Design and Synthesis of α-Carboxy Nucleoside Phosphonate Analogues and Evaluation as HIV-1 Reverse Transcriptase-Targeting Agents

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Design and Synthesis of α-Carboxy Nucleoside Phosphonate Analogues and Evaluation as HIV-1 Reverse Transcriptase-Targeting Agents

SJ Keane, A Ford, ND Mullins, NM Maguire, T Legigan, J Balzarini, AR Maguire.
Journal of Organic Chemistry, 6(5):2479-2493. 2015

The synthesis of the first series of a new class of nucleoside phosphonate analogues is described. Addition of a carboxyl group at the α position of carbocyclic nucleoside phosphonate analogues leads to a novel class of potent HIV reverse transcriptase (RT) inhibitors, α-carboxy nucleoside phosphonates (α-CNPs). Key steps in the synthesis of the compounds are Rh-catalyzed O-H insertion and Pd-catalyzed allylation reactions. In cell-free assays, the final products are markedly inhibitory against HIV RT and do not require phosphorylation to exhibit anti-RT activity, which indicates that the α-carboxyphosphonate function is efficiently recognized by HIV RT as a triphosphate entity, an unprecedented property of nucleoside monophosph(on)ates.


Source: http://www.ncbi.nlm.nih.gov/pubmed/25532055

 

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