Abstract
New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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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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Biological Availability
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Caspase 3 / metabolism
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Cell Cycle / drug effects
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Cell Line
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Furans / chemical synthesis
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Furans / chemistry
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Furans / pharmacology
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Humans
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Injections, Intravenous
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Male
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Mice
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Mice, Nude
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Microsomes, Liver / metabolism
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Solubility
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Structure-Activity Relationship
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Thiophenes / chemical synthesis
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Thiophenes / chemistry
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Thiophenes / pharmacology
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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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Antineoplastic Agents
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Furans
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Indoles
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Pyrroles
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Thiophenes
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Tubulin Modulators
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Caspase 3