

AU - Valoti, Ermanno

PY - 2011/9/15

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N2 - 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.

AB - 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.

KW - Antiproliferative agents

KW - Antitumors

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KW - Peptidomimetic inhibitors

KW - Prenylation inihibitors

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Thiazole- and imidazole-containing peptidomimetic inhibitors of protein farnesyltransferase

Abstract

Keywords

ASJC Scopus subject areas

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