Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization

Umed Singh; Girija Pawge; Sarita Rani; Chia-Hung Christine Hsiao; Andrew J. Wiemer; David F. Wiemer

doi:10.1021/acs.jmedchem.3c01358

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Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization

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Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization

Umed Singh, Girija Pawge, Sarita Rani, Chia-Hung Christine Hsiao, Andrew J. Wiemer and David F. Wiemer

Journal of medicinal chemistry, Vol.66(22), pp.15309-15325

11/23/2023

DOI: 10.1021/acs.jmedchem.3c01358

PMCID: PMC10683022

PMID: 37934915

Appears in UI Libraries Support Open Access

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Abstract

Activation of Vγ9Vδ2 T cells with butyrophilin 3A1 (BTN3A1) agonists such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) has the potential to boost the immune response. Because HMBPP is highly charged and metabolically unstable, prodrugs may be needed to overcome these liabilities, but the prodrugs themselves may be limited by slow payload release or low plasma stability. To identify effective prodrug forms of a phosphonate agonist of BTN3A1, we have prepared a set of diesters bearing one aryl and one acyloxymethyl group. The compounds were evaluated for their ability to stimulate Vγ9Vδ2 T cell proliferation, increase production of interferon γ, resist plasma metabolism, and internalize into leukemia cells. These bioassays have revealed that varied aryl and acyloxymethyl groups can decouple plasma and cellular metabolism and have a significant impact on bioactivity (>200-fold range) and stability (>10 fold range), including some with subnanomolar potency. Our findings increase the understanding of the structure–activity relationships of mixed aryl/acyloxymethyl phosphonate prodrugs.

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Details

Title: Subtitle: Diester Prodrugs of a Phosphonate Butyrophilin Ligand Display Improved Cell Potency, Plasma Stability, and Payload Internalization
Creators: Umed Singh - University of Iowa
Girija Pawge - University of Connecticut
Sarita Rani - University of Connecticut
Chia-Hung Christine Hsiao - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092, United States
Andrew J. Wiemer - University of Connecticut
David F. Wiemer - University of Iowa
Resource Type: Journal article
Publication Details: Journal of medicinal chemistry, Vol.66(22), pp.15309-15325
DOI: 10.1021/acs.jmedchem.3c01358
PMID: 37934915
PMCID: PMC10683022
NLM abbreviation: J Med Chem
ISSN: 0022-2623
eISSN: 1520-4804
Publisher: American Chemical Society
Grant note: DOI: 10.13039/100000054, name: National Cancer Institute, award: CA266138
Language: English
Electronic publication date: 11/07/2023
Date published: 11/23/2023
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9984507027202771

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