Abstract
A new epothilone, 10,11-didehydroepothilone D (5), was isolated from a strain of the heterologous host Myxococcus xanthus genetically engineered to produce epothilone D (4). The structure of 5 was determined from NMR and MS data. The epothilone polyketide synthase was further modified in a recombinant M. xanthus strain to produce 5 as the major epothilone-related metabolite. The cytotoxicity of 5 against a panel of tumor cell lines, including several with multidrug resistance, and its effect on tubulin polymerization were comparable to epothilone D (4).
MeSH terms
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / isolation & purification*
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Antineoplastic Agents / pharmacology
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Base Sequence
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Binding Sites
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Breast Neoplasms
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Drug Screening Assays, Antitumor
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Epothilones*
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Epoxy Compounds / chemical synthesis
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Epoxy Compounds / chemistry
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Epoxy Compounds / isolation & purification*
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Epoxy Compounds / pharmacology
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Female
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Genetic Engineering
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Glioma
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HL-60 Cells / drug effects
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Humans
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Inhibitory Concentration 50
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Leukemia, Promyelocytic, Acute
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Leukemia, T-Cell
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Lung Neoplasms
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Mass Spectrometry
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Molecular Sequence Data
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Molecular Structure
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Multienzyme Complexes
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Myxococcus xanthus
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Nuclear Magnetic Resonance, Biomolecular
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Thiazoles / chemical synthesis
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Thiazoles / chemistry
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Thiazoles / isolation & purification*
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Thiazoles / pharmacology
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Tubulin
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Tumor Cells, Cultured / drug effects
Substances
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10,11-didehydroepothilone D
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Antineoplastic Agents
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Epothilones
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Epoxy Compounds
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Multienzyme Complexes
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Thiazoles
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Tubulin
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desoxyepothilone B