Abstract
The efficient total synthesis of the natural substance largazole is described. Using this strategy, a small library of largazole analogs was developed. Structure-activity relationship studies suggested that the geometry of the alkene in the side chain is critical. While the largazole's analogues with trans-alkene are potent for the antiproliferative effect, those with cis-alkene are completely inactive. Most importantly, replacement of valine with tyrosine in largazole increased selectivity toward human cancer cells over human normal cells more than 100-fold.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Depsipeptides / chemical synthesis*
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Depsipeptides / chemistry
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Depsipeptides / pharmacology*
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Drug Screening Assays, Antitumor
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Humans
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Models, Molecular
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Molecular Conformation
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Stereoisomerism
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Structure-Activity Relationship
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Substrate Specificity
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology*
Substances
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Antineoplastic Agents
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Depsipeptides
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Thiazoles
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largazole