N⁴-alkyloxycarbonyl derivatives of cytosine: physicochemical characterisation, and cytosine regeneration rates and release from alginic acid gels

Nucleobase containing compounds might constitute a potential alternative to conventional antibiotics in the treatment of Helicobacter pylori infections. N4-alkyloxycarbonyl-cytosine derivatives were synthesized and subjected to basic physicochemical characterisation including assessment of hydrolytic stability in various matrices. pH-rate profiles of selected compounds (range 0–12) were constructed. Hydrolysis of the derivatives in slightly alkaline solution (60 °C) resulted in quantitative conversion to parent cytosine whereas at acidic pH (60 °C) liberation of cytosine was in most cases accompanied by the parallel formation of uracil. Interestingly the lipophilic N4-adamantyloxycarbonyl-cytosine prodrug exhibited a half-life of 41 min (pH 1.1 at 37 °C) with quantitative conversion to parent cytosine, the degradation rate being approximately 200 times faster than that of the non-cyclic aliphatic derivatives investigated. The presence of pig stomach homogenates, pepsin A and H. pylori did not have a noteworthy catalytic effect on the hydrolysis of the derivatives. The release of parent cytosine was markedly delayed from alginic acid gels loaded with the acid-labile and poorly soluble ADC prodrug as compared to gels loaded with parent cytosine.