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Description
Nucleoside analogues are commonly used in the treatment of viral infections and cancers. The effectiveness of the nucleoside analogue is generally dependent on the ability for the nucleoside analogue to be incorporated into viral or cancerous DNA/RNA. In order for this to occur, the nucleoside analogue must undergo a series of phosphorylation steps by kinases to become a nucleoside 5′-triphosphate (NTP) and then utilized by polymerases for insertion into the new DNA/RNA strand. However, these nucleoside analogues are usually poor substrates for kinases, and thus their efficacy is suboptimal. As such, NTP prodrug strategies to bypass the kinases are of particular interest for the development of nucleoside analogue therapeutics. We report on our endeavors to generate a NTP prodrug strategy. The first method we pursued was to generate methylene bisphosphonate and methylene bisphosphonite reagents. Subsequently, these bisphosphonate/ite reagents could be coupled to a nucleoside/tide to afford the desired nucleoside triphosphate species. This method did not produce favorable results, and so we proceeded to developing an alternative method using diazoalkanes. Diazoalkanes have been shown to be powerful and selective esterifying reagents for carboxylic acids. We recently adapted a diazoalkane esterification method from Furrow and Myers utilizing protected hydrazones to generate the diazo compounds in situ via oxidation with a hypervalent iodine species. We successfully applied this method to a simple phosphonate model compound (benzylphosphonic acid) utilizing several hydrazone derivatives of benzaldehyde. We also investigated the selectivity of these diazo mediated esterification reactions using Fmoc-O-phospho-L-tyrosine, a compound containing both a phosphoric and carboxylic acid group. NMR spectroscopy utilizing 3JH,P coupling suggests that the desired phosphoric ester formed, but it is inconclusive as to whether the carboxylic ester formed, and in what ratios. Lastly, we applied this diazo-esterification method to nucleotides, including the trisodium salt of UTP. Mass spectrum analysis supports the formation of the desired nucleotide esters. This diazo-esterification method paves the way for the development of our desired NTP prodrugs, in addition to the ability to modify other phosph(on)ate bearing species.
