The development of group VIII trinuclear transition metal complexes as chemotherapeutic and photodynamic therapy agents

Welsh, Athi

The development of group VIII trinuclear transition metal complexes as chemotherapeutic and photodynamic therapy agents

Thesis / Dissertation

2024

Publisher

University of Cape Town

Department

Department of Chemistry

Faculty

Faculty of Science

Abstract

Cancer is a non-communicable disease that remains one of the leading causes of morbidity and mortality globally. The detrimental effects of cancer are exacerbated by the emergence and development of resistance to current treatment modalities. The development of new treatment modalities, along with novel therapeutic agents, are vital tools in tackling this resistance. Metal-based complexes offer aid in overcoming chemotherapy resistance, as metal complexes may be used in various treatment modalities for cancer and as novel chemotherapeutic drugs. The enhanced biological activity and novel mechanisms of action of trimetallic complexes, as exemplified by BBR3464, lend impetus to the investigation of trinuclear complexes which may lead to the identification of new metallodrug candidates. The purpose of this study was to investigate the synthesis and characterization of a series of trinuclear transition metal- containing complexes based on the benzimidazole scaffold, and the investigation of the applicability of these complexes as different treatment modalities for cancer. A series of trimetallic 2-ferrocenylbenzimidazole complexes, along with their respective mononuclear congeners, were prepared. The 5-position of the benzimidazole scaffold was substituted with varying hydrophobic electron-withdrawing or -donating functionalities, to offer insight into the effect of these substituents on the overall biological activity. However, due to the observed limited aqueous solubility of the trinuclear 2-ferrocenylbenzimidazole complexes, attempts at the improvement of the water solubility of the aforementioned complexes was undertaken. Several strategies were employed, including the use of chemical oxidants and β-cyclodextrin inclusion, with limited success. The preliminary evaluation of the in vitro cytotoxicity of the series of mono- and tri-nuclear 2-ferrocenylbenzimidazole complexes revealed that the trinuclear complexes were initially soluble in biological media. However, the trinuclear complexes gradually precipitated out of biological media within a few hours. On the other hand, the mononuclear complexes showed very mild cytotoxic activity in the MCF-7 breast cancer cell line and no significant activity in the triple-negative MDA-MB-231 breast cancer cell line at the tested concentrations. Additionally, in silico molecular docking studies of all the complexes revealed that the trinuclear 2-ferrocenylbenzimidazole complexes were predicted to bind and interact with oncogenic proteins more favourably relative to their mononuclear congeners. A second series of novel trinuclear benzimidazole-based ruthenium(II) polypyridyl complexes, were synthesized and characterized. The ruthenium(II) polypyridyl complexes were fully characterized using an array of spectroscopic and analytical techniques, including one- and two-dimensional Nuclear Magnetic Resonance (NMR) spectroscopy, Infrared (IR) spectroscopy and high-resolution electrospray ionisation mass spectrometry. These complexes comprised of either the trisamine or the s-triazine core/ central functionality to probe the effects of the aforementioned central moieties on the applicability of the complexes as photosensitizers for photodynamic therapy (PDT). Investigation of the photophysicochemical properties of the ruthenium(II) polypyridyl complexes revealed that the complexes produce a substantial quantity of singlet oxygen in both N,N-dimethylformamide (DMF) and aqueous media. Additionally, the ruthenium(II) complexes were noted to show appreciable photostability and have significant emission quantum yields (ɸem). In the dark, all the ruthenium(II) polypyridyl complexes showed negligible in vitro cytotoxicity in the HeLa cervical cancer cell line at all the tested concentrations (up to 300 µM). However, upon irradiation with blue light (at 455 nm), all the complexes showed appreciable cytotoxicity, with phototoxicity index (P.I.) values greater than some clinically used PDT agents. Furthermore, investigation of the long-term photocytotoxicity of the ruthenium(II) polypyridyl complexes revealed that these complexes show appreciable long-term cytotoxicity upon light irradiation in HeLa cells in a concentration-dependent manner. This highlights the ability of the complexes to reduce the probability of cervical cancer recurrence. Importantly, in both the short-term and long-term cytotoxic evaluations, the trinuclear complexes were noted to show enhanced photocytotoxicity relative to the mononuclear complex. A third, and final, series of benzimidazole-based ruthenium(II) arene complexes were prepared. These ruthenium(II) arene complexes all consisted of the same 2-quinolylbenzimidazole ligand, however, the η6-arene ancillary ligand bound to the ruthenium(II) metal centers was varied. This was to investigate the crucial role of the η6-arene ligand in modulating the overall cytotoxicity of the resultant trinuclear complexes. All the synthesized arene complexes showed appreciable stability in biological media at physiological conditions. Preliminary in vitro cytotoxicity investigations at two fixed concentrations (10 µM and 20 µM) in an eight-cancer cell line panel revealed that the complexes showed enhanced cytotoxicity in the rhabdomyosarcoma (RMS) cell lines. Further biological evaluation at various concentrations resulted in the identification of one lead complex which shows enhanced cytotoxicity and selectivity towards RMS relative to clinically used cisplatin. Additionally, investigation of the long-term cytotoxicity of the lead ruthenium(II) complex brought to light that the complex maintains its superior cytotoxicity and selectivity relative to cisplatin in the long-term (>15 days after treatment). Remarkably, the lead ruthenium(II) complex inhibits the migratory ability of metastatic RMS cells and maintains its enhanced cytotoxicity compared to cisplatin in the 3D multicellular tumour spheroid model. Mechanism of action studies showed that the lead ruthenium(II) complex effectively induces genomic DNA damage, initiates autophagy and up-regulates both the intrinsic and extrinsic apoptotic pathways to elicit cell death in RMS cells.

Keywords

Chemistry

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Collections

PhD / Doctoral

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