Evaluation of a 7-Methoxycoumarin-3-carboxylic Acid Ester Derivative as a Fluorescent, Cell-Cleavable, Phosphonate Protecting Group

Andrew J Wiemer; Rebekah R Shippy; Ashley M Kilcollins; Jin Li; Chia-Hung Christine Hsiao; Rocky J Barney; M Lei Geng; David F Wiemer

doi:10.1002/cbic.201500484

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Evaluation of a 7-Methoxycoumarin-3-carboxylic Acid Ester Derivative as a Fluorescent, Cell-Cleavable, Phosphonate Protecting Group

Journal article

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Peer reviewed

Evaluation of a 7-Methoxycoumarin-3-carboxylic Acid Ester Derivative as a Fluorescent, Cell-Cleavable, Phosphonate Protecting Group

Andrew J Wiemer, Rebekah R Shippy, Ashley M Kilcollins, Jin Li, Chia-Hung Christine Hsiao, Rocky J Barney, M Lei Geng and David F Wiemer

Chembiochem : a European journal of chemical biology, Vol.17(1), pp.52-55

01/01/2016

DOI: 10.1002/cbic.201500484

PMCID: PMC4746711

PMID: 26503489

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Abstract

Cell-cleavable protecting groups often enhance cellular delivery of species that are charged at physiological pH. Although several phosphonate protecting groups have achieved clinical success, it remains difficult to use these prodrugs in live cells to clarify biological mechanisms. Here, we present a strategy that uses a 7-methoxycoumarin-3-carboxylic acid ester as a fluorescent protecting group. This strategy was applied to synthesis of an (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) analogue to assess cellular uptake and human Vγ9Vδ2 T cell activation. The fluorescent ester displayed low cellular toxicity (IC50 >100 μm) and strong T cell activation (EC50 =0.018 μm) relative to the unprotected anion (EC50 =23 μm). The coumarin-derived analogue allowed no-wash analysis of biological deprotection, which revealed rapid internalization of the prodrug. These results demonstrate that fluorescent groups can be applied both as functional drug delivery tools and useful biological probes of drug uptake.

Fluorescent Dyes - chemistry

Humans

Coumarins - chemistry

Structure-Activity Relationship

Coumarins - pharmacology

Dose-Response Relationship, Drug

Organophosphonates - chemical synthesis

Organophosphonates - pharmacology

T-Lymphocytes - drug effects

Coumarins - chemical synthesis

K562 Cells

Organophosphonates - chemistry

Molecular Structure

Details

Title: Subtitle: Evaluation of a 7-Methoxycoumarin-3-carboxylic Acid Ester Derivative as a Fluorescent, Cell-Cleavable, Phosphonate Protecting Group
Creators: Andrew J Wiemer - University of Connecticut
Rebekah R Shippy - Department of Chemistry, University of Iowa, E531 Chemistry Building, Iowa City, IA, 52242, USA
Ashley M Kilcollins - University of Connecticut
Jin Li - University of Connecticut
Chia-Hung Christine Hsiao - University of Connecticut
Rocky J Barney - Department of Chemistry, Western Wyoming Community College, 1204-A, Rock Springs, WY, 82901, USA
M Lei Geng - Department of Chemistry, Optical Science and Technology Center, University of Iowa, 330 IATL, Iowa City, IA, 52242, USA
David F Wiemer - Department of Chemistry, University of Iowa, E531 Chemistry Building, Iowa City, IA, 52242, USA. david-wiemer@uiowa.edu
Resource Type: Journal article
Publication Details: Chembiochem : a European journal of chemical biology, Vol.17(1), pp.52-55
DOI: 10.1002/cbic.201500484
PMID: 26503489
PMCID: PMC4746711
NLM abbreviation: Chembiochem
ISSN: 1439-4227
eISSN: 1439-7633
Publisher: Germany
Grant note: R01 CA186935 / NCI NIH HHS R01A186935 / PHS HHS
Language: English
Date published: 01/01/2016
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9983985869202771

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