ANTINEOPLASTIC AGENTS-322 - SYNTHESIS OF COMBRETASTATIN A-4 PRODRUGS

Combretastatin A-4 (1a), the principal cancer cell growth-inhibitory c onstituent of the Zulu medicinal plant Combretum caffrum, has been und ergoing preclinical development. However, the very limited water solub ility of this phenol has complicated drug formation. Hence, derivative s of the combretastatin A-4 (1a) 3'-phenol group were prepared for eva luation as possible water-soluble prodrugs. As observed for combretast atin 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 r eaction with water. A series of other simple derivatives (1d, 1f-j) pr oved unsatisfactory in terms of water solubility or stability, or both . The most soluble derivatives evaluated included the ammonium (1l), p otassium (1m) and sodium (1n) phosphate salts, where the latter two pr oved most stable and suitable. Both the potassium (1m) and sodium (1n) phosphate derivatives of combretastatin A-4 were also found to exhibi t the requisite biological properties necessary for a useful prodrug. Sodium salt 1n was selected for drug formulation and further pre-clini cal development.