Journal article
Synthesis and Evaluation of Triazole-Containing Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand
European journal of medicinal chemistry, Vol.287, 117345
02/01/2025
DOI: 10.1016/j.ejmech.2025.117345
PMCID: PMC11853949
PMID: 39919440
Abstract
The most effective natural ligand for the butyrophilins is (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate. However, due to its susceptibility to plasma hydrolysis and its high charge that limits passive diffusion across cell membranes, its potential as a drug is limited. Our efforts to identify compounds that stimulate γδ T cell proliferation have been focused on phosphonates to gain metabolic stability and phosphonate prodrugs to improve diffusion into cells. To identify potential prodrugs that are soluble, relatively stable in plasma, and undergo facile hydrolysis once inside the cell, we have prepared a series of aryl acyloxyesters where the acyl group includes a triazole moiety. Several of these novel prodrug forms have been shown to demonstrate nanomolar potency for T cell activation and relatively long half-lives in plasma. Interestingly, compound 26b stimulated T cells at sub-nanomolar levels (proliferation EC50 = 0.49 nM) while achieving a half-life of 63 minutes in human plasma. The details of these syntheses and the biological evaluation are presented here.
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•Novel phosphoantigen prodrugs have been prepared based on a 1,2,3-triazole system•These compounds stimulate proliferation of Vγ9Vδ2 T cells (EC50 = 490 pM to 7.4 nM)•These compounds stimulate interferon γ production (EC50 = 600 pM to 77 nM)•These prodrugs have improved stability in human plasma (T1/2 = 16 to 106 min)•Cells, but not plasma, release the desired dianionic phosphoantigen payload
Details
- Title: Subtitle
- Synthesis and Evaluation of Triazole-Containing Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand
- Creators
- Umed Singh - University of IowaGirija Pawge - University of ConnecticutParker A. Kintigh - University of IowaJoseph P. Sarno - University of ConnecticutSarita Rani - University of ConnecticutChia-Hung Christine Hsiao - University of ConnecticutAndrew J. Wiemer - University of ConnecticutDavid F. Wiemer - University of Iowa
- Resource Type
- Journal article
- Publication Details
- European journal of medicinal chemistry, Vol.287, 117345
- DOI
- 10.1016/j.ejmech.2025.117345
- PMID
- 39919440
- PMCID
- PMC11853949
- NLM abbreviation
- Eur J Med Chem
- ISSN
- 0223-5234
- eISSN
- 1768-3254
- Publisher
- Elsevier Masson SAS
- Grant note
- National Cancer Institute of the National Institutes of Health: CA266138, CA273042, AI150869
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under awards CA266138 and CA273042 and the National Institute of Allery and In-fectious Disease under award number AI150869 (A. J. W.) . The funding sources were not involved in the study design, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the article for publication.
- Language
- English
- Date published
- 02/01/2025
- Academic Unit
- Chemistry
- Record Identifier
- 9984786308702771
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