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

Abstract

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.

Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

“…4 Aminolysis of the carboxy methyl ester was achieved by stirring 34 for 65 h in a 7N solution of ammonia in methanol to afford 35 in 35% yield. The low yield may be explained by the fact that attack at the phosphonate ester groups is also possible under the reaction conditions.…”

“…4,5 Poly rA.oligo dT was used as the homopolymeric template/primer, and [ 3 H]dTTP as the radiolabeled substrate. The IC 50 (50% inhibitory concentration) was determined as the compound concentration required to inhibit RT-catalysed dTTP incorporation into the growing DNA strain.…”

“…Visualization was achieved by UV (254 nm) detection and/or staining with vanillin or permanganate. Compounds 6 , 4 7 , 4 26 32-34 and 30 36 were prepared by literature methods.…”

“…Data are the mean ± SD of at least 3 to 4 independent experiments. c Synthesis ( 1 , 1a , 1b , 36 , 6 and 7 ) and IC 50 data ( 1 , 1a , 1b , 36 ) see Ref 4 . …”

“…Accordingly, the malonate 2 , bisphosphonates 3 and 4 and the amide 5 were chosen as potential targets. In addition, previously synthesized esters 4 6 and 7 were also included in the evaluation (Figure 2). The key aspect we wish to investigate is whether the activity of the α-carboxy phosphonate could be mimicked through the diacid 2 or the bisphosphonates, or indeed whether the carboxylic acid could be replaced by a primary amide in 5 or an ester in 6 and 7 , thereby determining whether the ionizable acid is essential, or whether the metal ion coordinating ability of a primary amide is sufficient to maintain the inhibitory activity of the α-CNPs against HIV-1 RT.…”