Ir(III) and Ru(II) polypyridyl complexes are promising photosensitizers (PSs) for photodynamic therapy (PDT)
due to their outstanding photophysical properties. Herein, one series of cyclometallated Ir(III) complexes and
two series of Ru(II) polypyridyl derivatives bearing three different thiazolyl-β-carboline N^N′ ligands have been
synthesized, aiming to evaluate the impact of the different metal fragments ([Ir(C^N)2]
+ or [Ru(N^N)2]
2+) and
N^N’ ligands on the photophysical and biological properties. All the compounds exhibit remarkable photo
stability under blue-light irradiation and are emissive (605 < λem < 720 nm), with the Ru(II) derivatives dis
playing higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pKa
values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pKa > 9.3). The presence of the
deprotonated form in the Ir-PSs favours the generation of reactive oxygen species (ROS) since, according to
theoretical calculations, it features a low-lying ligand-centered triplet excited state (T1 = 3
LC) with a long
lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1–3 exhibit the highest cyto
toxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation,
resulting in nanomolar IC50 values and phototoxicity indexes (PIs) between 70 and 201 in different cancer cell
lines. The Ir(III) PSs are also activated by green (with PI between 16 and 19.2) and red light in the case of
complex 3 (PI = 8.5). Their antitumor efficacy is confirmed by clonogenic assays and using spheroid models. The
Ir(III) complexes rapidly enter cells, accumulating in mitochondria and lysosomes. Upon photoactivation, they
generate ROS, leading to mitochondrial dysfunction and lysosomal damage and ultimately cell apoptosis.
Additionally, they inhibit cancer cell migration, a crucial step in metastasis. In contrast, Ru(II) complex 6 exhibits moderate mitochondrial activity. Overall, Ir(III) complexes 1–3 show potential for selective light-controlled cancer treatment, providing an alternative mechanism to chemotherapy and the ability to inhibit lethal cancer cell dissemination.
