Abstract
[structure: see text] (-)-16-Normethyldictyostatin has been made by total synthesis and is a potent antitumor agent in cells expressing wild-type tubulin and in one mutant cell line that is resistant to paclitaxel, but it is much less active than dictyostatin in another paclitaxel-resistant cell line where Val is substituted for Phe270. This provides strong evidence that the C16 methyl group of the dictyostatins is oriented toward Phe270 in the paclitaxel-binding site on beta-tubulin.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
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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Brain / anatomy & histology
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Cattle
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Macrolides / chemical synthesis*
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Macrolides / chemistry
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Macrolides / pharmacology*
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Molecular Structure
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Paclitaxel / pharmacology
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Phenylalanine / genetics
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Stereoisomerism
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Structure-Activity Relationship
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Tubulin / biosynthesis*
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Valine / genetics
Substances
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16-normethyldictyostatin
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Antineoplastic Agents
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Macrolides
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Tubulin
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dictyostatin
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Phenylalanine
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Valine
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Paclitaxel