Synthesis and antineoplastic properties of 3′-deoxy-3′-fluoroketonucleoside derivatives. Correlations between structure and biological activity

Abstract

Three fluoroketonucleosides ( 6, 8, and 11) have been synthesized by direct oxidation of the fluoro precursors. The presence of the highly electronegative fluorine atom in the α position to the carbonyl group favours hydration leading to the gem-diol form so that the β-elimination process to afford 6 and 8 was made difficult and failed in the case of the difluoro compound 11. The biological activity of compounds 6, 8 and 11 was tested on human peripherical blood lymphocytes stimulated by PHA, and on RAJI and DAUDI cells. The IC 50 values showed that, surprisingly, the 3′-enopyranosyl-2′-uloses 6 and 8 have much better antineoplastic activities than their 2′-enopyranosyl-4′-ulose analogues 14 and 15 obtained previously. Moreover, compound 11, which is difluorinated at C-3′ and C-6′ but does not have a C=C C=O group in its structure, is also very active. These results emphasize the important biological role played by the fluorine atom in this family of compounds and suggest a peculiar mechanism of action which is until now unspecified.