Antineoplastic agents 322. Synthesis of combretastatin A-4 prodrugs

George Pettit, C. Temple, V. L. Narayanan, R. Varma, M. J. Simpson, M. R. Boyd, G. A. Rener, N. Bansal

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287 Scopus citations


Combretastatin A-4 (1a), the principal cancer cell growth-inhibitory constituent of the Zulu medicinal plant Combretum caffrum, has been undergoing preclinical development. However, the very limited water solubility of this phenol has complicated drug formation. Hence, derivatives of the combretastatin A-4 (1a) 3'-phenol group were prepared for evaluation as possible water-soluble prodrugs. As observed for combretastatin A-4, the sodium salt (1b), potassium salt (1c) and hemi-succinic acid ester (1e) derivatives of phenol 1a were essentially insoluble in water. Indeed, these substances regenerated combretastatin A-4 upon reaction with water. A series of other simple derivatives (1d, 1f-j) proved unsatisfactory in terms of water solubility or stability, or both. The most soluble derivatives evaluated included the ammonium (1l), potassium (1m) and sodium (1n) phosphate salts, where the latter two proved most stable and suitable. Both the potassium (1m) and sodium (1n) phosphate derivatives of combretastatin A-4 were also found to exhibit the requisite biological properties necessary for a useful prodrug. Sodium salt In was selected for drug formulation and further pre-clinical development.

Original languageEnglish (US)
Pages (from-to)299-309
Number of pages11
JournalAnti-Cancer Drug Design
Issue number4
StatePublished - 1995


  • Combretastatin A-4 prodrug

ASJC Scopus subject areas

  • Biochemistry
  • Oncology
  • General Biochemistry, Genetics and Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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