Designing multi-action platinum(IV) derivatives for cancer therapy

Abstract

Cancer is one of the leading causes of death worldwide and due to an ageing and growing population, cancer incidence and mortality are rising worldwide. Treatment for cancer is chemotherapy, often involving Pt(II) complexes such as cisplatin, carboplatin and oxaliplatin. The mechanism of action of these traditional Pt(II) complexes is covalently binding to DNA to cause apoptosis. Whilst these complexes do cause the death of cancer cells, the clinical efficacy of these complexes is limited by low specificity resulting severe effects, intrinsic and acquired resistance. In order to overcome the limitations of traditional Pt(II) chemotherapeutics, unconventional Pt(II) complexes of the type [Pt(II)(PL)(AL)]2+ consisting of a polyaromatic (PL) and ancillary ligand (AL) were developed. The complexes exhibit a fundamentally different mechanism of action and enhanced activity, achieving up to 1000-fold increase in cytotoxicity than clinically used cisplatin. Additionally, these complexes have been oxidised to form Pt(IV) complexes which are more kinetically inert and only become active, exerting cytotoxic activity, once reduced to platinum(II). Therefore, these complexes are less likely to have unwanted interactions within the body before reaching the tumour, reducing toxicities and allowing the potential for oral administration. These Pt(IV) complexes can also be enhanced through the addition of independently bioactive molecules in the axial positions, potentially improving tumour cell selectivity and cytotoxicity. Within this project, novel multi-action Pt(IV) complexes were developed via the mono and di-coordination of 3-pyridinepropionic acid (3PPA) to Pt(IV) complexes of the type [Pt(IV)(PL)(AL)(OH)2]2+ where AL is 1S,2S-diaminocyclohexane and PL is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline. The complexes were characterised using nuclear magnetic resonance, high-performance liquid chromatography, electrospray-ionisation mass-spectroscopy, circular dichroism and infrared spectroscopy. The synthesis of the novel multi-action Pt(IV) complexes, allowed the development of an optimised synthetic protocol for the preferential synthesis of mono or di-coordinated Pt(IV) complexes in good purity and yield. This was achieved by functionalising 3PPA as either an NHS ester which formed the mono-coordinated complex or as an HOBt ester which formed the di-coordinated Pt(IV) complex preferentially. This is useful as the asymmetric design of the mono coordinated complex would allow further derivatisation at the hydroxyl group at the axial other position of the Pt(IV) complex. This protocol is valuable in assisting in the convenient synthesis of symmetric and asymmetric Pt(IV) complexes. The use of microwave chemistry to streamline synthesis of the Pt(II) intermediates was compared to batch methods used in previous literature. The microwave reaction protocol developed to synthesise the intermediate Pt(SS-dach)Cl2 and the Pt(II) complexes used in this project drastically reduced reaction times and produced comparably pure products in greater yields, confirmed with NMR and HPLC. Pt(IV) dihydroxy complexes were developed using a simultaneous counter-ion conversion and oxidation that contributed to significantly reduced reaction times while affording purer products in comparable yields, verified through NMR and HPLC. The cytotoxicity of a final complex, PHENSS(3PPA)(OH), was evaluated as preliminary measurement across various cell lines. The GI50 of the complex analysed and it was revealed that the biological activity was greater than clinically used cisplatin, carboplatin, oxaliplatin and the Pt(II) and Pt(IV) dihydroxy complexes synthesised. Interestingly, as 3PPA was chosen to emulate 4-phenylbutyrate (4PhB), a histone deacetylase inhibitor, it was observed that PHENSS(3PPA)(OH) exhibited equivalent if not greater cytotoxic activity across all cell lines compared to the complex PHENSS(OH)(4PhB). This finding suggests that 3PPA could be used instead of 4PhB to produce similar biological activity with the advantage of coordinating other metal centres such as platinum or ruthenium as a consequence of the nitrogen in the pyridine ring, expanding the design possibilities of multi-action anticancer complexes.

Date of Award	2019
Original language	English