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Prodrugs of aza nucleosides based on proton transfer reaction

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Abstract

DFT calculation results for intramolecular proton transfer reactions in Kirby’s enzyme models 1–7 reveal that the reaction rate is quite responsive to geometric disposition, especially to distance between the two reactive centers, r GM, and the angle of attack, α (the hydrogen bonding angle). Hence, the study on the systems reported herein could provide a good basis for designing aza nucleoside prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for prodrug 1ProD is predicted to be about 1010 times faster than that for prodrug 7ProD and about 104 times faster than prodrug 3ProD: rate 1ProD  > rate 3ProD  > rate 7ProD . Hence, the rate by which the prodrug releases the aza nucleoside drug can be determined according to the structural features of the linker (Kirby’s enzyme model).

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Acknowledgments

The Karaman Co. and the German-Palestinian-Israeli fund agency are thanked for support of our computational facilities. Special thanks are given to Angi Karaman, Donia Karaman, Rowan Karaman and Nardene Karaman for technical assistance.

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  1. Faculty of Pharmacy, Al-Quds University, P. O. Box 20002, Jerusalem, Palestine

    Rafik Karaman

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  1. Rafik Karaman
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Correspondence to Rafik Karaman.

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Karaman, R. Prodrugs of aza nucleosides based on proton transfer reaction. J Comput Aided Mol Des 24, 961–970 (2010). https://doi.org/10.1007/s10822-010-9389-6

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