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 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.
Petersson
Karsten
K
Department of Pharmaceutics, The Danish University of Pharmaceutical Sciences, Universitetsparken 2, DK-2100 Copenhagen, Denmark. kap@dfuni.dk
Pedersen
Brian Thoning
BT
Staerk
Dan
D
Krogfelt
Karen A
KA
Larsen
Claus
C
D000464:Alginates / Q000737:chemistry* / Q000493:pharmacokinetics*; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003596:Cytosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D005782:Gels; D020723:Glucuronic Acid / Q000737:chemistry* / Q000493:pharmacokinetics*; D006603:Hexuronic Acids / Q000737:chemistry* / Q000493:pharmacokinetics*; D013552:Swine
D000464:Alginates; D003692:Delayed-Action Preparations; D005782:Gels; D006603:Hexuronic Acids; D020723:Glucuronic Acid; D003596:Cytosine