Conformation of a water-soluble derivative of taxol in water by 2D-NMR spectroscopy

Luigi Gomez Paloma, R. Kiplin Guy, W. Wrasidlo, K. C. Nicolaou

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

Background: Taxol is a natural product produced by the Pacific yew, Taxus brevifolia, that has emerged as a prominent chemotherapeutic agent for the treatment of solid tumors. It binds to microtubules, stabilizing them and arresting cells in mitosis. Taxol has been produced synthetically and a wealth of structure-activity data has recently emerged. To date, however, no single conformational model exists for the interpretation of these data. Studies of taxol and its analogs in organic solvents showed two distinct conformations, one in which the 3′-benzamido group and the 2-benzoyl group are in close proximity, and another in which the 2-benzoyl group is instead close to the 3′-phenyl group. We decided to use a derivative of taxol that has improved water-solubility to determine the structure of taxol in water. Results: We have synthesized and characterized a stable water-soluble derivative of taxol that binds to microtubules and has a cytotoxicity profile very similar to that of taxol. 1D and 2D 1H NMR experiments with this bioactive compound in D2O indicate the presence of one conformer with a well-defined structure. In this structure, the 2-benzoyl group is clustered with the 3′-phenyl group. Conclusion: The determination of the conformation of taxol in water may allow quantitative three-dimensional interpretation of the structure-activity data obtained for taxol, and hence enable the design of novel taxol mimics.

Original languageEnglish
Pages (from-to)107-112
Number of pages6
JournalChemistry and Biology
Volume1
Issue number2
DOIs
StatePublished - Oct 1994

Keywords

  • molecular design
  • solution NMR
  • taxol

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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