Journal
ACS CENTRAL SCIENCE
Volume 3, Issue 1, Pages 20-30Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscentsci.6b00276
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Funding
- MRC [MR/N009460/1]
- BBSRC [BB/L016214/1]
- Novartis
- Cancer Research UK
- St Hugh's College, Oxford
- Biotechnology and Biological Sciences Research Council [1512853] Funding Source: researchfish
- Cancer Research UK [16466, 19276] Funding Source: researchfish
- Medical Research Council [MR/N009460/1, 1477558] Funding Source: researchfish
- BBSRC [BB/L016214/1] Funding Source: UKRI
- MRC [MR/N009460/1] Funding Source: UKRI
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Azide-containing compounds have broad utility in organic synthesis and chemical biology. Their use as powerful tools for the labeling of biological systems in vitro has enabled insights into complex cellular functions. To date, fluorogenic azide-containing compounds have primarily been employed in the context of click chemistry and as sensitive functionalities for hydrogen sulfide detection. Here, we report an alternative use of this functionality: as fluorogenic probes for the detection of depleted oxygen levels (hypoxia). Oxygen is imperative to all life forms, and probes that enable quantification of oxygen tension are of high utility in many areas of biology. Here we demonstrate the ability of an azide-based dye to image hypoxia in a range of human cancer cell lines. We have found that cytochrome P450 enzymes are able to reduce these probes in an oxygen-dependent manner, while hydrogen sulfide does not play an important role in their reduction. These data indicate that the azide group is a new bioreductive functionality that can be employed in prodrugs and dyes. We have uncovered a novel mechanism for the cellular reduction of azides, which has implications for the use of click chemistry in hypoxia.
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