Advances in the Synthesis of Bioorthogonal Reagents: s-Tetrazines, 1,2,4-Triazines, Cyclooctynes, Heterocycloheptynes, and trans-Cyclooctenes

Fang, Yinzhi; Hillman, Ashlyn S.; Fox, Joseph M.

doi:10.1007/s41061-024-00455-y

“…11,12 Phosphorescent cyclometallated iridium(III) complexes were developed as bioorthogonal reagents incorporating a variety of click groups. 3 Inverse electron demand Diels-Alder reaction (IEDDA) is the fastest in the repertoire of bioorthogonal chemistry 13 and several examples of metal complexes were reported in the literature. 14 Of particular interest are complexes in which coordination of the Ir(III) metal centre to the diene facilitates the reaction kinetics.…”

Section: Introductionmentioning

confidence: 99%

Annealing 1,2,4-Triazine to Iridium(III) Complexes Induces Luminogenic Behaviour in Bioorthogonal Reactions with Stain Alkynes.

Cooke,

Gristwood,

Adamson

et al. 2024

Preprint

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Phenanthroline-type ligand containing annealed 1,2,4-triazine ring was used to prepare novel Ir(III) complexes 3 and 4. The complexes are non-luminescent but show luminogenic behaviour following inverse electron demand Diels-Alder (IEDDA) reaction with bicyclononyne (BCN) derivatives. It was observed that the complex 3 reacts with BCN-C10 three times faster than the corresponding free ligand 7. The magnitude of this accelerating metal-coordination effect, however, is less profound that in previously reported Ir(III) complexes of 1,2,4-triazines in which the triazine was directly coordinated to Ir(III) metal centre. Nevertheless, luminogenic behaviour opens prospects for the use of such complexes in bioimaging applications, which was demonstrated by developing a convenient methodology using “chemistry on the complex” concept for labelling antibodies with luminescent Ir(III) complexes. Bioorthogonal reactivity of the complex 4 was then evaluated by metabolically labelling live cells with BCN groups followed by luminogenic IEDDA reaction with the triazine iridium complex.

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Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

Rahm,

Keppel,

Šlachtová

et al. 2024

Angewandte Chemie

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Bioorthogonal reactions that enable switching molecular functions by breaking chemical bonds have gained prominence, with the tetrazine‐mediated cleavage of trans‐cyclooctene caged compounds (click‐to‐release) being particularly noteworthy for its high versatility, biocompatibility, and fast reaction rates. Despite several recent advances, the development of highly reactive tetrazines enabling quantitative elimination from trans‐cyclooctene linkers remains challenging. In this study, we present the synthesis and application of sulfo‐tetrazines, a class of derivatives featuring phenolic hydroxyl groups with increased acidity constants (pKa). This unique property leads to accelerated elimination and complete release of the caged molecules within minutes. Moreover, the inclusion of sulfonate groups provides a valuable synthetic handle, enabling further derivatization into sulfonamides, modified with diverse substituents. Significantly, we demonstrate the utility of sulfo‐tetrazines in efficiently activating fluorogenic compounds and prodrugs in living cells, offering exciting prospects for their application in bioorthogonal chemistry.

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Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

Rahm,

Keppel,

Šlachtová

et al. 2024

Angew Chem Int Ed

0

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Bioorthogonal reactions that enable switching molecular functions by breaking chemical bonds have gained prominence, with the tetrazine‐mediated cleavage of trans‐cyclooctene caged compounds (click‐to‐release) being particularly noteworthy for its high versatility, biocompatibility, and fast reaction rates. Despite several recent advances, the development of highly reactive tetrazines enabling quantitative elimination from trans‐cyclooctene linkers remains challenging. In this study, we present the synthesis and application of sulfo‐tetrazines, a class of derivatives featuring phenolic hydroxyl groups with increased acidity constants (pKa). This unique property leads to accelerated elimination and complete release of the caged molecules within minutes. Moreover, the inclusion of sulfonate groups provides a valuable synthetic handle, enabling further derivatization into sulfonamides, modified with diverse substituents. Significantly, we demonstrate the utility of sulfo‐tetrazines in efficiently activating fluorogenic compounds and prodrugs in living cells, offering exciting prospects for their application in bioorthogonal chemistry.

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Advances in the Synthesis of Bioorthogonal Reagents: s-Tetrazines, 1,2,4-Triazines, Cyclooctynes, Heterocycloheptynes, and trans-Cyclooctenes

Cited by 6 publications

References 282 publications

Annealing 1,2,4-Triazine to Iridium(III) Complexes Induces Luminogenic Behaviour in Bioorthogonal Reactions with Stain Alkynes.

Annealing 1,2,4-Triazine to Iridium(III) Complexes Induces Luminogenic Behaviour in Bioorthogonal Reactions with Stain Alkynes.

Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

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Advances in the Synthesis of Bioorthogonal Reagents: s-Tetrazines, 1,2,4-Triazines, Cyclooctynes, Heterocycloheptynes, and trans-Cyclooctenes

Cited by 6 publications

References 282 publications

Annealing 1,2,4-Triazine to Iridium(III) Complexes Induces Luminogenic Behaviour in Bioorthogonal Reactions with Stain Alkynes.

Annealing 1,2,4-Triazine to Iridium(III) Complexes Induces Luminogenic Behaviour in Bioorthogonal Reactions with Stain Alkynes.

Sulfonated Hydroxyaryl‐Tetrazines with Increased pKa for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

Sulfonated Hydroxyaryl‐Tetrazines with Increased pKa for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

Contact Info

Product

Resources

About

Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells

Sulfonated Hydroxyaryl‐Tetrazines with Increased pK_a for Accelerated Bioorthogonal Click‐to‐Release Reactions in Cells