Synthesis and biological evaluation of bis and monocarbonate prodrugs of 10-hydroxycamptothecins

In an effort to improve the stability of labile lactone ring of camptothecins, the his and mono-alkyl carbonate prodrugs of 10-hydroxycamptothecins were synthesized and their chemical and enzymatical stability as well as antitumor activity were studied. The in vitro evaluation of the stability of these carbonates indicates that the 10,20-biscarbonates are firstly hydrolyzed to afford the stable 20-monocarbonates. And the 10-carbonates are not stable in human plasma, mouse plasma and pH 7.4 phosphate buffer, while the 20-carbonates are relatively stable in the three media and can be readily cleaved by porcine liver esterase. The overall toxicity of the tested carbonate against mice bearing S 180 sarcoma is much lower when compared with the parent compound, and the antitumor activity is maintained. (C) 2004 Elsevier Ltd. All rights reserved.