The Development of Novel Metal Complexes to Target the Hedgehog Pathway as an Anticancer Strategy

Platinum-based chemotherapeutic, cisplatin is a leading treatment for many types of cancer worldwide. Given its toxic side-effects and acquired and intrinsic resistance, many efforts have been made to improve on this treatment since its regulatory approval in 1978. The development of platinum-based anticancer complexes has expanded exponentially over the years in a bid to overcome the problems associated with cisplatin. This thesis explores four separate strategies to potentially improve anticancer metal complexes.

Abnormal signalling in the Hedgehog (Hh) pathway is known to play a key role in the development of many types of cancer, including the proliferation and maintenance of cancer stem cells (CSCs). Often existing as a small sub-population of stem-like cells within a tumour, CSCs are involved in the development of primary tumours, metastasis of tumours to secondary sites, and resistance to chemotherapeutics, as they are not killed by clinical treatments. Targeting of CSCs via inhibition of the Hh pathway is therefore an exciting and rapidly growing area of research. GANT61 is a downstream inhibitor of the Hh pathway, inhibiting DNA transcription by blocking Gli transcription factors. GANT61 is therefore a promising molecule for developing anticancer treatments.

Chapter 1 briefly describes the biology behind cancer and CSCs, and the problems posed with current treatments. The history of metal-based chemotherapeutics and the chemistry of transition metals used in this research follow. The remaining sections cover traditional, approved platinum-based drugs, expanding to newer ‘non-traditional’ structures such as monofunctional Pt(II) complexes and Pt(IV) pro-drugs. Non-platinum anticancer candidates will also be discussed in the context of ruthenium-based therapies. Finally, the role of the Hh pathway in the development of cancer, and Hh inhibitor GANT61, which releases the bioactive species, GANT61-D and byproduct, 4-PCA following hydrolysis.

Chapter 2 is an experimental chapter, which covers materials and methods, in particular the synthesis of known ligands and precursors, and novel, derivatised ligands as well as a diverse range of novel metal complexes.

Chapter 3 explores the coordination chemistry of GANT61-D with Group 10 metals, Ni(II), Pd(II), and Pt(II). The four N-donor atoms can form a range of interesting metal complexes, including bidentate and tridentate binding modes. The novel complexes include a traditional Pt(II) anticancer-type complex and a non-traditional Pt(II) monofunctional-type complex. The Pd(II) complex resembles monofunctional-type, and the Ni(II) complex displays pro-drug-like properties.

Chapter 4 focuses on the chemistry of Pt(II)-dmso precursors, which may be used in the synthesis of traditional or non-traditional platinum-based anticancer complexes. The trans effect is known to play a pivotal role in the synthesis of Pt(II) coordination complexes. This work investigates the synthesis of trans and cis Pt(II)-dmso complexes with GANT61 and 4-PCA as the N-donor ligand.

The incorporation of bioactive molecules into Pt(IV) pro-drugs in the axial position is an established strategy for developing bifunctional anticancer treatments.

Chapter 5 describes multiple synthetic strategies to derivatise GANT61 with an O-donor atom with the intention of conjugating the derivatised molecule to a Pt(IV) pro-drug complex as an axial ligand.

NAMI-A, a non-platinum anticancer complex, was the first ruthenium-based drug candidate to enter clinical trials in 1999 and is known for its impressive anti-metastatic activity.

Chapter 6 investigates the incorporation of GANT61 and 4-PCA as N-donor ligands in NAMI- and NAMI-A-type Ru(III) complexes as anticancer drug candidates. In the case of GANT61 the resulting complexes are expected to induce a cytotoxic effect whilst indirectly targeting CSCs via Hh pathway inhibition and retaining the anti-metastatic properties of NAMI/-A.

GANT61 and its hydrolysis products, GANT61-D and 4-PCA, proved to be very interesting and valuable ligands, not only for developing metal complexes as potential anticancer agents targeting the Hh pathway, but also in exploring the rich chemistry of the platinum group metals and ruthenium.