1. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer.
- Author
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La Regina G, Bai R, Coluccia A, Famiglini V, Pelliccia S, Passacantilli S, Mazzoccoli C, Ruggieri V, Sisinni L, Bolognesi A, Rensen WM, Miele A, Nalli M, Alfonsi R, Di Marcotullio L, Gulino A, Brancale A, Novellino E, Dondio G, Vultaggio S, Varasi M, Mercurio C, Hamel E, Lavia P, and Silvestri R
- Subjects
- Aniline Compounds chemical synthesis, Aniline Compounds pharmacology, Animals, Antineoplastic Agents chemical synthesis, 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 pharmacology, Hedgehog Proteins antagonists & inhibitors, Humans, M Phase Cell Cycle Checkpoints drug effects, Mice, Molecular Docking Simulation, Neoplasms drug therapy, Neoplasms pathology, Polymerization, Protein Binding, Pyrroles chemical synthesis, Pyrroles pharmacology, Signal Transduction, Structure-Activity Relationship, Tubulin chemistry, Tubulin Modulators chemical synthesis, Tubulin Modulators pharmacology, Aniline Compounds chemistry, Antineoplastic Agents chemistry, Guanidines chemistry, Hedgehog Proteins metabolism, Neoplasms metabolism, Pyrroles chemistry, Tubulin Modulators chemistry
- 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.
- Published
- 2014
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