A New Cytotoxic Epothilone from Modified Polyketide Synthases Heterologously Expressed in Myxococcus xanthus

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 recombina...

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Veröffentlicht in:	Journal of natural products (Washington, D.C.) D.C.), 2002-07, Vol.65 (7), p.1061-1064
Hauptverfasser:	ARSLANIAN, Robert L., TANG, Li, BLOUGH, Shannon, MA, Wei, QIU, Rong-Guo, KATZ, Leonard, CARNEY, John R.
Format:	Artikel
Sprache:	eng
Schlagworte:	Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents Antineoplastic Agents - chemistry Antineoplastic Agents - isolation & purification Antineoplastic Agents - pharmacology Applied microbiology Base Sequence Binding Sites Biological and medical sciences Breast Neoplasms Chemotherapic agents Drug Screening Assays, Antitumor Epothilones Epoxy Compounds - chemical synthesis Epoxy Compounds - chemistry Epoxy Compounds - isolation & purification Epoxy Compounds - pharmacology Female Fundamental and applied biological sciences. Psychology Genetic Engineering Glioma HL-60 Cells - drug effects Humans Inhibitory Concentration 50 Leukemia, Promyelocytic, Acute Leukemia, T-Cell Lung Neoplasms Mass Spectrometry Microbiology Molecular Sequence Data Molecular Structure Multienzyme Complexes Myxococcus xanthus Nuclear Magnetic Resonance, Biomolecular Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - isolation & purification Thiazoles - pharmacology Tubulin Tumor Cells, Cultured - drug effects
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Zusammenfassung:	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).
ISSN:	0163-3864 1520-6025
DOI:	10.1021/np020120f