Abstract
The total synthesis of C25-benzyloxy epothilone C is described. A sequential Suzuki-Aldol-Yamaguchi macrolactonization strategy was utilized employing a novel derivatized C8-C12 fragment. The C25-benzyloxy analog exhibited significantly reduced biological activity in microtubule assembly and cytotoxicity assays. Molecular modeling simulations indicated that excessive steric bulk in the C25 position may reduce activity by disrupting key hydrogen bonds that are crucial for epothilone binding to beta-tubulin.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / toxicity*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Epothilones / chemical synthesis*
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Epothilones / chemistry
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Epothilones / toxicity*
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Humans
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Hydrogen Bonding / drug effects
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Tubulin / biosynthesis*
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Tubulin / metabolism
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Tubulin Modulators / chemical synthesis*
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Tubulin Modulators / chemistry
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Tubulin Modulators / toxicity*
Substances
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Antineoplastic Agents
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Epothilones
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Tubulin
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Tubulin Modulators
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epothilone C