Journal article
Synthesis and Metabolism of BTN3A1 Ligands: Studies on Modifications of the Allylic Alcohol
ACS medicinal chemistry letters, Vol.12(1), pp.136-142
01/14/2021
DOI: 10.1021/acsmedchemlett.0c00586
PMCID: PMC7812676
PMID: 33488975
Abstract
(E)-4-Hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) and its phosphonate analogs are potent phosphoantigens. HMBPP contains an (E)-allylic alcohol which interacts with the molecular target BTN3A1 giving an antigenic signal to activate Vγ9Vδ2 T cells. As probes of BTN3A1 function, we prepared prodrug derivatives of the HMBPP analog C-HMBP that lack the (E)-allylic alcohol or have modified it to an aldehyde or aldoxime and evaluated their biological activity. Removal of the alcohol completely abrogates phosphoantigenicity in these compounds while the aldoxime modification decreases potency relative to the (E)-allylic alcohol form. However, homoprenyl derivatives oxidized to an aldehyde stimulate Vγ9Vδ2 T cells at nanomolar concentrations. Selection of phosphonate protecting groups (i.e., prodrug forms) impacts the potency of phosphoantigen aldehydes, with mixed aryl acyloxyalkyl forms exhibiting superior activity relative to aryl amidate forms. The activity correlates with the cellular reduction of the aldehyde to the alcohol form. Thus, the functionality on this ligand framework can be altered concurrently with phosphonate protection to promote cellular transformation to highly potent phosphoantigens.
Details
- Title: Subtitle
- Synthesis and Metabolism of BTN3A1 Ligands: Studies on Modifications of the Allylic Alcohol
- Creators
- Nicholas A Lentini - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United StatesChloe M Schroeder - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United StatesNyema M Harmon - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United StatesXueting Huang - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United StatesMegan A Schladetsch - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United StatesBenjamin J Foust - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United StatesMichael M Poe - Department of Chemistry, Western Michigan University, Kalamazoo, Michigan 49008-5413, United StatesChia-Hung Christine Hsiao - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United StatesAndrew J Wiemer - Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-3092,United States, Institute for Systems Genomics, University of Connecticut, Storrs, Connecticut 06269-3092, United StatesDavid F Wiemer - Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294, United States, Department of Pharmacology, University of Iowa, Iowa City, Iowa 52242-1109, United States
- Resource Type
- Journal article
- Publication Details
- ACS medicinal chemistry letters, Vol.12(1), pp.136-142
- DOI
- 10.1021/acsmedchemlett.0c00586
- PMID
- 33488975
- PMCID
- PMC7812676
- ISSN
- 1948-5875
- eISSN
- 1948-5875
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: CA186935; DOI: 10.13039/100001205, name: F. M. Kirby Foundation, award: PF-18-119-01-LIB; DOI: 10.13039/100008893, name: University of Iowa; DOI: 10.13039/100000048, name: American Cancer Society, award: PF-18-119-01-LIB; DOI: 10.13039/100000002, name: National Institutes of Health, award: AI150869; DOI: 10.13039/100008038, name: Herman Frasch Foundation for Chemical Research, award: HF17; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: 01-224; name: GAANN, award: P200A150065
- Language
- English
- Date published
- 01/14/2021
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9984216699702771
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