Evaluation of a 7-Methoxycoumarin-3-carboxylic Acid Ester Derivative as a Fluorescent, Cell-Cleavable, Phosphonate Protecting Group
| Autor: | Rocky J. Barney, Ashley M Kilcollins, Andrew J. Wiemer, Jin Li, M. Lei Geng, David F. Wiemer, Chia-Hung Christine Hsiao, Rebekah R. Shippy |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Carboxylic acid media_common.quotation_subject Organophosphonates 01 natural sciences Biochemistry Article Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Coumarins Humans Protecting group Internalization Molecular Biology IC50 Fluorescent Dyes media_common chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry Prodrug Fluorescence Combinatorial chemistry Phosphonate 0104 chemical sciences 030104 developmental biology chemistry Drug delivery Molecular Medicine K562 Cells |
| Zdroj: | ChemBioChem. 17:52-55 |
| ISSN: | 1439-4227 |
| DOI: | 10.1002/cbic.201500484 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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