A second-generation series of biscyclometalated 2-(5-aryl-thienyl)-benzimidazole and -benzothiazole Ir(III) dppz complexes [Ir(C^N)2(dppz)]+, Ir1-Ir4, were rationally designed and synthesized, where the aryl group attached to the thienyl ring was p-CF3C6H4 or p-Me2NC6H4. These new Ir(III) complexes were assessed as photosensitizers to explore the structure-activity correlations for their potential use in biocompatible anticancer photodynamic therapy. When irradiated with blue light, the complexes exhibited high selective potency across several cancer cell lines predisposed to photodynamic therapy; the benzothiazole derivatives (Ir1 and Ir2) were the best performers, Ir2 being also activatable with green or red light. Notably, when irradiated, the complexes induced leakage of lysosomal content into the cytoplasm of HeLa cancer cells and induced oncosis-like cell death. The capability of the new Ir complexes to photoinduce cell death in 3D HeLa spheroids has also been demonstrated. The investigated Ir complexes can also catalytically photo-oxidate NADH and photogenerate 1O2 and/or •OH in cell-free media.

• MeSH
• Benzothiazoles MeSH
• Photosensitizing Agents pharmacology   therapeutic use   MeSH
• Dermatitis, Phototoxic * drug therapy   MeSH
• Iridium pharmacology   MeSH
• Coordination Complexes * pharmacology   MeSH
• Humans MeSH
• Lysosomes MeSH
• Cell Line, Tumor MeSH
• Neoplasms * drug therapy   MeSH
• Antineoplastic Agents * pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Benzothiazoles MeSH
• Photosensitizing Agents MeSH
• Iridium MeSH
• Coordination Complexes * MeSH
• Antineoplastic Agents * MeSH

We present the synthesis and characterization of six new heteroleptic osmium(II) complexes of the type [Os(C^N)(N^N)2]OTf (N^N = 2,2'-bipyridine and dipyrido[3,2-d:2',3'-f]quinoxaline; C^N = deprotonated methyl 1-butyl-2aryl-benzimidazolecarboxylate) with varying substituents in the R3 position of the phenyl ring of the cyclometalating C^N ligand. The new compounds are highly kinetically inert and absorb a full-wavelength range of visible light. An investigation of the antiproliferative activity of the new compounds has been performed using a panel of human cancer and noncancerous 2D cell monolayer cultures under dark conditions and green light irradiation. The results demonstrate that the new Os(II) complexes are markedly more potent than conventional cisplatin. The promising antiproliferative activity of selected Os(II) complexes was also confirmed using 3D multicellular tumor spheroids, which have the characteristics of solid tumors and can mimic the tumor tissue microenvironment. The mechanism of antiproliferative action of complexes has also been investigated and revealed that the investigated Os(II) complexes activate the endoplasmic reticulum stress pathway in cancer cells and disrupt calcium homeostasis.

• MeSH
• Benzimidazoles pharmacology   MeSH
• Homeostasis MeSH
• Coordination Complexes * pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Neoplasms * MeSH
• Osmium pharmacology   MeSH
• Antineoplastic Agents * pharmacology   MeSH
• Calcium MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Benzimidazoles MeSH
• Coordination Complexes * MeSH
• Osmium MeSH
• Antineoplastic Agents * MeSH
• Calcium MeSH