Fluorine sugar moiety

P. Herdewijin, A. Van Aerschot, and L. Kerreinans, Synthesis of nucleosides fluorinated in the sugar moiety, Nucleosides Nucleotides 8 65 (1989). 

The introduction of the strongly electron-withdrawing fluorine atom into different positions on the aglycones and on the sugar moiety allowed a study of the stability and effect of an increase in Hpophilicity, thus enabling elucidation of a more precise relationship between the structure and antitiunor activity of these compounds. 

Generally, fluorinated anthracyclines are obtained via total synthesis of the aglycone or sugar moieties to introduce the fluorine into the specific position. 

From a historical point of view, the first introduction of fluorine atoms was performed on the D-ring of the aglycone and on C-6 of the sugar moiety, as a trifluoromethyl derivative. Subsequently, Terajima et al. described the introduction of a fluorine atom at C-14 of the aglycone and later Arcamone et al. 

Anthracyclinones fluorinated on the D-ring were used to obtain the different anthracyclines 9 and also derivatives modified on the sugar moiety, such as morpholinyl-10 [11] or 4 -epi-4 amino-anthracyclines 11 (Fig. 3) [12]. 

The literature reports several examples of substitution of the natural sugar moiety of anthracyclines (daunosamine) with different modified sugars. One of these modifications was the use of a fluorinated sugar. 

Deoxy-4 -fluoro-DOXO was the object of studies, together with several other derivatives, for determination of the influence of lipophilicity on the cytotoxicity of anthracyclines in LoVo and LoVo/Dx human cell lines. The lipophilic character of selected anthracyclines was measured by means of reverse-phase HPLC, under appropriate experimental conditions. The results obtained in these in vitro models indicate that lipophilicity plays a role in anthracycline activity, influencing drug availability at the site of action. The introduction of a fluorine atom in the sugar moiety structure increases the lipophilicity and cytotoxicity of the drug [84]. 

Many studies have been performed on fluorinated anthraqrclines and their comparison with non-fluorinated analogues allow a better and deeper knowledge of the biological mechanisms involved in the activity of this class of drugs. We now know the influence of this small electrophilic atom, when introduced on different positions of the aglycone and sugar moiety. 

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. ... 

Seela F, Xu K, Chittepu P, Ming X (2007) Fluorinated 7-deazapurine 2 -deoxyribonucleosides modification at the nucleobase and the sugar moiety. Nucleosides Nucleotides Nucleic Acids 26 607-610... 

There are many examples of purine nucleosides fluorinated in the 2 - and 3 positions of the sugar moiety (Figure 1) that are making an impact in chemistry, biochemistry, and drug development. 

In conclusion, it appears that conformational factors play the most important role in nucleophilic substitution with fluorine at C 2 of the sugar moiety but are not necessarify crucial in a similar nucleophilic displacement at C 3. It was reported that nucleophilic displacement of the 3 -hydroxyl group in 9-(2-deojgr-6-D-xylofuranosyI)adenine with DAST was completed Avithin 1 hour, whereas the same reaction with the 2 -hydroxy group of 9-(3-deoxy-6-D-arabinofuranosyl)adenine required 14 hours. This reflects an unfavorable electronic factors at C 2 due to the proximity of the anomeric center. Also, steric factors are in favor of the S 2 conversion of nucleoside 87 with DAST, since nucleophilic attack fi-om the a-side of the nucleoside is much more efficient than that from the B-side. Therefore, even unfavorable C 3 -endo conformation of 87 did not cause elimination and 3 -a-fluoro substituted derivative 90 was obtained in good yield. In contrast, displacement of the 2 -hydroxyl group in the ribo configuration, such as conversion of 25 to 27,31 to 35, or 41 to 42, is much more difficult, which requires the favorable C 2 -endo conformation in order to prevent undesired elimination. 

Influence of fluorination of the sugar moiety on the anti-HIV-1 activity of 2 ,3 -dideoxy-nucleosides, Nucleosides Nucleotides 8 1121 (1989). 

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