Phosphorescent heteroleptic iridium(III) complexesapplications for therapy and photodynamic therapy of cancer

Abstract

Cancer is the second deadliest disease globally, and the number of newly diagnosed cases keeps rising every year. Octahedral cyclometalated iridium complexes have aroused great interest since, in addition to presenting antitumor properties, they possess an intrinsic luminescence so that they can be used simultaneously in therapy and diagnosis. In addition, they have attracted much attention as possible photodynamic therapy (PDT) agents due to precisely their tunable photophysical properties. This thesis is outlined in the context of the synthesis and characterization of new octahedral Ir(III) complexes and the study of their potential as anti-cancer drugs in the therapy and phototherapy of cancer. The work has been structured in eight chapters, including a general introduction (chapter 1) and final conclusions (chapter 8). In chapter 2, a structure-activity relationship (SAR) study for in vitro antiproliferative activity of a new series of cationic iridium complexes of the type [Ir(C^N)2(N^N)][PF6] has been performed. We have demonstrated that the auxiliary N^N ligand (phen, dpq, dppz, dppn, and dppz-izdo) affects both the photophysical properties and the antitumor activity of the complexes. The complexes with dppn and dppz-izdo show no cytotoxicity under dark conditions, but an enhancement of the activity is observed under blue light irradiation with a marked increase in intracellular reactive oxygen species (ROS). In chapter 3, a second SAR study has been performed by modifying the C^N ligand based on 2-phenyl-, 2-(naphthalen-2-yl)- or 2-(thiophen-2-yl)-benzimidazole scaffolds in complexes of the general formula [Ir(C^N)2(dppz)][PF6]. The ROS production investigated by DHE and SOSG staining assays with sulfur-containing complexes shows that the generation of superoxide radicals competed with singlet oxygen production in cells in normoxia but became dominant under hypoxia. The importance of this switch from Type II to Type I photochemical mechanism by the new compounds is that they can be active in all areas of a solid tumor, adapting their mechanism of action according to the oxygen concentration. In chapter 4, we have observed that the introduction of a benzimidazole scaffold with NH groups in the auxiliary ligand of [Ir(C^N)2(N^N)][PF6] complexes results in very low cytotoxicity to their correspondent compounds in the dark, a crucial condition to be met for the design of ideal photosensitizers. The new complexes show high phototoxicity by blue light irradiation in human skin melanoma and cervix adenocarcinoma cells. In addition, one of these complexes induces immunogenic cell death in melanoma cells and shows a potent ability to inhibit the growth of cancer stem cells, only if the cells are irradiated by light. On the other hand, combining two transition metals in a single molecule in the dinuclear Ir(III)-Pt(II) complex of chapter 5 reveals the promising activity of this new compound to overcome resistance to drugs such as cisplatin. The Ir(III)-Pt(II) complex can kill cisplatin-resistant cervical and ovarian cancer cells, and exhibits no effect in non-tumorigenic normal renal cells, showing its better selectivity towards cancer cells. In chapter 6, a new cyclometalated iridium complex has been synthesized to study the antitumor action prevalence when moving from two-dimensional in vitro models to the in vivo environment. This compound containing a new 2-benzothiazol-yl benzimidazole core as N^N ligand reduces the tumor size as much as cisplatin in the in vivo C. elegans tumoral model, being less toxic for the animals. Finally, in Chapter 7, the design of luminescent neutral Ir(III) complexes of the type [Ir(C^N)3] and [Ir(C^N)2(C´^N´)] proves the influence of their neutral nature in the biological study. These complexes can’t penetrate the cell due to their lack of charge. Therefore, two of them were encapsulated using polyurethane-polyurea hybrid nanocapsules to improve their biocompatibility, cellular accumulation, and cytotoxic action against HeLa cancer cells.