Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors.

Abstract

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.

• Authors: Giuseppe La Regina, Ruoli Bai, Whilelmina Maria Rensen, Erica Di Cesare, Antonio Coluccia, Francesco Piscitelli, Valeria Famiglini, Alessia Reggio, Marianna Nalli, Sveva Pelliccia, Eleonora Da Pozzo, Barbara Costa, Ilaria Granata, Amalia Porta, Bruno Maresca, Alessandra Soriani, Maria Luisa Iannitto, Angela Santoni, Junjie Li, Marlein Miranda Cona, Feng Chen, Yicheng Ni, Andrea Brancale, Giulio Dondio, Stefania Vultaggio, Mario Varasi, Ciro Mercurio, Claudia Martini, Ernest Hamel, Patrizia Lavia, Ettore Novellino, Romano Silvestri
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 1 Pg. 123-49 (Jan 10 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23214452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(1H-imidazol-1-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
• 2-(pyridin-4-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
• Antineoplastic Agents
• Cytochrome P-450 Enzyme Inhibitors
• Imidazoles
• Indoles
• Pyridines
• Reactive Oxygen Species
• Tubulin
• Tubulin Modulators

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Caco-2 Cells
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cytochrome P-450 Enzyme Inhibitors
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Indoles (chemical synthesis, chemistry, pharmacology)
• Liver Neoplasms (blood supply, drug therapy)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Microsomes, Liver (metabolism)
• Mitosis (drug effects)
• Permeability
• Polymerization
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Reactive Oxygen Species (metabolism)
• Rhabdomyosarcoma (blood supply, drug therapy)
• Solubility
• Structure-Activity Relationship
• Tubulin (chemistry)
• Tubulin Modulators (chemical synthesis, chemistry, pharmacology)