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

• Published in: Journal of medicinal chemistry 2014-08, Vol.57 (15), p.6531-6552
• Main Authors: La Regina, Giuseppe, Bai, Ruoli, Coluccia, Antonio, Famiglini, Valeria, Pelliccia, Sveva, Passacantilli, Sara, Mazzoccoli, Carmela, Ruggieri, Vitalba, Sisinni, Lorenza, Bolognesi, Alessio, Rensen, Whilelmina Maria, Miele, Andrea, Nalli, Marianna, Alfonsi, Romina, Di Marcotullio, Lucia, Gulino, Alberto, Brancale, Andrea, Novellino, Ettore, Dondio, Giulio, Vultaggio, Stefania, Varasi, Mario, Mercurio, Ciro, Hamel, Ernest, Lavia, Patrizia, Silvestri, Romano
• Format: Article
• Language: English
• Subjects: Aniline Compounds - chemical synthesis; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Death - drug effects; Cell Line, Tumor; Cell Membrane Permeability - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Colchicine - chemistry; Drug Screening Assays, Antitumor; Guanidines - chemical synthesis; Guanidines - chemistry; Guanidines - pharmacology; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - metabolism; Humans; M Phase Cell Cycle Checkpoints - drug effects; Mice; Molecular Docking Simulation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Polymerization; Protein Binding; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Signal Transduction; Structure-Activity Relationship; Tubulin - chemistry; Tubulin Modulators - chemical synthesis; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm500561a

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.