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American Chemical Society, Journal of Medicinal Chemistry, 15(57), p. 6531-6552, 2014

DOI: 10.1021/jm500561a

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New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer

Journal article published in 2014 by Giuseppe La Regina, Ruoli Bai, Antonio Coluccia, Valeria Famiglini, Sveva Pelliccia ORCID, Sara Passacantilli ORCID, Carmela Mazzoccoli, Vitalba Ruggieri, Lorenza Sisinni, Alessio Bolognesi, Whilelmina Maria Rensen, Andrea Miele, Marianna Nalli, Romina Alfonsi ORCID, Lucia Di Marcotullio and other authors.
This paper is available in a repository.
This paper is available in a repository.

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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.