Abstract
Combretastatin A-4 is an antitumoral and antitubulin agent that is active only in its cis configuration. In the present manuscript, we have synthesized cis-locked combretastatins containing a triazole ring (combretatriazoles). To achieve this, we have developed a column chromatography-free parallel solution-phase synthesis that exploits the reaction between azides and alpha-keto phosphorus ylids, which is known to regioselectively generate the 1,5-disubstituted triazoles. The prepared compounds were screened as antitubulinic agents, allowing us to identify three new compounds with high potency, two of which show a new mechanism of action that induces cells to appear multinucleated and display a high number of mitotic spindles.
Publication types
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Evaluation Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Phytogenic / chemical synthesis
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Antineoplastic Agents, Phytogenic / pharmacology*
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Catalysis
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Cell Line, Tumor / drug effects
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Cell Line, Tumor / pathology
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Chromatography, High Pressure Liquid
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Dose-Response Relationship, Drug
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Inhibitory Concentration 50
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Microscopy, Electron, Scanning
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Ruthenium / chemistry
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Solutions / chemistry
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Stereoisomerism
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Stilbenes / chemical synthesis
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Stilbenes / pharmacology*
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Structure-Activity Relationship
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Triazoles / chemical synthesis
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Triazoles / pharmacology*
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Tubulin Modulators / chemical synthesis
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Tubulin Modulators / pharmacology*
Substances
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Antineoplastic Agents, Phytogenic
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Solutions
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Stilbenes
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Triazoles
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Tubulin Modulators
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Ruthenium
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fosbretabulin