Cellular consequences of copper complexes used to catalyze bioorthogonal click reactions

  1. Get@NRC: Cellular consequences of copper complexes used to catalyze bioorthogonal click reactions (Opens in a new window)
DOIResolve DOI: http://doi.org/10.1021/ja2083027
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Journal titleJournal of the American Chemical Society
Pages1799318001; # of pages: 9
SubjectAzide-alkyne cycloaddition; Bio-conjugation; Cell surfaces; Cellular metabolism; Cellular uptake; Click reaction; Coherent anti-Stokes Raman scattering microscopy; Copper complexes; Copper toxicity; Copper-based catalysts; Critical factors; Critical issues; Glycosylated; Human cell lines; Human hepatoma cells; In-vivo; L-histidine; Lipid metabolisms; Live cell; Living systems; Mammalian cells; Metabolic changes; Micromolar concentration; Mitochondrial activity; Three parameters; Acetylene; Amino acids; Biological systems; Bromine compounds; Catalyst activity; Cell culture; Cell membranes; Coherent scattering; Copper; Inductively coupled plasma; Inductively coupled plasma mass spectrometry; Ligands; Mammals; Metabolism; Physiology; Raman scattering; Raman spectroscopy; Sugars; Toxicity; Copper compounds; 3 (4,5 dimethyl 2 thiazolyl) 2,5 diphenyltetrazolium bromide; copper complex; disufenton sodium; edetic acid; histidine derivative; article; catalysis; cell metabolism; cell strain HEK293; cell surface; cell transport; cell viability; chemical structure; cycloaddition; female; heavy metal poisoning; HeLa cell; hepatoma cell; human; human cell; IC 50; ligand binding; lipid metabolism; mass spectrometry; Raman spectrometry; Catalysis; Cell Survival; Cells, Cultured; Copper; Fluorescent Dyes; HEK293 Cells; HeLa Cells; Humans; Microscopy, Fluorescence; Mitochondria; Molecular Structure; Organometallic Compounds; Structure-Activity Relationship
AbstractCopper toxicity is a critical issue in the development of copper-based catalysts for copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions for applications in living systems. The effects and related toxicity of copper on mammalian cells are dependent on the ligand environment. Copper complexes can be highly toxic, can induce changes in cellular metabolism, and can be rapidly taken up by cells, all of which can affect their ability to function as catalysts for CuAAC in living systems. Herein, we have evaluated the effects of a number of copper complexes that are typically used to catalyze CuAAC reactions on four human cell lines by measuring mitochondrial activity based on the metabolism of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to study toxicity, inductively coupled plasma mass spectrometry to study cellular uptake, and coherent anti-Stokes Raman scattering (CARS) microscopy to study effects on lipid metabolism. We find that ligand environment around copper influences all three parameters. Interestingly, for the Cu(II)-bis-l-histidine complex (Cu(his) 2), cellular uptake and metabolic changes are observed with no toxicity after 72 h at micromolar concentrations. Furthermore, we show that under conditions where other copper complexes kill human hepatoma cells, Cu(I)-l-histidine is an effective catalyst for CuAAC labeling of live cells following metabolic incorporation of an alkyne-labeled sugar (Ac 4ManNAl) into glycosylated proteins expressed on the cell surface. This result suggests that Cu(his) 2 or derivatives thereof have potential for in vivo applications where toxicity as well as catalytic activity are critical factors for successful bioconjugation reactions. © 2011 American Chemical Society.
Publication date
AffiliationNational Research Council Canada (NRC-CNRC); NRC Steacie Institute for Molecular Sciences (SIMS-ISSM); NRC Institute for National Measurement Standards (INMS-IENM)
Peer reviewedYes
NPARC number21271109
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Record identifier03f13a27-4442-4667-961f-aab5a0c0ff13
Record created2014-03-24
Record modified2016-05-09
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