2. Academic Validation
  3. Design and synthesis of 2-heterocyclyl-3-arylthio-1H-indoles as potent tubulin polymerization and cell growth inhibitors with improved metabolic stability

Design and synthesis of 2-heterocyclyl-3-arylthio-1H-indoles as potent tubulin polymerization and cell growth inhibitors with improved metabolic stability

  • J Med Chem. 2011 Dec 22;54(24):8394-406. doi: 10.1021/jm2012886.
Giuseppe La Regina 1,  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
Affiliations

Affiliation

  • 1 Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
PMID: 22044164 DOI: 10.1021/jm2012886
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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