Department of Chemistry, The University of Iowa, Iowa City, IA 52245, United States.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States.
Bioorg Med Chem. 2020 Oct 1;28(19):115666. doi: 10.1016/j.bmc.2020.115666. Epub 2020 Jul 29.
Phosphoantigens are ligands of BTN3A1 that stimulate anti-cancer functions of γδ T cells, yet the potency of natural phosphoantigens is limited by low cell permeability and low metabolic stability. Derivatives of BTN3A1 ligand prodrugs were synthesized that contain an acetate-protected allylic alcohol and act as doubly protected prodrugs. A novel set of phosphonates, phosphoramidates, and phosphonamidates has been prepared through a new route that simplifies synthesis and postpones the point of divergence into different prodrug forms. One of the new prodrugs, compound 11, potently stimulates γδ T cell proliferation (72 h EC = 0.12 nM) and interferon γ response to loaded leukemia cells (4 h EC = 19 nM). This phosphonamidate form was > 900x more potent than the corresponding phosphoramidate, and the phosphonamidate form was also significantly more stable in plasma following acetate hydrolysis. Therefore, prodrug modification of phosphonate butyrophilin ligands at the allylic alcohol can both facilitate chemical synthesis and improve potency of γδ T cell stimulation.
磷酸抗原是刺激γδ T 细胞抗癌功能的 BTN3A1 的配体，但天然磷酸抗原的效力受到细胞通透性低和代谢稳定性低的限制。合成了 BTN3A1 配体前药的衍生物，其中含有乙酸酯保护的烯丙醇，并且作为双重保护前药。通过一种新的路线，已经制备了一组新的膦酸酯、磷酰胺酯和磷酰胺酯，该路线简化了合成并推迟了不同前药形式分歧的时间点。新前药之一 11 强烈刺激 γδ T 细胞增殖（72 h EC = 0.12 nM），并刺激负载白血病细胞的干扰素 γ 反应（4 h EC = 19 nM）。这种磷酰胺酯形式比相应的磷酰胺酯强 900 倍以上，并且在乙酸盐水解后在血浆中的稳定性也显著提高。因此，在烯丙醇处对磷酸丁酰磷配体进行前药修饰既可以促进化学合成，又可以提高 γδ T 细胞刺激的效力。
