Isocyanides: Promising Functionalities in Bioorthogonal Labeling of Biomolecules.

Yuchen Zhu,Jia-Yu Liao,Linghui Qian

doi:10.3389/fchem.2021.670751

Yuchen Zhu, Jia-Yu Liao + Show 1 more

Open Access

https://doi.org/10.3389/fchem.2021.670751

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Abstract

Isocyanides have drawn increasing attention in biological applications due to their attractive properties and unique reactivities, which can undergo various reactions, such as multicomponent reactions, α-addition reactions, [4 + 1] cycloaddition reactions, and the reaction scope keeps expanding. In addition to acting as reactants for the preparation of structurally interesting and diverse N-heterocycles or peptidomimetics, this type of functionality may be a good choice in the labeling and modulation of biomolecules due to the high biocompatibility and small size to minimize modifications on the parent molecule. It has been demonstrated that isocyanides can participate in biomolecule labeling through three strategies, including the two-component bioorthogonal reaction, multicomponent reaction, and metal chelation. Among them, the isocyanide-tetrazine reaction has been better studied recently, augmenting the potency of isocyanide as a bioorthogonal handle. This review will focus on the recent progress in isocyanide chemistry for labeling of biomolecules. Meanwhile, methods to introduce isocyano groups into biomacromolecules are also described to facilitate wider applications of this unique functionality.

Highlights

Isocyanides are a class of highly versatile and irreplaceable reagents as the isocyano group may serve as both nucleophile and electrophile in chemical reactions (Nenajdenko, 2012)
It is expected to achieve the activation of specific proteases and targeted drug release when used in combination with other strategies (Zhang et al, 2020)
A problem with this strategy is that the C-S bond is not stable under physiological conditions, and reverse Michael addition may cause cleavage of the isocyanide side chain

Summary

Introduction

Isocyanides are a class of highly versatile and irreplaceable reagents as the isocyano group may serve as both nucleophile and electrophile in chemical reactions (Nenajdenko, 2012). Such bioorthogonal bond cleavage reactions were thoroughly reviewed by Chen’s group in 2016, highlighting their applications in regulating cellular proteins or manipulating biological functions (Li and Chen, 2016; Zhang et al, 2016). Xiao et al (Chen et al, 2019) designed a tert-butyl isocyano group conjugated lysine (NCibK) for protein labeling via [4 + 1] cycloaddition reaction with tetrazine probes (Figure 3B).

Results

Conclusion