Nucleotide prodrugs are commonly functionalized with masking groups (i.e., POM, SATE) that are cleaved in vivo by esterases or other enzymes to yield monophosphates that can subsequently be phosphorylated to give the active triphosphate drug. Boronate esters and boronic acids are known to selectively react with hydrogen peroxide to undergo oxidative cleavage. Several disease states are characterized by oxidative stress leading to the generation of reactive oxygen species which are then converted into hydrogen peroxide. This poster describes the design and implementation of vinyl boronates as caging groups for simple monophosphates and nucleotides. The substrates were synthesized through either a P(III) or P(V) route depending on the number of functional handles installed. The substrates’ rates of release in the presence of hydrogen peroxide were studied using 1H-NMR spectroscopy to show the propensity of the system to yield the desired monophosphates and relevant by-products. A boronate-caged AZT monophosphate was synthesized and in vitro studies with hydrogen peroxide were also performed.

Hydrogen peroxide-mediated release of boronate-caged monophosphates

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ACS Fall 2022

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