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Review
. 2021 Apr 29:9:670751.
doi: 10.3389/fchem.2021.670751. eCollection 2021.

Isocyanides: Promising Functionalities in Bioorthogonal Labeling of Biomolecules

Yuchen Zhu  1 , Jia-Yu Liao  1   2 , Linghui Qian  1   2   3   4
Affiliations
Review

Isocyanides: Promising Functionalities in Bioorthogonal Labeling of Biomolecules

Yuchen Zhu et al. Front Chem. .

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.

Keywords: biomolecule labeling; bioorthogonal chemistry; cleavage; isocyanide; ligation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Comparison of the size of isocyano group with other commonly used bioorthogonal functionalities. Molecules are shown with the corresponding methyl derivatives.
FIGURE 2
FIGURE 2
Mechanism of the reaction between isocyanides and tetrazines.
FIGURE 3
FIGURE 3
Application of isocyanide-tetrazine chemistry for bioorthogonal ligation with (A) glycans or (B) proteins.
FIGURE 4
FIGURE 4
Application of isocyanide-tetrazine chemistry for bioorthogonal cleavage in (A) single release of small molecules, (B) single release of proteins, or (C) dual release of fluorophores.
FIGURE 5
FIGURE 5
(A) Mechanism of the reaction between isocyanides and chlorooximes. (B) Isocyanide-chlorooxime ligation for the labeling of biomolecules in live cells. Re-printed with permission from American Chemistry Society Publications 2019 (Schäfer et al., 2019).
FIGURE 6
FIGURE 6
Isocyanide-based MCRs applied to bioconjugation include (A) Passerini reaction, (B) Ugi reaction and (C) Ugi-azide reaction. All the substituents (R1−R5) can be biomolecular fragments.
FIGURE 7
FIGURE 7
(A) Ugi reaction for the conjugation of single residue of native proteins. (B) Ugi reaction for the conjugation of two neighboring residues of native proteins.
FIGURE 8
FIGURE 8
(A) 10 valence-electron CO and [NC]− that function as terminal ligands to transition metals. (B) Isocyano-containing biomolecules can be labelled via metal chelation. M = transition metal.
FIGURE 9
FIGURE 9
Preparation of isocyanides by (A) the reaction of silver cyanide with alkyl iodide, (B) Hoffman carbylamine reaction with phase transfer catalysis, (C) ring-opening reaction of oxazole, (D) one-pot reaction using trimethylsilyl cyanide (TMSCN) and benzylic/tertiary alcohol, or (E) dehydration of formamide.
FIGURE 10
FIGURE 10
An isocyano-containing linker tagged to the protein through cysteine ligation.
FIGURE 11
FIGURE 11
(A) Metabolic oligosaccharide engineering. (B) Chemoenzymatic glycan labeling.
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