Exploiting the Potential of Iridium(III) bis-Nitrone Complexes as Phosphorogenic Bifunctional Reagents for...

Area of Science:

• Bioorthogonal Chemistry
• Coordination Chemistry
• Chemical Biology
• Photochemistry

Background:

• Cross-linking strategies are vital in chemical biology for biomolecule labeling and protein-protein interaction studies.
• Nitrone chemistry, particularly strain-promoted alkyne-nitrone cycloaddition (SPANC), offers versatile bioorthogonal labeling capabilities.
• Cyclometalated iridium(III) polypyridine complexes are explored for their photophysical properties in biological applications.

Purpose of the Study:

• To design and synthesize novel phosphorogenic bioorthogonal reagents based on iridium(III) complexes functionalized with nitrone units.
• To investigate the photophysical properties and bioorthogonal reactivity of these complexes with strained alkynes.
• To evaluate their potential in bioimaging, phototherapeutics, and the development of advanced materials like hydrogels and modified peptides.

Main Methods:

• Synthesis and characterization of four cyclometalated iridium(III) polypyridine complexes bearing two nitrone units.
• Spectroscopic studies (emission, lifetime) to assess photophysical properties and reactivity with bicyclo[6.1.0]non-4-yne (BCN) derivatives (mono-BCN and bis-BCN).
• Computational studies (MECP analysis) to understand emission quenching mechanisms.
• Live-cell imaging and photocytotoxicity assays to evaluate biological applications.
• Development and testing of a nanosized hydrogel and stapled/cyclized peptides.

Main Results:

• The iridium(III) complexes exhibited efficient emission quenching, attributed to a nonradiative decay pathway via a low-lying T1/S0 minimum energy crossing point (MECP).
• Upon reaction with BCN derivatives, significant emission enhancement and lifetime extension were observed, indicating successful bioorthogonal reactions.
• A remarkably higher reaction rate was observed with bis-BCN compared to mono-BCN.
• Live-cell imaging demonstrated effective bioorthogonal labeling, and photocytotoxicity studies revealed enhanced singlet oxygen generation and efficacy in bis-BCN-pretreated cells.
• A hydrogel formulation showed potential as a drug delivery system, and modified peptides exhibited p53-Mdm2 inhibitory activity and cancer selectivity.

Conclusions:

• The designed iridium(III) complexes serve as effective phosphorogenic bioorthogonal reagents for SPANC reactions.
• Their tunable photophysical properties and enhanced reactivity with bis-alkynes enable efficient bioimaging and phototherapeutics.
• These complexes hold significant promise for developing advanced functional materials, including drug delivery systems and targeted cancer therapeutics.