Design and synthesis of α-carboxy nucleoside phosphonate analogues and evaluation as HIV-1 reverse transcriptase-targeting agents
Keane, Sarah J Ford, Alan Mullins, Nicholas D Maguire, Nuala M Legigan, Thibaut Balzarini, Jan Maguire, Anita R # ×
American Chemical Society
Journal of Organic Chemistry vol:80 pages:2479-2493
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.