Journal article
Synthesis and Bioactivity of the Alanyl Phosphonamidate Stereoisomers Derived from a Butyrophilin Ligand
ACS medicinal chemistry letters, Vol.10(9), pp.1284-1289
09/12/2019
DOI: 10.1021/acsmedchemlett.9b00153
PMCID: PMC6746094
PMID: 31531198
Abstract
Aryloxy phosphonamidate derivatives of a butyrophilin 3A1 ligand are stimulants of Vγ9 Vδ2 T cells. However, when bonded to an aryl ester and an amine, the phosphorus is stereogenic, and past compounds were studied as racemates. To determine the impact of stereochemistry on the activity, we now have prepared phosphonate derivatives of l- and d-alanine ethyl ester, separated the diastereomers, and evaluated their biological activity as single stereoisomers. The results demonstrate that phosphonamidates substituted with l-alanine stimulate Vγ9 Vδ2 T cells at lower concentrations than the racemic glycine counterpart, while those derived from d-alanine require higher concentrations. All four diastereomers are more active than charged phosphoantigens such as HMBPP. Surprisingly, only a 2-fold difference was observed between the l-alanine phosphorus isomers, with the R P isomer more potent. This suggests that the small phosphoantigen scaffold reduces but does not eliminate dependence upon phosphorus stereochemistry for cellular activity.
Details
- Title: Subtitle
- Synthesis and Bioactivity of the Alanyl Phosphonamidate Stereoisomers Derived from a Butyrophilin Ligand
- Creators
- Nicholas A Lentini - Department of ChemistryChia-Hung Christine Hsiao - Department of Pharmaceutical SciencesGeorge B Crull - Department of ChemistryAndrew J Wiemer - University of ConnecticutDavid F Wiemer - University of Iowa
- Resource Type
- Journal article
- Publication Details
- ACS medicinal chemistry letters, Vol.10(9), pp.1284-1289
- Publisher
- American Chemical Society
- DOI
- 10.1021/acsmedchemlett.9b00153
- PMID
- 31531198
- PMCID
- PMC6746094
- ISSN
- 1948-5875
- eISSN
- 1948-5875
- Grant note
- DOI: 10.13039/100000054, name: National Cancer Institute, award: R01CA186935; 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
- Language
- English
- Date published
- 09/12/2019
- Academic Unit
- Neuroscience and Pharmacology; Chemistry
- Record Identifier
- 9984216675602771
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