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 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).
Arslanian
Robert L
RL
Kosan Biosciences, Inc., 3832 Bay Center Place, Hayward, California 94545, USA.
Tang
Li
L
Blough
Shannon
S
Ma
Wei
W
Qiu
Rong-Guo
RG
Katz
Leonard
L
Carney
John R
JR
D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones; D004852:Epoxy Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D005260:Female; D005818:Genetic Engineering; D005910:Glioma; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D015473:Leukemia, Promyelocytic, Acute; D015458:Leukemia, T-Cell; D008175:Lung Neoplasms; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009097:Multienzyme Complexes; D016941:Myxococcus xanthus; D019906:Nuclear Magnetic Resonance, Biomolecular; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D014404:Tubulin; D014407:Tumor Cells, Cultured / Q000187:drug effects
C465909:10,11-didehydroepothilone D; D000970:Antineoplastic Agents; D034261:Epothilones; D004852:Epoxy Compounds; D009097:Multienzyme Complexes; D013844:Thiazoles; D014404:Tubulin; C114026:desoxyepothilone B