Unusual “mesoionic” N^S biscyclometallated iridium( <scp>iii</scp> ) polypyridine complexes as photosensitisers for photodynamic therapy and type II immunogenic cell death inducers

Historically, the classification of mesoionic compounds has been disconcerting, with more confusion arising when these molecules are used as ligands for metal complexes. Many mesoionic compounds are also biologically active and widely used in various therapeutic applications, but mesoionic metal complexes have not seen much prevalence in the field. In this work, we determine the "mesoionic" nature of an unusual and rare series of N^S biscyclometallated iridium(iii) complexes [Ir(N^C)₂(p-ttqt)] (p-Httqt = 1-phenyl-5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5-<i>c</i>]quinazolin-1-ium-2-thiolate; HN^C = 2-phenylpyridine (Hppy) (1), 7,8-benzoquinoline (Hbzq) (2), 2-phenylbenzothiazole (Hbt) (3) and 2-(1-naphthyl)benzothiazole (Hbsn) (4)) as photodynamic therapy (PDT) agents and immunogenic cell death (ICD) inducers. X-ray, infrared spectroscopy and density functional theory studies demonstrate that the mesoionic nature is retained in the iridium(iii) complexes. These complexes are ideal PDT agents with no cytotoxicity at micromolar concentrations (IC₅₀,_dark > 25 μM), remarkable photocytotoxicity at nanomolar concentrations and PI values (IC₅₀,_light = 1.5-69 nM; PI = 362-33 333), and exquisite selectivity towards cancer cells. Furthermore, their localisation in the endoplasmic reticulum (ER) and efficient reactive oxygen species (ROS) generation enable them to act as photoactivated type II ICD inducers.