Diazo compounds for the bioreversible esterification of proteins

McGrath, Nicholas A.; Andersen, Kristen A.; Davis, Amy K. F.; Lomax, Jo E.; Raines, Ronald T.

doi:10.1039/c4sc01768d

Cited by 77 publications

(87 citation statements)

References 34 publications

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“…Maintaining chemoselectivity in the presence of water and other biological nucleophiles has been a primary challenge in developing diazo compounds as useful tools for protein chemistry. 128,129 …”

Section: Protein Alkylationmentioning

confidence: 99%

“…This idea was later explored, and did indeed increase the efficiency of protein esterification. 128 Although α-diazoacetamide was more selective than diazomethane, it still S -alkylated sulfhydryl groups.…”

Section: Protein Alkylationmentioning

confidence: 99%

“…128 Of these compounds, only 9-diazofluorene esterified a panel of carboxylic acids efficiently in the presence of water. This diazo compound was used to label two model proteins, ribonuclease A and red fluorescent protein.…”

Section: Bioreversible Protein Modificationmentioning

confidence: 99%

See 2 more Smart Citations

Diazo Compounds: Versatile Tools for Chemical Biology

2016

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Diazo groups have broad and tunable reactivity. That and other attributes endow diazo compounds with the potential to be valuable reagents for chemical biologists. The presence of diazo groups in natural products underscores their metabolic stability and anticipates their utility in a biological context. The chemoselectivity of diazo groups, even in the presence of azido groups, presents many opportunities. Already, diazo compounds have served as chemical probes and elicited novel modifications of proteins and nucleic acids. Here, we review advances that have facilitated the chemical synthesis of diazo compounds, and we highlight applications of diazo compounds in the detection and modification of biomolecules.

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Section: Protein Alkylationmentioning

confidence: 99%

Section: Protein Alkylationmentioning

confidence: 99%

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Diazo Compounds: Versatile Tools for Chemical Biology

2016

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“…43 Recently, we found that appropriately tuned diazo compounds can esterify protein carboxyl groups, providing a second type of bioreversible modification. 44,45 In this work, we report on a bioreversible modification of protein amino groups that is distinct from others 46–48 in its reliance on enzymatic catalysis. With its traceless utility in promoting cellular uptake, B-TML–NHS ester provides new opportunities in chemical biology and pharmacology.…”

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confidence: 97%

Boronic Acid for the Traceless Delivery of Proteins into Cells

et al. 2015

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The use of exogenous proteins as intracellular probes and chemotherapeutic agents is in its infancy. A major hurdle has been the delivery of native proteins to an intracellular site of action. Herein, we report on a compact delivery vehicle that employs the intrinsic affinity of boronic acids for the carbohydrates that coat the surface of mammalian cells. In the vehicle, benzoxaborole is linked to protein amino groups via a “trimethyl lock”. Immolation of this linker is triggered by cellular esterases, releasing native protein. Efficacy is demonstrated by enhanced delivery of green fluorescent protein and a cytotoxic ribonuclease into mammalian cells. This versatile strategy provides new opportunities in chemical biology and pharmacology.

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“…We had shown previously that the basicity of such diazo compounds enables the efficient esterification of carboxylic acids in an aqueous environment. 16 Now, we exploited the modular nature of this scaffold. Specifically, we deimidogenated azide precursors 16,17 to access diazo compounds 1 – 6 , which span a range of hydrophobicity (Figure 1).…”

mentioning

confidence: 99%

Cytosolic Delivery of Proteins by Bioreversible Esterification

Lomax²,

2017

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Cloaking its carboxyl groups with a hydrophobic moiety is shown to enable a protein to enter the cytosol of a mammalian cell. Diazo compounds derived from (p-methylphenyl)glycine were screened for the ability to esterify the green fluorescent protein (GFP) in an aqueous environment. Esterification of GFP with 2-diazo-2-(p-methylphenyl)-N,N-dimethylacetamide was efficient. The esterified protein entered the cytosol by traversing the plasma membrane directly, like a small-molecule prodrug. As with prodrugs, the nascent esters are substrates for endogenous esterases, which regenerate native protein. Thus, esterification could provide a general means to deliver native proteins to the cytosol.

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Diazo compounds for the bioreversible esterification of proteins

Cited by 77 publications

References 34 publications

Diazo Compounds: Versatile Tools for Chemical Biology

Diazo Compounds: Versatile Tools for Chemical Biology

Boronic Acid for the Traceless Delivery of Proteins into Cells

Cytosolic Delivery of Proteins by Bioreversible Esterification

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