The photochemical thiol-ene reaction as a versatile method for the synthesis of glutathione S-conjugates targeting the bacterial potassium efflux system Kef

Jess Healy, Tim Rasmussen, Samantha Miller, Ian R. Booth, Stuart J. Conway

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Abstract

The thiol-ene coupling reaction is emerging as an important conjugation reaction that is suitable for use in a biological setting. Here, we explore the utility of this reaction for the synthesis of glutathione-S-conjugates (GSX) and present a general, operationally simple, protocol with a wide substrate scope. The GSX afforded are an important class of compounds and provide invaluable molecular tools to study glutathione-binding proteins. In this study we apply the diverse library of GSX synthesised to further our understanding of the structural requirements for binding to the glutathione-binding protein, Kef, a bacterial K(+) efflux system, found in many bacterial pathogens. This system is vital to the survival of bacteria upon exposure to electrophiles, and plays an essential role in the maintenance of intracellular pH and K(+) homeostasis. Consequently, Kef is an appealing target for the development of novel antibacterial drugs.

Original languageEnglish
Pages (from-to)439-446
Number of pages8
JournalOrganic chemistry frontiers : an international journal of organic chemistry / Royal Society of Chemistry
Volume3
Issue number4
Early online date15 Feb 2016
DOIs
Publication statusPublished - 1 Apr 2016

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Sulfhydryl Compounds
Glutathione
Potassium
Carrier Proteins
Pathogens
Bacteria
Substrates
Pharmaceutical Preparations

Cite this

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title = "The photochemical thiol-ene reaction as a versatile method for the synthesis of glutathione S-conjugates targeting the bacterial potassium efflux system Kef",
abstract = "The thiol-ene coupling reaction is emerging as an important conjugation reaction that is suitable for use in a biological setting. Here, we explore the utility of this reaction for the synthesis of glutathione-S-conjugates (GSX) and present a general, operationally simple, protocol with a wide substrate scope. The GSX afforded are an important class of compounds and provide invaluable molecular tools to study glutathione-binding proteins. In this study we apply the diverse library of GSX synthesised to further our understanding of the structural requirements for binding to the glutathione-binding protein, Kef, a bacterial K(+) efflux system, found in many bacterial pathogens. This system is vital to the survival of bacteria upon exposure to electrophiles, and plays an essential role in the maintenance of intracellular pH and K(+) homeostasis. Consequently, Kef is an appealing target for the development of novel antibacterial drugs.",
author = "Jess Healy and Tim Rasmussen and Samantha Miller and Booth, {Ian R.} and Conway, {Stuart J.}",
note = "Acknowledgements This work was funded by The Wellcome Trust (WT092552MA) and the Oxford University Press John Fell fund (093/380). SJC thanks St Hugh’s College, Oxford, for research support.",
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AU - Healy, Jess

AU - Rasmussen, Tim

AU - Miller, Samantha

AU - Booth, Ian R.

AU - Conway, Stuart J.

N1 - Acknowledgements This work was funded by The Wellcome Trust (WT092552MA) and the Oxford University Press John Fell fund (093/380). SJC thanks St Hugh’s College, Oxford, for research support.

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AB - The thiol-ene coupling reaction is emerging as an important conjugation reaction that is suitable for use in a biological setting. Here, we explore the utility of this reaction for the synthesis of glutathione-S-conjugates (GSX) and present a general, operationally simple, protocol with a wide substrate scope. The GSX afforded are an important class of compounds and provide invaluable molecular tools to study glutathione-binding proteins. In this study we apply the diverse library of GSX synthesised to further our understanding of the structural requirements for binding to the glutathione-binding protein, Kef, a bacterial K(+) efflux system, found in many bacterial pathogens. This system is vital to the survival of bacteria upon exposure to electrophiles, and plays an essential role in the maintenance of intracellular pH and K(+) homeostasis. Consequently, Kef is an appealing target for the development of novel antibacterial drugs.

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