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American Chemical Society, Journal of Medicinal Chemistry, 24(54), p. 8394-8406, 2011

DOI: 10.1021/jm2012886

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

Journal article published in 2011 by Giuseppe La Regina, Ruoli Bai, Willeke Rensen, Antonio Coluccia ORCID, Francesco Piscitelli, Valerio Gatti, Alessio Bolognesi, Antonio Lavecchia, Ilaria Granata, Amalia Porta, Bruno Maresca, Alessandra Soriani, Maria Luisa Iannitto, Marisa Mariani, Angela Santoni and other authors.
This paper is available in a repository.
This paper is available in a repository.

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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.