Incorporation of a FRET pair within a phosphonate diester

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

doi:10.1016/j.bioorg.2021.105048

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Incorporation of a FRET pair within a phosphonate diester

Journal article

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Incorporation of a FRET pair within a phosphonate diester

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

Bioorganic chemistry, Vol.114, pp.105048-105048

09/2021

DOI: 10.1016/j.bioorg.2021.105048

PMCID: PMC8387413

PMID: 34126576

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Abstract

[Display omitted] •Phosphonate acyloxymethyl derivatives of the quencher DABCYL have been synthesized.•Complex aryl acyloxymethyl phosphonates have sub-nanomolar activity as BTN3 agonists.•A tyramine linker to the phosphonate enables coumarin fluorescence and FRET. Cell-cleavable protecting groups are an effective tactic for construction of biological probes because such compounds can improve problems with instability, solubility, and cellular uptake. Incorporation of fluorescent groups in the protecting groups may afford useful probes of cellular functions, especially for payloads containing phosphonates that would be highly charged if not protected, but little is known about the steric or electronic factors that impede release of the payload. In this report we present a strategy for the synthesis of a coumarin fluorophore and a 4-((4-(dimethylamino)phenyl)diazenyl)benzoic acid (DABCYL) ester chromophore incorporated as a FRET pair within a single phosphonate. Such compounds were designed to deliver a BTN3A1 ligand payload to its intracellular receptor. Both final products and some synthetic intermediates were evaluated for their ability to undergo metabolic activation in γδ T cell functional assays, and for their photophysical properties by spectrophotometry. One phosphonate bearing a DABCYL acyloxyester and a novel tyramine-linked coumarin fluorophore exhibited strong, rapid, and potent cellular activity for γδ T cell stimulation and also showed FRET interactions. This strategy demonstrates that bioactivatable phosphonates containing FRET pairs can be utilized to develop probes to monitor cellular uptake of otherwise charged payloads.

BTN3A1

Dark quencher

Forster resonance energy transfer

FRET

Phosphoantigen

Prodrug

Details

Title: Subtitle: Incorporation of a FRET pair within a phosphonate diester
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
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 chemistry, Vol.114, pp.105048-105048
DOI: 10.1016/j.bioorg.2021.105048
PMID: 34126576
PMCID: PMC8387413
NLM abbreviation: Bioorg Chem
ISSN: 0045-2068
eISSN: 1090-2120
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: AI150869, CA186935; DOI: 10.13039/100000138, name: Department of Education, award: P200A150065; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: 01-224; DOI: 10.13039/100006298, name: Graduate College, University of Illinois at Urbana-Champaign; DOI: 10.13039/100008038, name: Herman Frasch Foundation for Chemical Research, award: HF17; DOI: 10.13039/100008893, name: University of Iowa
Language: English
Date published: 09/2021
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9984216709502771

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