Keane, SJ;Ford, A;Mullins, ND;Maguire, NM;Legigan, T;Balzarini, J;Maguire, AR

2015

March

The Journal of Organic Chemistry

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

Validated

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IMMUNODEFICIENCY-VIRUS TYPE-1 IN-VITRO CARBOCYCLIC NUCLEOSIDES DERIVATIVES DRUGS TRIPHOSPHATES INHIBITORS POTENT MECHANISM DISCOVERY

80

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 a position of carbocyclic nucleoside phosphonate analogues leads to a novel class of potent HIV reverse transcriptase (RT) inhibitors, alpha-carboxy nucleoside phosphonates (alpha-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 alpha-carboxyphosphonate function is efficiently recognized by HIV RT as a triphosphate entity, an unprecedented property of nucleoside monophosph(on)ates

WASHINGTON

0022-3263

10.1021/jo502549y