Alarmingly, one in every two individuals in Australia are diagnosed with some type of cancer by the age of 85, according to the Australian Institute of Health and Welfare. There are several clinical strategies to treat cancer patients that include surgery, chemotherapy, radiotherapy, and immunotherapy, depending on the stage of their disease, with greater than 50% receiving chemotherapy at some point in their treatment plan. Medicinal inorganic chemistry has advanced as a direct result of the use of metal complexes as therapeutic agents because they coordinate a range of bioactive ligands and exhibit rich redox properties that contribute to various applications. They interact with biomolecules like DNA, in addition to other important cellular structures. The discovery of the cellular effects of cisplatin was responsible for initiating platinum(II) research. Cisplatin and carboplatin as well as oxaliplatin are the “standard of care” anticancer agents. Platinum drugs are reported to be utilised for the treatment of various cancers including breast, colorectal, lung, ovarian, testicular, cervical and brain cancers, yet significant side effects like nephrotoxicity and hepatotoxicity, and intrinsic and acquired resistance in cancer cells accompany treatment. Accordingly, research has evolved to design platinum complexes with fewer clinical side-effects. In this pursuit platinum(IV) prodrugs are a prominent strategy due to kinetic stability, unique mechanisms of action, increased selectivity for cancer cells, increased efficacy, and the prospect of limiting side effects. Prodrugs are biologically inactive complexes, which activate after reaching cancer cells where they transform into their pharmacologically active form via intracellular activities like reducing or hypoxic environments. Platinum(IV) complexes offer synthetic advantages of being able to coordinate bioactive/non-bioactive ligands to improve the pharmacokinetics. This project investigates the potent platinum(IV) prodrugs with the base structure [Pt(AL)(PL)(X)(Y)]2+ where AL is the chiral ligand 1S,2S-diaminocyclohexane (1S,2Sdach); PL= is a polyaromatic ligand like 1,10-phenanthroline (Phen) or a methylate derivative, whereas X and Y can be the same of different bioactive/lipophilic axial ligands (such as chlorambucil or 5-fluorouracil). Cell survival assays will be used to ascertain the potency of the complexes in comparison with cisplatin. Further in vitro studies will be used to explicate the mechanism of action and in vivo studies will explore the toxicity profile of complexes and the efficacy of selected complexes on breast or colorectal cancer models.
In vitro and in vivo investigation of potent platinum(IV) prodrugs for clinical anticancer therapy
Elias, M. G. (Author). 2024
Western Sydney University thesis: Doctoral thesis