Abstract
The inverse electron-demand Diels-Alder (IEDDA or DAinv) reaction is an emerging bioorthogonal ligation reaction that finds application in all areas of chemistry and chemical biology. In this review we highlight its application in metabolic glycoengineering (MGE). MGE is a versatile tool to introduce unnatural sugar derivatives that are modified with a chemical reporter group into cellular glycans. The IEDDA reaction can then be used to modify the chemical reporter group allowing, for instance, the visualization or isolation of glycoconjugates. During the last years, many different sugar derivatives as well as reporter groups have been published. These probes are summarized, and their chemical and biological properties are discussed. Furthermore, we discuss examples of MGE and subsequent IEDDA reaction that highlight its suitability for application within living systems.
Highlights
The Diels-Alder reaction (Diels and Alder, 1928) is widely used for stereoselective synthesis of complex molecules, such as many natural products or pharmaceuticals (Brieger and Bennett, 1980; Nicolaou et al, 2002; Funel and Abele, 2013)
The rate constants of the IEDDA reaction can span a range of many orders of magnitude depending on the used tetrazine and dienophile structure, and it can be performed in aqueous media which even accelerates the reaction (Wijnen et al, 1996)
Norbornene and especially TCO derivatives react rapidly in the IEDDA reaction even exceeding the kinetics of well-established bioorthogonal ligation reactions, such as the coppercatalyzed azide-alkyne [3 + 2] cycloaddition (CuAAC) (Rostovtsev et al, 2002; Tornøe et al, 2002), their size limits potential applications as reporter groups for metabolic labeling
Summary
The Diels-Alder reaction (Diels and Alder, 1928) is widely used for stereoselective synthesis of complex molecules, such as many natural products or pharmaceuticals (Brieger and Bennett, 1980; Nicolaou et al, 2002; Funel and Abele, 2013). In 2013, the Devaraj group introduced the mannosamine analogue Ac4ManNCyc modified with the same amide-linked methylcyclopropene used by Prescher (Cole et al, 2013) They could show that the sugar is processed by different human cancer cell lines and displaced on the cell surface allowing visualization by confocal fluorescence microscopy after IEDDA labeling with a tetrazine-dye conjugate. The higher IEDDA reactivity of the carbamate-linked cyclopropene significantly reduced the time needed for the labeling step compared to the amide-linked cyclopropene enabling an efficient one-step labeling approach with a tetrazine-dye conjugate This improved methylcyclopropene reporter was used to modify glucosamine (Ac4GlcNCyoc) as well as galactosamine (Ac4GlcNCyoc) (Späte et al, 2014b; Patterson et al, 2014). The use of galactose analogues modified with terminal alkenes (Kitowski and Bernardes, 2020), a TCO-modified mannosamine derivative (Ac4ManNTCO) (Zhang et al, 2020) and the butenoyl derivatives Ac4GlcNBtl and Ac4GalNBtl (Dold and Wittmann, 2021) were reported
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