Syntheses and Evaluations of Antitumor and Antiangiogenic Compounds Conjugated with 5-Fluorouracil and Ascorbic Acid

ABSTRACT: The new multifunctional antitumor conjugates containing ascor-bic acid and 5-fluorouracil (5-FU) were synthesized from bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride, ascorbic acid and/or a chain spacer, followed by condensation with 5-FU. The synthesized conjugates were identified by 1H and 13C NMR spectroscopies and elemental analysis. The in vitro cytotoxicities of these conjugates were determined and their antitumor activity was evaluated. The IC50 values (drug concentration for 50 % inhibition of tumor growth) indicated that the synthesized conjugates were better inhibitors against cancer cells and were lower in cytotoxicity than the free 5-FU. The in vivo antitumor activity of the conjugates was examined against mice bearing the sarcoma 180 tumor cells. The life spans (T/C) of mice treated with the conjugates were higher than for the free 5-FU. In addition, the synthesized conjugates showed excellent antiangiogenic activity, based on the embryo chorioallantoic membrane assay. KEY WORDS: antitumor activity, drug conjugates, 5-fluorouracil, 5-fluorouracil conjugates, ascorbic acid, in vitro cytotoxicity, antiangiogenesis