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Novel cyclic phosphate prodrug approach for cytochrome P450-activated drugs containing an alcohol functionality
Kristiina M Huttunen1, Niina Mähönen, Jukka Leppänen
1Department of Pharmaceutical Chemistry, University of Kuopio, 70211, Kuopio, Finland. Kristiina.Huttunen@uku.fi
Purpose:
A cyclic phosphate prodrug of a descriptive molecule containing an alcohol functionality was designed, synthesized and characterized in vitro as a cytochrome P450 (CYP) -selective prodrug.
Materials And Methods:
To achieve efficient CYP-oxidation and prodrug bioconversion, 1,3-cyclic propyl ester of phosphate was designed to have a C4-aryl substituent and synthesized using phosphorus(III) chemistry. The two-step bioconversion of the cyclic phosphate prodrug was evaluated in vitro using human liver microsomes and recombinant CYP enzymes.
Results:
This cyclic phosphate prodrug underwent initial CYP-catalyzed oxidation and was mainly catalyzed by the CYP3A4 form. The hydroxylated product was slowly converted to a ring-opened intermediate, which subsequently transformed by beta-elimination reaction to a free phosphate. The free phosphate was further dephosphorylated by microsomal phosphatases, releasing the parent molecule with a free hydroxyl group. The cyclic phosphate was reasonably stable in buffer solutions at the pH range 1.0-9.0.
Conclusions:
Since CYP enzymes reside predominantly in the liver and secondarily in the small intestine, the results indicate that cyclic phosphate prodrugs represent a very feasible liver- or intestinal-targeted drug delivery strategy for drug molecules containing an alcohol functionality. This may potentially improve the efficacy and the safety profile of the alcoholic parent drugs.
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