Pettit G R, Temple C, Narayanan V L, Varma R, Simpson M J, Boyd M R, Rener G A, Bansal N
Cancer Research Institute, Arizona State University, Tempe 85287-1604, USA.
Anticancer Drug Des. 1995 Jun;10(4):299-309.
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 hemisuccinic 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 1n was selected for drug formulation and further pre-clinical development.
康普瑞他汀A-4（1a）是祖鲁药用植物南非风车子中主要的癌细胞生长抑制成分，一直在进行临床前开发。然而，这种酚类物质极低的水溶性给药物制剂带来了困难。因此，制备了康普瑞他汀A-4（1a）3'-酚基团的衍生物，以评估其作为可能的水溶性前药的效果。正如对康普瑞他汀A-4的观察结果一样，酚1a的钠盐（1b）、钾盐（1c）和半琥珀酸酯（1e）衍生物基本上不溶于水。实际上，这些物质与水反应后会再生出康普瑞他汀A-4。一系列其他简单衍生物（1d、1f-j）在水溶性或稳定性方面，或两者都不理想。评估的最易溶衍生物包括铵盐（1l）、钾盐（1m）和钠盐（1n），其中后两者被证明最稳定且合适。康普瑞他汀A-4的钾盐（1m）和钠盐（1n）衍生物也被发现具有作为有用前药所需的生物学特性。选择钠盐1n用于药物制剂和进一步的临床前开发。
