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
  • 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.