Intraligand Excited States Turn a Ruthenium Oligothiophene Complex into a Light-Triggered Ubertoxin with Anticancer Effects in Extreme Hypoxia

Ru(II) complexes that undergo photosubstitution reactions from triplet metal-centered ((MC)-M-3) excited states are of interest in photochemotherapy (PCT) due to their potential to produce cytotoxic effects in hypoxia. Dual-action systems that incorporate this stoichiometric mode to complement the oxygendependent photosensitization pathways that define photodynamic therapy (PDT) are poised to maintain antitumor activity regardless of the oxygenation status. Herein, we examine the way in which these two pathways influence photocytotoxicity in normoxia and in hypoxia using the [Ru(dmp)(2)(IP-nT)](2+) series (where dmp = 2,9-dimethyl-1,10-phenanthroline and IP-nT = imidazo[4,5-f][1,10]phenanthroline tethered to n = 0-4 thiophene rings) to switch the dominant excited state from the metal-based (MC)-M-3 state in the case of Ru-phen-Ru-1T to the ligand-based (ILCT)-I-3 state for Ru-3T and Ru-4T. Ru-phen-Ru-1T, having dominant (MC)-M-3 states and the largest photosubstitution quantum yields, are inactive in both normoxia and hypoxia. Ru-3T and Ru-4T, with dominant (IL)-I-3/(ILCT)-I-3 states and long triplet lifetimes (tau(TA) = 20-25 mu s), have the poorest photosubstitution quantum yields, yet are extremely active. In the best instances, Ru-4T exhibit attomolar phototoxicity toward SKMEL28 cells in normoxia and picomolar in hypoxia, with phototherapeutic index values in normoxia of 10(5)-10(12) and 10(3)-10(6) in hypoxia. While maximizing excited-state deactivation through photodissociative (MC)-M-3 states did not result in bonafide dual-action PDT/PCT agents, the study has produced the most potent photosensitizer we know of to date. The extraordinary photosensitizing capacity of Ru-3T and Ru-4T may stem from a combination of very efficient O-1(2) production and possibly complementary type I pathways via (ILCT)-I-3 excited states.