Phosphorogenic Iridium(III) bis‐Tetrazine Complexes for Bioorthogonal Peptide Stapling, Bioimaging, Photocytotoxic Applications, and the Construction of Nanosized Hydrogels

Abstract

The dual functionality of 1,2,4,5-tetrazine as a bioorthogonal reactive unit and a luminescence quencher has shaped tetrazine-based probes as attractive candidates for luminogenic labeling of biomolecules in living systems. In this work, three cyclometalated iridium(III) complexes featuring two tetrazine units were synthesized and characterized. Upon photoexcitation, the complexes were non-emissive but displayed up to 3900-fold emission enhancement upon the inverse electron-demand Diels-Alder (IEDDA) [4+2] cycloaddition with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) substrates. The rapid reaction kinetics (k 2 up to 1.47 × 10 4 M À 1 s À 1 ) of the complexes toward BCN substrates allowed effective peptide labeling. The complexes were also applied as live cell bioimaging reagents and photocytotoxic agents. One of the complexes was utilized in the preparation of luminescent nanosized hydrogels that exhibited interesting cargo delivery properties.

Luminescent and Photofunctional Transition Metal Complexes: From Molecular Design to Diagnostic and Therapeutic Applications

“…Complex 72b exhibits higher photocytotoxic activity toward HeLa cells containing BCN-modified HaloTag protein (IC 50,light = 0.26 μM) than those with unmodified and TCO-modified HaloTag protein (IC 50,light = 0.68 and 1.00 μM, respectively). Iridium­(III) complexes featuring two tetrazine units ( 73 ) have been developed as phosphorogenic bioorthogonal probes for bis-cyclooctynylated substrates . These complexes show extremely weak emission and 1 O 2 photosensitization (Φ Δ = 0.02–0.07) due to the tetrazine moiety, but react very rapidly with substrates carrying two BCN motifs to give bis-pyridazine conjugates with significantly enhanced emission ( I / I o = 1008.2–3885.7) and 1 O 2 generation (Φ Δ = 0.62–0.77), rendering them promising activatable bioimaging reagents and phototherapeutic agents.…”

Tetrazine bioorthogonal chemistry makes nanotechnology a powerful toolbox for biological applications

“…Over the past decade, plenty of studies reported applications of materials relied on the employ of tetrazine bioorthogonal reactions 9,25 Mostly abundant applications in this field should refer to the preparation of biologically functionalized hydrogels for therapeutic, diagnostic, and target molecule delivery applications. 26–31 Those studies mainly depended on the Diels–Alder ligation between 1,2,4,5-tetrazine and various dienophiles, especially the trans -cyclooctene (TCO) derivatives. Alternatively, a novel photocatalytic activating technique depending on the conversion of the inactivated tetrazine motif, dihydrotetrazine, to activated tetrazine for hydrogel formation was designed.…”

Two birds one stone: β-fluoropyrrolyl-cysteine SNAr chemistry enabling functional porphyrin bioconjugation

“…To date, it is still far from well recognized that a significant opportunity exists in implementing bioconjugation: that is, to tailor the structural and functional diversity of small molecules beyond establishing a robust connection with biomolecules. 9–11 Such recognition is particularly relevant to fabricating porphyrin bioconjugates for diagnostic or therapeutic purposes, as described in this work.…”