Abstract
Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their phosphoramidate prodrugs exhibited distinct stability profiles in aqueous environments, which we show is due to the position of the allyl bond in the backbones of the IPP and DMAPP monophosphates. As the IPP monophosphate aryloxy triester phosphoramidates showed favorable stability, they were subsequently investigated for their ability to activate Vγ9/Vδ2 T cells and they showed promising activation of this subset of T cells. Together, these findings represent the first report of IPP and DMAPP monophosphate prodrugs and the ability of IPP aryloxy triester phosphoramidate prodrugs to activate Vγ9/Vδ2 T cells highlighting their potential as possible immunotherapeutics.
Highlights
Vγ9/Vδ2 T cells, the predominant subtype of γδ T cells in peripheral blood, have received substantial attention in recent years due to their role in infectious and autoimmune diseases as well as cancer.[1]
Among the key small molecule activators of Vγ9/Vδ2 T cells is Zoledronate (1, Figure 1A), which inhibits farnesyl diphosphate synthase, and this leads to intracellular accumulation of isopentenyl pyrophosphate (IPP 2, Figure 1A) and dimethylallyl pyrophosphate (DMAPP 3, Figure 1A).[4]
The intracellular accumulation of IPP and DMAPP has been shown to lead to the activation of Vγ9/Vδ2 T cells via their binding to the intracellular B30.2 domain of Butyrophilin 3 A1 (BTN3A1)[5], in a process that
Summary
Is dependent upon co-expression of Butyrophilin 2 A1, a direct ligand for the Vγ9Vδ2 T cell receptor (TCR).[6]. Chemical or enzymatic dephosphorylation of these compounds when used exogenously may be another reason To address these drawbacks, we decided to first reduce the polarity of IPP and DMAPP and simplify the chemistry by applying biocleavable masking groups to the monophosphate derivatives of IPP and DMAPP, namely 3-methylbut-3-en-1-yl dihydrogen phosphate (4, Figure 1B) and 3-methylbut-2-en-1-yl dihydrogen phosphate (5, Figure 1B). We decided to first reduce the polarity of IPP and DMAPP and simplify the chemistry by applying biocleavable masking groups to the monophosphate derivatives of IPP and DMAPP, namely 3-methylbut-3-en-1-yl dihydrogen phosphate (4, Figure 1B) and 3-methylbut-2-en-1-yl dihydrogen phosphate (5, Figure 1B) Pyrophosphates to monophosphates in the design of small molecule Vγ9/Vδ2 T cell activators was previously used with success.[9]
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