New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.

Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability / LA REGINA, Giuseppe; Ruoli, Bai; Willeke, Rensen; Coluccia, Antonio; Piscitelli, Francesco; Gatti, Valerio; Alessio, Bolognesi; Antonio, Lavecchia; Ilaria, Granata; Amalia, Porta; Bruno, Maresca; Soriani, Alessandra; Iannitto, MARIA LUISA; Marisa, Mariani; Santoni, Angela; Andrea, Brancale; Cristiano, Ferlini; Giulio, Dondio; Mario, Varasi; Ciro, Mercurio; Ernest, Hamel; Patrizia, Lavia; Ettore, Novellino; Silvestri, Romano. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 54:24(2011), pp. 8394-8406. [10.1021/jm2012886]

Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability

LA REGINA, GIUSEPPE;COLUCCIA, Antonio;PISCITELLI, FRANCESCO;GATTI, VALERIO;SORIANI, Alessandra;IANNITTO, MARIA LUISA;SANTONI, Angela;SILVESTRI, Romano
2011

Abstract

New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/502225
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