Potent double prodrug forms of synthetic phosphoantigens

Nyema M Harmon; Xueting Huang; Megan A Schladetsch; Chia-Hung Christine Hsiao; Andrew J Wiemer; David F Wiemer

doi:10.1016/j.bmc.2020.115666

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Potent double prodrug forms of synthetic phosphoantigens

Journal article

Peer reviewed

Potent double prodrug forms of synthetic phosphoantigens

Nyema M Harmon, Xueting Huang, Megan A Schladetsch, Chia-Hung Christine Hsiao, Andrew J Wiemer and David F Wiemer

Bioorganic & medicinal chemistry, Vol.28(19), pp.115666-115666

10/01/2020

DOI: 10.1016/j.bmc.2020.115666

PMCID: PMC9491366

PMID: 32912439

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https://www.ncbi.nlm.nih.gov/pmc/articles/9491366View

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Abstract

[Display omitted] 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.

BTN3A1

Butyrophilin

Ligand

Phosphoantigen

Phosphonate

Prodrug

Details

Title: Subtitle: Potent double prodrug forms of synthetic phosphoantigens
Creators: Nyema M Harmon - Department of Chemistry, The University of Iowa, Iowa City, IA 52245, United States
Xueting Huang - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States
Megan A Schladetsch - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States
Chia-Hung Christine Hsiao - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States
Andrew J Wiemer - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT 06269, United States
David F Wiemer - Department of Chemistry, The University of Iowa, Iowa City, IA 52245, United States
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry, Vol.28(19), pp.115666-115666
DOI: 10.1016/j.bmc.2020.115666
PMID: 32912439
PMCID: PMC9491366
NLM abbreviation: Bioorg Med Chem
ISSN: 0968-0896
eISSN: 1464-3391
Publisher: Elsevier Ltd
Grant note: name: GAANN Program, award: P200A150065; name: National Cancer Institute of the National Institutes of Health, award: R01CA186935; DOI: 10.13039/100008038, name: Frasch Foundation, award: HF17; DOI: 10.13039/100001024, name: Carver Charitable Trust, award: 01-224
Language: English
Date published: 10/01/2020
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9984216684902771

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