A new cytotoxic epothilone from modified polyketide synthases heterologously expressed in Myxococcus xanthus

J Nat Prod. 2002 Jul;65(7):1061-4. doi: 10.1021/np020120f.

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

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / isolation & purification*
  • Antineoplastic Agents / pharmacology
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms
  • Drug Screening Assays, Antitumor
  • Epothilones*
  • Epoxy Compounds / chemical synthesis
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / isolation & purification*
  • Epoxy Compounds / pharmacology
  • Female
  • Genetic Engineering
  • Glioma
  • HL-60 Cells / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Leukemia, Promyelocytic, Acute
  • Leukemia, T-Cell
  • Lung Neoplasms
  • Mass Spectrometry
  • 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

Substances

  • 10,11-didehydroepothilone D
  • Antineoplastic Agents
  • Epothilones
  • Epoxy Compounds
  • Multienzyme Complexes
  • Thiazoles
  • Tubulin
  • desoxyepothilone B