Potent double prodrug forms of synthetic phosphoantigens |
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| Affiliation: | 1. Department of Chemistry, The University of Iowa, Iowa City, IA 52245, United States;2. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States;3. Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, United States;4. Department of Pharmacology, University of Iowa, Iowa City, IA 52242, United States;1. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, United States;2. Department of Pharmacy Practice, University of Nebraska Medical Center, Omaha, NE, United States;3. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, United States;4. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States;1. HiPep Laboratories, Kyoto 602-8158, Japan;2. The First School of Clinical Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China;1. Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA;2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;3. Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA;1. Department of Chemistry, University of Iowa, Iowa City, IA 52245, United States;2. Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States;1. Organic Synthesis and Process Chemistry Division, CSIR-Indian Insititute of Chemical Technology, Hyderabad 500007, India;2. Academy of Scientific and Innovative Research (AcSIR), Mathura Road, New Delhi 110 025, India;3. School of Science, Indrashil University, Kadi, Gujarat 382740, India |
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| Abstract: | 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 EC50 = 0.12 nM) and interferon γ response to loaded leukemia cells (4 h EC50 = 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. |
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| Keywords: | Phosphonate Prodrug Phosphoantigen Butyrophilin BTN3A1 Ligand |
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