Design of a Tris-Heteroleptic Ru(II) Complex with Red-Light Excitation and Remarkably Improved Photobiological Activity.

Ru(II)-polypyridyl complexes are of increasing interest in photodynamic therapy (PDT) due to their easily tunable photophysical and photochemical properties. However, short-wavelength absorption of Ru(II)-polypyridyl complexes has limited their penetration depth in PDT. Herein, the series of Ru(II)-polypyridyl complexes 1-4 was designed by replacing one bipyridine in [Ru(bpy)3]Cl2 with Schiff bases (iminopyridine or iminoquinoline analogues) to achieve red-shifted absorption of Ru(II)-polypyridyl photosensitizers. To further shift the absorption to longer wavelength and improve the photobiological activity of Ru(II)-polypyridyl complexes, the three tris-heteroleptic Ru(II) complexes 5-7 with benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn) as a ligand were designed to achieve long-lived intraligand (3IL) excited states. Cytotoxicity data against A549 and HepG2 cells revealed that complex 7 showed extraordinarily high cytotoxicity under 650 nm irradiation, resulting in IC50 values of 56 and 63 nM with exceptionally large phototoxicity index (PI) values of 763 and 613, respectively. Thus, the resulting complex 7 with considerable red-light photocytotoxicity and high PI values shows a promising potential for therapeutic applications, which represents a new scaffold of Ru(II)-polypyridyl photosensitizers for PDT in the "therapeutic window". This study delivers a rational strategy for the design of tris-heteroleptic Ru(II) complexes as promising photosensitizers for cancer therapy.