A Sterically Open Ruthenium-Based Photocage Activated by Red and Far-Red Light for a Wide Range of Drugs

Herein we report a novel ruthenium-based photocage for photoactivated chemotherapy (PACT) that can deliver a variety of experimental and clinically approved anticancer drugs using red and far-red light. The new caging moiety is based on the polypyridine pentadentate ligand N⁶,N^6″-di(pyridin-2-yl)-[2,2':6',2″-terpyridine]-6,6″-diamine (baptpy), which once coordinated to ruthenium(II) can form the helically chiral [Ru(baptpy)(L)]X₂ prodrugs [6]Cl₂-[16]Cl₂. A total of ten active pharmaceutical ingredients (L) have been successfully conjugated to this photocage, including well-known agents such as Albendazole, Gemcitabine, Bosutinib, Neratinib, and Ponatinib. The X-ray crystal structures of seven complexes were obtained, showing coordination of ligand L via its thioether, nitrile, pyridine or imidazole moieties. All prepared ruthenium compounds showed selective photosubstitution of the monodentate ligand under 625 (red) and 730 nm (far-red) light irradiation with good (0.005-0.05) to excellent (0.05-0.10) quantum yields, while no singlet oxygen generation was observed. As calculated by density functional theory and time-dependent density functional theory, the high-wavelength light absorption of [Ru(baptpy)(L)]X₂ complexes and their favorable ligand exchange behavior under low-energy light are the consequence of the strong distortion of the first coordination sphere, combined with the electronic effect of the amine bridges of the baptpy ligand. Preliminary biological activity of complexes [6]Cl₂-[16]Cl₂ was investigated in vitro by cytotoxicity studies in the dark and under red light irradiation in normoxic A375 and U-87MG human cancer cell lines. Several of the obtained PACT prodrugs exhibited micro- to nanomolar EC₅₀ values upon red light activation, with photoindexes as high as 7.5. [7]Cl₂ showed a photoindex of 6.2 upon far-red light activation (730 nm), which is unprecedented for a ruthenium-based PACT, while the ruthenium cage itself showed very low toxicity in both the dark and light irradiation.