Synthesis and antineoplastic properties of 3'-deoxy-3'-fluoroketonucleoside derivatives. Correlations between structure and biological activity.
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 alpha position to the carbonyl group favours hydration leading to the gem-diol form so that the beta-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 IC50 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.
Egron
M J
MJ
Laboratoire de Chimie Organique Biologique, I.R.S.C., C.N.R.S., Villejuif, France.
Leclercq
F
F
Antonakis
K
K
Bennani-Baiti
M I
MI
Frayssinet
C
C
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007202:Indicators and Reagents; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013806:Theophylline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003853:Deoxyribonucleosides; D007202:Indicators and Reagents; D013806:Theophylline