School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff, CF10 3NB, UK.
Cancer Immunology and Immunotherapy Centre, University of Birmingham Edgbaston, Birmingham, B15 2TT, UK.
ChemMedChem. 2021 Aug 5;16(15):2375-2380. doi: 10.1002/cmdc.202100198. Epub 2021 May 19.
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.
作为亲脂性衍生物，芳氧基三酯膦酰胺前药被合成以提高细胞摄取率，这些前药是异戊烯焦磷酸（IPP）和二甲基烯丙基焦磷酸（DMAPP）的单磷酸盐衍生物。尽管 IPP 和 DMAPP 结构相似，但我们注意到它们的膦酰胺前药在水性环境中表现出明显不同的稳定性谱，这是由于 IPP 和 DMAPP 单磷酸盐骨架中烯丙基键的位置不同。由于 IPP 单磷酸盐芳氧基三酯膦酰胺前药表现出良好的稳定性，因此随后研究了它们激活 Vγ9/Vδ2 T 细胞的能力，结果显示它们对这一类 T 细胞具有很好的激活作用。总之，这些发现代表了 IPP 和 DMAPP 单磷酸盐前药的首次报道，以及 IPP 芳氧基三酯膦酰胺前药激活 Vγ9/Vδ2 T 细胞的能力，这突出了它们作为潜在免疫疗法的可能性。
