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

Abstract

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 degrees C) resulted in quantitative conversion to parent cytosine whereas at acidic pH (60 degrees 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 degrees 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.

Biological Activity of Adamantane-Containing Mono- and Polycyclic Pyrimidine Derivatives* (A Review)

“…The chemical stability and stability in biological fluids of N 4 -alkyloxycarbonyl cytosine derivatives, i.e., compounds capable potentially of exhibiting activity against Helicobacter pylori (Gram-negative bacterium and the main cause of chronic gastritis and stomach ulcers), were studied [8]. These properties are important if the drugs are to be used for therapy.…”

Биологическая Активность Адамантансодержащих Моно- И Полициклических Пиримидиновых Производных (Обзор)

“… ðàáîòå [8] ñîîáùàëîñü î ïðîâåäåííîì èçó÷åíèè õèìè÷åñêîé ñòàáèëüíîñòè è ñòàáèëüíîñòè â áèîëîãè÷åñêèõ ñðåäàõ N 4 -àëêèëîêñèêàðáîíèëïðîèçâîäíûõ öèòîçèíà -ñîåäèíåíèé, ïîòåíöèàëüíî ñïîñîáíûõ ïðîÿâèòü àêòèâ-íîñòü â îòíîøåíèè Helicobacter pylory (ãðàìîòðèöàòåëüíàÿ áàêòåðèÿ, ÿâëÿþùàÿñÿ ãëàâíûì âîçáóäèòåëåì õðîíè-÷åñêèõ ãàñòðèòîâ è ÿçâ aeåëóäêà). Èçó÷àåìûå ñâîéñòâà èãðàþò âàaeíóþ ðîëü ïðè èñïîëüçîâàíèè ïðåïàðàòîâ â ëå-êàðñòâåííîé òåðàïèè.…”