Abstract
As an excellent representative of metal-based anticancer drugs, cisplatin has achieved great clinical success since the discovery of its antitumor property. The analogues of cisplatin including carboplatin, oxaliplatin, nedaplatin, lobaplatin, et al. have also been approved for clinical use. Despite the efficiency of Pt-based drugs in chemotherapy, severe side effects and acquired/inherent resistance remain a big problem. Besides, cancer metastasis has become the bottle-neck in cancer therapy. New strategies are highly desired to circumvent the drawbacks, including the design of Pt(IV) prodrugs and introducing other types of metals. In this thesis, we describe the design, synthesis, and biological assessment of different Pt(IV) prodrugs with improved anticancer activities and/or antimetastatic properties.In Chapter II, we report the design, synthesis, and biological evaluation of a dicarboxylated Pt(IV) anticancer prodrug chalcoplatin, which contains two chalcone molecules as the axial ligands. The inert Pt(IV) moiety is supposed to be reduced to its active Pt(II) form after cellular entrance and to subsequently induce Pt-DNA adducts. In the meantime, the bioactive chalcone ligands are released and break the interactions between MDM2 and p53. Improved cytotoxicities are obtained in p53 wild-type but not p53 null human cancer cells. Detailed mechanism study reveals that chalcoplatin is able to stabilize p53 and kill cancer cells through the induction of apoptosis.
In the following two chapters, we highlight a novel strategy to design Pt(IV) prodrugs through tuning the cellular accumulation and the way of executing functions. In Chapter III, we expand the story of chalcoplatin to monochalcoplatin, a monocarboxylated Pt(IV) complex with chalcone as the axial ligand. In comparison to its dicarboxylated counterpart, monochalcoplatin displays significantly improved cytotoxicities in both cisplatin-sensitive and -resistant cancer cell lines, which is up to 422-fold higher than cisplatin, making this compound among the most active Pt(IV) prodrugs to date. Mechanism studies show that monochalcoplatin enters cells with great efficiency within a short period of time and is reduced to its Pt(II) form quickly followed by fast apoptosis induction in a p53-independent pathway. In the meantime, ER stress is detected after the treatment of the Pt(IV) prodrug. The unexpected high cellular accumulation is likely related to a transporter-mediated process instead of its lipophilicity only. Furthermore, monochalcoplatin inhibits the growth of tumor more effectively than cisplatin in vivo.
In Chapter IV, a series of Pt(IV) complexes were evaluated. The Pt(IV) scaffolds include cisplatin and oxaliplatin. Both monocarboxylated and dicarboxylated Pt(IV) complexes were investigated. The in vitro cytotoxicities, lipophilicities, and cellular accumulation of these Pt(IV) complexes were examined. The results show the consistence between the cytotoxicity and the whole cell accumulation; however, the accumulation levels of the complexes are mainly attributed to their structures instead of lipophilicity. The reduction of the Pt(IV) compounds by reducing agents are illustrated by RP-HPLC. Among the complexes, mFPA-Pt(IV) displays the highest cytotoxicities with nanomolar IC50 values, and the prodrug is effective in cisplatin-resistant cancer cells. Detailed studies reveal that mFPA-Pt(IV) is able to enter cells efficiently and be reduced quickly. Furthermore, mFPA-Pt(IV) kills cancer cells through apoptosis, and elevated expression levels of γH2A.X are detected.
In Chapter V and VI, we aim to overcome drug resistance and tumor metastases by introducing an arene Ru(II) moiety to Pt(IV) prodrugs by coordination chemistry. In Chapter V, a series of bifunctional heterodinuclear Pt(IV)–Ru(II) complexes, ruthplatins, are described. A monosubstituted Pt(IV) moiety containing a cisplatin-scaffold was coordinated to the arene Ru(II) center through a pyridine ring to build ruthplatins. The Pt(IV) moiety is responsible for the cytotoxicity and the Ru(II) part is supposed to inhibit cancer metastases. Ruthplatins display submicromolar and nanomolar cytotoxicity in the human cancer cells tested. Encouragingly, ruthplatins are able to overcome cisplatin resistance in different cisplatin-resistant cell lines, and the cytotoxicities are up to 107-times higher than those of cisplatin. Furthermore, ruthplatins can effectively suppress the migration of MDA-MB-231 cells compared to the corresponding mononuclear Ru(II) complexes as well as the mixture of cisplatin and Ru(II) complex.
Although different types of metal-based anticancer complexes have been synthesized, novel complexes to reduce the severe side effect of cisplatin and conquer cancer metastasis are still highly desired. In Chapter VI, we report the synthesis, characterization, and biological activity of complex 5, a novel heterodinuclear Pt(IV)–Ru(II) anticancer prodrug. Complex 5 is formed by coordinating an asymmetric substituted Pt(IV) complex to arene Ru(II) center through an imidazole ring. Biological evaluation reveals that complex 5 utilizes the advantages of two metal centers to have both cytotoxicity and antimetastatic property as designed. Although complex 5 has comparable cytotoxicities to cisplatin in tested cancer cell lines, and this prodrug selectively kills cancer but not normal cells. The cancer cell-selectivity is further demonstrated by a cancer-normal cell co-culture system. In addition, the antimetastatic properties of complex 5 are assessed by using highly metastatic human breast cancer cells, and the results show that the migration and invasion of cancer cells are effectively restrained after the treatment. Moreover, complex 5 displays lower toxicity than cisplatin in developing zebrafish embryos.
| Date of Award | 29 Sept 2017 |
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| Original language | English |
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| Supervisor | Guangyu ZHU (Supervisor) |