New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer

  • J Med Chem. 2014 Aug 14;57(15):6531-52. doi: 10.1021/jm500561a.
Giuseppe La Regina  1 ,  Ruoli Bai ,  Antonio Coluccia ,  Valeria Famiglini ,  Sveva Pelliccia ,  Sara Passacantilli ,  Carmela Mazzoccoli ,  Vitalba Ruggieri ,  Lorenza Sisinni ,  Alessio Bolognesi ,  Whilelmina Maria Rensen ,  Andrea Miele ,  Marianna Nalli ,  Romina Alfonsi ,  Lucia Di Marcotullio ,  Alberto Gulino ,  Andrea Brancale ,  Ettore Novellino ,  Giulio Dondio ,  Stefania Vultaggio ,  Mario Varasi ,  Ciro Mercurio ,  Ernest Hamel ,  Patrizia Lavia ,  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: 25025991 DOI: 10.1021/jm500561a
Abstract

We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential Anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and Cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of Medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and Cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.