Precious metals in the fight against cancer

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Bedford, Rebecca Amelia ORCID: https://orcid.org/0009-0001-0042-3017 (2024). Precious metals in the fight against cancer. University of Birmingham. Ph.D.

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Abstract

Being the second biggest global killer, despite an array of pharmaceutical and treatment interventions, cancer is a prominent strain on healthcare. Currently, the precious metal complex cisplatin and its second-generation platinum complexes, carboplatin and oxaliplatin, are essential in the management of many cancers, being utilised in around 50% of all treatment regimens. Nonetheless, their use is fraught with deleterious side effects, a common problem with many non-targeted chemotherapies.

Platinum-based treatments are front line choices in malignancies such as ovarian cancer. As the sixth most common cancer, it tends to have a positive initial response from surgery and chemotherapy regimens, but relapse is frequent and often associated to resistance. This has led to ovarian cancer having a 66% death rate. Such treatment failures have inspired research into the potential of other precious metals. Ruthenium, for example, is a transition metal like platinum but it has the potential for improved qualities including wider coordination space, broader capacity to hold variations in chemical moieties and iron-mimicking. A large number of ruthenium complexes have been synthesised thus far with exceptional anticancer activity, and singular examples have reached clinical studies.

In this work, ruthenium piano-stool complexes with a bidentate iminopyridine ligand with differing bioisosteric replacements in the phenyl ring have been investigated. Replacing small moieties in drug-like molecules have shown to make significant differences in their potency. This work uses such strategy to investigate ruthenium-based complexes as anticancer agents. The research has successfully led to the synthesis, physiochemical and biological investigation of 22 piano-stool complexes differing in bioisosteric replacements, and their further investigation into the death mechanisms, DNA, and cell membrane targeting mechanisms of action of four lead complexes.

The complexes with modified ligands explored demonstrate the high potential of ruthenium piano-stools in the treatment of ovarian cancer and the potential of bioisosteric replacements.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):