Design and Synthesis of 2-Heterocyclyl-3-arylthio-1H-indoles as Potent Tubulin Polymerization and Cell Growth Inhibitors with Improved Metabolic Stability
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- 作者：Giuseppe La Regina ; Ruoli Bai ; Willeke Rensen ; Antonio Coluccia ; Francesco Piscitelli ; Valerio Gatti ; Alessio Bolognesi ; Antonio Lavecchia ; Ilaria Granata ; Amalia Porta ; Bruno Maresca ; Alessandra Soriani ; Maria Luisa Iannitto ; Marisa Mariani ; Angela Santoni ; Andrea Brancale ; Cristiano Ferlini ; Giulio Dondio ; Mario Varasi ; Ciro Mercurio ; Ernest Hamel ; Patrizia Lavia ; Ettore Novellino ; Romano Silvestri
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：December 22, 2011
- 年：2011
- 卷：54
- 期：24
- 页码：8394-8406
- 全文大小：533K
- 年卷期：v.54,no.24(December 22, 2011)
- ISSN：1520-4804
文摘
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.