Lentini Nicholas A, Huang Xueting, Schladetsch Megan A, Hsiao Chia-Hung Christine, Wiemer David F, Wiemer Andrew J
Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States.
Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269-3092, United States.
Bioorg Med Chem Lett. 2022 Jun 15;66:128724. doi: 10.1016/j.bmcl.2022.128724. Epub 2022 Apr 8.
Bis-amidate derivatives have been viewed as attractive phosphonate prodrug forms because of their straightforward synthesis, lack of phosphorus stereochemistry, plasma stability and nontoxic amino acid metabolites. However, the efficiency of bis-amidate prodrug forms is unclear, as prior studies on this class of prodrugs have not evaluated their activation kinetics. Here, we synthetized a small panel of bis-amidate prodrugs of butyrophilin ligands as potential immunotherapy agents. These compounds were examined relative to other prodrug forms delivering the same payload for their stability in plasma and cell lysate, their ability to stimulate T cell proliferation in human PBMCs, and their activation kinetics in a leukemia co-culture model of T cell cytokine production. The bis-amidate prodrugs demonstrate high plasma stability and improved cellular phosphoantigen activity relative to the free phosphonic acid. However, the efficiency of bis-amidate activation is low relative to other prodrugs that contain at least one ester such as aryl-amidate, aryl-acyloxyalkyl ester, and bis-acyloxyalkyl ester forms. Therefore, bis-amidate prodrugs do not drive rapid cellular payload accumulation and they would be more useful for payloads in which slower, sustained-release kinetics are preferred.
双酰胺衍生物因其合成简单、不存在磷立体化学、血浆稳定性以及无毒氨基酸代谢产物等特点，被视为具有吸引力的膦酸酯前药形式。然而，双酰胺前药形式的效率尚不清楚，因为此前对这类前药的研究并未评估其活化动力学。在此，我们合成了一小批作为潜在免疫治疗药物的嗜乳脂蛋白配体双酰胺前药。相对于递送相同有效载荷的其他前药形式，对这些化合物在血浆和细胞裂解物中的稳定性、在人外周血单核细胞中刺激T细胞增殖的能力以及在T细胞细胞因子产生的白血病共培养模型中的活化动力学进行了研究。与游离膦酸相比，双酰胺前药表现出高血浆稳定性和改善的细胞磷酸抗原活性。然而，相对于其他含有至少一个酯的前药，如芳基酰胺、芳基酰氧基烷基酯和双酰氧基烷基酯形式，双酰胺活化的效率较低。因此，双酰胺前药不会促使细胞有效载荷快速积累，它们对于更倾向于较慢、缓释动力学的有效载荷会更有用。
