New Pyrrole Derivatives with Potent Tubulin Polymerization Inhibiting Activity As Anticancer Agents Including Hedgehog-Dependent Cancer
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- 作者：Giuseppe La Regina ; 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
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：August 14, 2014
- 年：2014
- 卷：57
- 期：15
- 页码：6531-6552
- 全文大小：1104K
- ISSN：1520-4804
文摘
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.