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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Caco-2 Cells
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Cell Cycle / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cytochrome P-450 Enzyme Inhibitors
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Liver Neoplasms / blood supply
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Liver Neoplasms / drug therapy
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Microsomes, Liver / metabolism
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Mitosis / drug effects
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Permeability
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Polymerization
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Reactive Oxygen Species / metabolism
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Rhabdomyosarcoma / blood supply
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Rhabdomyosarcoma / drug therapy
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Solubility
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Structure-Activity Relationship
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Tubulin / chemistry
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Tubulin Modulators / chemical synthesis*
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Tubulin Modulators / chemistry
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Tubulin Modulators / pharmacology
Substances
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2-(1H-imidazol-1-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
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2-(pyridin-4-yl)-3-((3,4,5-trimethoxyphenyl)thio)-1H-indole
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Antineoplastic Agents
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Cytochrome P-450 Enzyme Inhibitors
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Imidazoles
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Indoles
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Pyridines
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Reactive Oxygen Species
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Tubulin
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Tubulin Modulators