Ru(II) Dyads Derived from 2-(1-Pyrenyl)-1H-imidazo[4,5-f][1 Ru(II) Dyads Derived from 2-(1-Pyrenyl)-1H-imidazo[4,5-f][1.10]phenanthroline: Versatile Photosensitizers for Photodynamic Applications Raymond Twumasi

Photosensitizers Therapeutic agents and diagnostic tools Utilize light as an external trigger for temporal and spatial selectivity in various applications PDT and PDI Applications include photodynamic therapy (PDT) of cancer and age-related macular degeneration to photodynamic inactivation (PDI) of microorganisms. http://photobiology.info/Oleinick.html

Advantages Minimization of collateral damage Localized and immediate burst of cytotoxic agents Rapid cellular destruction Less chance for resistance Minimization of collageral damage to healthy tissue and off-shite toxicity Key advantage PDT holds over traditional cancer chemotherapy Less chance for the development of intrinsic or acquired resistance Particularly important when considering prolonged treatment of the widespread use of targeted antibiotics Periodontology 2000 2011, 55, 143-166

Disadvantages Tendency to photobleach Poor aqueous solubility Prolonged retention in tissues Organic-porphyrin based systems employ triplet excited states to photogenerate cytotoxic singlet oxygen and other ROS upon light activation Dalton Trans. 2009, 10690 – 10701

Organic PSs vs Metal Complexes Capable of photochemistry with wider breadth of wavelengths of light Metal complexes have a variety of excited state configuration MLCT, MC, LC, IL, ILCT, MMCT Combinations Low-lying 3IL excited states Metal complexes have a variety of excited state configurations that can easily be accessed through rational changes to their scaffolds. Wavelengths of light ranging from UV to near-IR Low-lying 3IL excited states with slow kinetics are of immense interest because they can prolong the lifetimes of Ru(II) coordination complexes Does this through equilibrium with MLCT states or by acting as distinct states. Isr. J. Chem. 2013, 53, 391 – 400

Other work in field Wrighton and coworkers: Organic chromophores + metal complexes = extend excited state lifetimes Ford & Rogers applied this concept to Ru(II) complexes Lifetimes above 150 µs have been reported for pure 3IL states. Wrighton and coworkers demonstrated in the 70s that organic chromophores could be tethered to metal complexes to extend their excited state lifetimes 5-8.. Ford & Rogers later applied this concept to Ru(II) complexes 9. In order to lengthen their typical 1 µs lifetimes 100-fold

Previous work 3IL states with lifetimes as long as 240 µs (from 22 µs) 5-(puren-1-ylethynyl)-1,10-phenantholine (5-EPP) They did this by changing the attachment point between the pyrenyethnyl group and the coordinating [1,10]-phenanthroline (phen) ligand in complexes of the type [Ru(LL)2(EPP)]2+ or the number of EPP ligands All structural isomers gave very potent PDT effect in cancer cells. Potency derives from ligands that impart low-lying 3IL states and long excited state lifetimes. JACS. 2013, 135, 17161 – 17175

Problem Blue/green-absorbing PSs can be activated despite no absorption of light at these wavelengths PSs can be activated in the PDT window despite no absorption of light at these wavelengths, which underscores the efficiency of such highly photosensitizing excited states. Problem holds for both contiguously fused π–systems and true tethered dyads, where π–expansive organic chromophore is attached to a coordinating ligand such as bpy of phen. Inorg. Chem. 2014, 53, 4548 – 4559

Purpose: outline photophysical properties and photodynamic potency of another type of metal-organic dyad with a low-lying 3IL state. Goal: To expand the repertoire of Ru (II) complexes that exhibit unusual potency due to low-lying 3IL excited states

Compound 1 = previously studied in the context of remarkable luminescent oxygen sensing Compound 2 = DNA affinity and photocleavage J. Phys. Chem. A 2014, 118, 10507 – 10521

Results – UV Vis Bpy or phen LC (or IL) transitions (1LC π to π* - based on extinction coefficients) Ippy LC or pyrene-based transitions (1LC π to π*) Typical MLCT transitions – metal with ippy ligand (1MLCT dπ to ippy π*) J. Phys. Chem. A 2014, 118, 10507 – 10521

Results – Resonance Raman Recorded at 458, 476, 488 nm In order to confirm MLCT transition involved ippy All spectra were normalized to the intensity of bpy band at 1490 cm-1 Bands associated with the vibrational modes of ippy ligand are highlighted As longer excitation wavelengths were employed, the contribution of the ippy-related vibrational modes to the RR spectra increased, as expected if the lowest-energy MLCT transition was Ru (dπ) to ippy (π*) J. Phys. Chem. A 2014, 118, 10507 – 10521

Compounds 1-4 were weakly emissive Compound 2 was most red-shifted and compound 1 was least Emission resolved into two components τ1 and τ2 Measured using stroboscopic detection Measured using a gated detector and constrained in the fit of the stroboscopic biexponential decay (done for precise determination of τ2) Contribution of τ2 is minor.

Electronic absorption signatures Dyads are weakly coupled systems with distinct chromophores 3MLCT state can exist in equilibrium with 3IL state of ippy Decay via a double exponential process Decay should be linear combination of deactivation rates for both states 2 possible reasons: luminescence from both states or luminescence from single state in which τ1 represents pre-equilibrium relaxation and τ2 involves decay from equilibrated mixture Gated emission measurements couldn’t isolate τ2. Could only find monoexponential decay (between 5 and 10 µs) suggesting the second reason 1MLCT 3MLCT 3IL 1Ground state

Emission decay kinetics Biexponential decay kinetics also observed in water τ2 plays more important role in excited state quenching by O2 High O2 quantum yields attributed to 3IL Potent photobiological agents for PDT

Absorption titration - DNA binding Binding constant (Kb): nonintercalating metal complex [Ru(phen)3]2+ is 1.65 x 104 M-1 intercalating complex [Ru(phen)2dppz]2+ is >10 M-1 Increasing Steric bulk = increasing DNA affinity

Photodynamic Activity Nanomolar light toxicities and PIs > 100 Highly photosensitizing excited states Such potency typical for low-lying 3IL states or 3IL-3MLCT equilibrium mixtures Prolonged lifetimes are particularly attractive features because they make complexes particularly sensitive to quenching by molecular oxygen. Very good for retaining activity in cancer cells

Conclusion Ru(II) dyads containing ippy can be used to achieve highly photosensitizing states Common factor among dyads is low-lying, long-lived 3IL state High light cytotoxicity against both cancer and bacteria cells Dark toxicities influenced by ancillary ligands Would’ve liked to see PSs that could be used for multiwavelength PDT which may be useful in specialized application (future)

Questions?