2. Academic Validation
  3. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer

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

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: 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.

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