Optimized Diazo Scaffold for Protein Esterification

Mix, Kalie A.; Raines, Ronald T.

doi:10.1021/acs.orglett.5b00840

Cited by 72 publications

(83 citation statements)

References 33 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%

“…129 A Hammett analysis of these compounds, which were derived from phenylglycine, revealed that electron-donating or electron-withdrawing groups on the aryl ring had a dramatic effect on the rate of esterification. Still, the compounds were similar in their selectivity for ester formation over hydrolysis of the diazo reagent.…”

Section: Bioreversible Protein Modificationmentioning

confidence: 99%

“…128,129 Diazo compound I is optimized for protein esterification. 129 (B) Putative mechanism of a diazo carbenoid insertion reaction, and its application to the site-specific modification of a proximal amino-acid residue. 161 …”

Section: Figurementioning

confidence: 99%

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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: Bioreversible Protein Modificationmentioning

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: 98%

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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“…Notably, the full mass of the diazo compound had been added to the peptide, ruling out the possibility of reaction by esterification, as is possible with diazo groups. 10 …”

mentioning

confidence: 99%

1,3-Dipolar Cycloadditions of Diazo Compounds in the Presence of Azides

2016

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The diazo group has untapped utility in chemical biology. The tolerance of stabilized diazo groups to cellular metabolism is comparable to that of azido groups. Yet, chemoselectivity has been elusive, as both groups undergo 1,3-dipolar cycloadditions with strained alkynes. Removing strain and tuning dipolarophile electronics yields diazo group-selective 1,3-dipolar cycloadditions that can be performed in the presence of an azido group. For example, diazoacetamide but not its azido congener react with dehydroalanine residues, as in the natural product nisin.

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Optimized Diazo Scaffold for Protein Esterification

Cited by 72 publications

References 33 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

1,3-Dipolar Cycloadditions of Diazo Compounds in the Presence of Azides

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