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Synthesis and Bioevaluation of 5-Fluorouracil Derivatives

As a part of research in our laboratories to develop novel anticancer agents, we have pursuing the synthesis of 1-sulfonyl-5-fluorouracil derivatives and “ reversed” nucleosides containing 5-fluorouracil base. The present work describes the coupling of sulfonyl chlorides or suitable activated sugar derivative with 5-fluorouracil base, using silyl method or condensation in presence of sodium hydride. The new derivatives were tested for their antiproliferative and cytotoxic effects on the growth of 6 different human tumor cell lines (cervical adenocarcinoma HeLa, laryngeal carcinoma HEp-2, pancreatic carcinoma MIAPaCa2, colon carcinoma HT-29, CaCo2, poorly differentiated cells from lymph node metastasis of colon carcinoma SW-620, and breast carcinoma MCF-7) and normal human fibroblasts WI38 in a parallel with 5-fluorouracil, as a standard antitumor drug. Cell lines were incubated with four 10-fold dilutions (10-8 to 10-4 M). After 72 hours of incubation the cell growth rate was evaluated using the MTT assay. Novel compounds displayed similar cell growth inhibition pattern in regard to structure similarity with 5-fluorouracil. The most pronounced growth inhibitory effect of FUTS and FUMS applied in all test concentration was observed on MIAPCa2 cells. Both sulfonyl compounds applied in the highest concentration (10-4 M) inhibited MIAPaCa2 cell growth for more than 80%. At the same time, maximal inhibitory capacity of 5-fluorouracil against the same cell line was 68%. In comparison with cytotoxicity of novel compounds, 5-fluorouracil was significantly more toxic (2-fold at the highest concentration applied) against normal human cells.

5-Fluorouracil; N-Sulfonyl Derivatives; Reversed Nucleosides

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