Fluorinated nucleosides, biological activity

The a,a-difluoro Reformatsky reagent has been applied extensively to the preparation of compounds containing the -CF2C(0)- group and its derivatives,2 since this functionality often confers enhanced biological activity. Typical examples include the preparation of selectively fluorinated thromboxane A2 analogues24 and the preparation of a difluoro-y-lactone intermediate which was subsequently converted to l-(2-deoxy-2,2-difluororibofuranosyl) pyrimidine nucleosides (Equation 4.10).25... 

Biological Activity of Fluorinated Nucleosides and Correlations with Their Conformations... 

As part of an issue of Carbohydrate Research devoted to reviewing the whole area of fluorinated sugars, Pankiewicz has discussed nucleosides fluorinated in the sugar moiety, covering both synthesis and biological activity. Another review has also covered recent strategies for the synthesis of fluoronucleosides, with some consideration of structure-activity relationships. ... 

Thymidine, Dideoxythymidine, and Fluorine Substituted Deoxyribonucleoside Geometry by the MINDO/3 Technique The Effect of Fluorine Substitution on Nucleoside Geometry and Biological Activity, Nucleosides Nucleotides 10 693 (1991). 

The 2 -chloro and 2 -bromo congeners of either 748 (FIAC) or 758 (FMAU) are more cytotoxic than FIAC and FMAU, suggesting that these chloro and bromo nucleosides, in contrast to the 2 -fluoro compounds, are comparatively better substrates for deoxycytidine kinase of human lymphocytes than the substrates for viral-specific thymidine kinase. The disposition of the 2 -fluoro group may also be important from the biological viewpoint. It should be noted that the structural difference between RNA and DNA is at the 2 -position. The ribo type of analog (738) of FIAC is 10 times less effective in suppression of HSV replication than is FIAC. Thus Fox, and Watanabe and coworkers concluded that the 2 - up fluorine disposition and the species of the substituent at C-5 are the two important factors influencing antiviral activity. Nevertheless, the mechanism of action of 2 -deoxy-2 -fluorocytidine (737) on certain herpes viruses, including HSV-1... 

Recently, the synthesis and biological evaluation of acid stable 2 -6-fluoro purine dideoxynucleosides as active agents against HIV have been reported Since it was established that introduction of fluorine to the 2 -6-position of nucleosides decreases chemical and phosphorylase (PNP) catalyzed hydrolysis in general and for purine nucleosides in particular (1, Figure 1), these 2 -fluoro analogues were designed to overcome the chemical and metabolic instability of the parent purine dideoxynucleosides. 

---