Unlocking the Potential of Ru(II) Dual‐action Compounds with the Power of the Heavy‐atom Effect^†

Abstract

We report the synthesis, photochemical and biological characterization of two new Ru(II) photoactivated complexes based on [Ru(tpy)(Me 2 bpy)(L)] 2+ (tpy = 2,2':6',2''terpyridine, Me 2 bpy = 6,6'-dimethyl-2,2'-bipyridine), where L = pyridyl-BODIPY (pyBOD). Two pyBOD ligands were prepared bearing flanking hydrogen or iodine atoms. Ru(II)bound BODIPY dyes show a red-shift of absorption maxima relative to the free dyes and undergo photodissociation of BODIPY ligands with green light irradiation. Addition of iodine into the BODIPY ligand facilitates intersystem crossing, which leads to efficient singlet oxygen production in the free dye, but also enhances quantum yield of release of the BODIPY ligand from Ru(II). This represents the first report of a strategy to enhance photodissociation quantum yields through the heavy-atom effect in Ru(II) complexes. Furthermore, Ru(II)-bound BODIPY dyes display fluorescence turnon once released, with a lead analog showing nanomolar EC 50 values against triple negative breast cancer cells, >100fold phototherapeutic indexes under green light irradiation, and higher selectivity toward cancer cells as compared to normal cells than the corresponding free BODIPY photosensitizer. Conventional Ru(II) photoactivated complexes require nonbiorthogonal blue light for activation and rarely show submicromolar potency to achieve cell death. Our study represents an avenue for the improved photochemistry and potency of future Ru(II) complexes.

Enhancing Precision in Photodynamic Therapy: Innovations in Light-Driven and Bioorthogonal Activation

“…In 2021, N. Toupin et al proposed to link a ruthenium PPG with the pyridyl-BODIPY photosensitizer, which has a high quantum yield of singlet oxygen ( Figure 14 ) [ 78 ]. Upon irradiation with green light (λ = 520–530 nm) for 15 min at an energy density of 50 J/cm 2 , the pyridyl-BODIPY ligand 15 was liberated from the conjugate 13 .…”

“…The authors also demonstrated that the released ruthenium complex 12 could inhibit the mitogen-activated protein kinase signaling pathway characteristic of tetrahydrocurcumin, thereby exerting an anticancer effect. In 2021, N. Toupin et al proposed to link a ruthenium PPG with the pyridyl-BODIPY photosensitizer, which has a high quantum yield of singlet oxygen (Figure 14) [78]. Upon irradiation with green light (λ = 520-530 nm) for 15 min at an energy density of 50 J/cm 2 , the pyridyl-BODIPY ligand 15 was liberated from the conjugate 13.…”

Photodynamic Therapy: Critical PDT Theory†

“…Any agent that requires a very high light dose in monolayer cell culture is unlikely to have much relevance in vivo. There are reports that indicate light doses as high as 50-100 J sq cm À1 for use in monolayer studies (27,28). Such agents are unlikely to be useful for clinical purposes, or even for eradicating cells in 3D culture where light doses are typically greater than what is required when dealing with only monolayers.…”

Ruthenium-Cathepsin Inhibitor Conjugates for Green Light-Activated Photodynamic Therapy and Photochemotherapy

“…While many photoactivated Ru­(II) complexes have been designed to display red-shifted absorption windows with high extinction coefficients, they generally feature π-extended ligands that reduce their solubility in aqueous media, organic chromophores that are responsible for its photosensitization properties, or nanoparticles that incorporate many Ru­(II) molecules. Moreover, in attempts to shift Ru­(II) complexes to the therapeutic window, the PCT mode is sacrificed for PDT capabilities; therefore, only a handful of dual PCT/PDT agents can be activated with green or red light. − In our synthetic design, we utilized an intermediate aldehyde that can be subjected to facile oxime formation via a “click” reaction to efficiently produce conjugates with green light activated dual action PCT/PDT analogs . The Ru PCT/PDT-cathepsin inhibitor conjugate prepared by this method efficiently inactivates purified cathepsins B and L both upon irradiation and when kept in the dark.…”