Synthesis and characterisation of novel platinum(IV)-based chemotherapeutic complexes

Abstract

Cancer is the second leading cause of death worldwide; this increases the need to find a treatment which is more plateable and does not negatively impact on an individual’s quality of life. Many current cancer treatments are platinum(II)-based including cisplatin, carboplatin and oxaliplatin. Cisplatin and its derivatives target and coordinate to DNA; however, their clinical applicability is limited by several factors, including drug resistance and severe side effects. Researchers are studying the use of platinum(IV) therapeutics to counteract the current clinical limitations in cancer treatment. Recent results demonstrate that the octahedral geometry of the platinum(IV) complexes allows for the synthetic coordination of non-bioactive and bioactive ligands to promote targetability, enhanced cytotoxicity and cellular uptake. Platinum(IV) ‘prodrugs’ activate, via reduction, within cancer cells rather than in the blood stream which decreases the potential for off-target interactions, therefore producing fewer side effects. This thesis reports on platinum(IV) prodrugs constructed from the precursor complexes, [(1,10-phenanthroline)(1S,2S-diaminocyclohexane) platinum(II)]Cl2 (PtIVPhenSS) and [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)(OH)2 platinum(IV)](NO3)2 (PtIV56MeSS), that have been axially coordinated with bioactive ligands. Specifically, the mitochondrial targeting ligand, (5-carboxypentyl)(triphenyl)phosphonium bromide (5TPP), which shows promise increasing the targetability and by enhancing the ability to effectively penetrate the highly impermeable inner mitochondrial membrane. Or the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), used in combination therapies for changing transcriptomic profiles and promoting cell death. The resulting prodrugs, [PtIV(1,10-phenanthroline)(1S,2S- diaminocyclohexane)(OH)(SAHA) platinum(IV)](NO3)2] (PtIVPhenSS(SAHA)), [PtIV(1,10- phenanthroline)(1S,2S-diaminocyclohexane)(hexanoate triphenylphosphonium bromidebromide)(OH)](NO3)2 (PtIVPhenSS(5TPP)) and [PtIV(5,6-dimethyl-1,10- phenanthroline)(1S,2S-diaminocyclohexane)(5TPP)(OH)](NO3)2,] (PtIV56MeSS(5TPP)) were synthesised, purified, and characterised through HPLC, MS, UV-Vis, CD and NMR spectroscopy before in vitro cytotoxicity studies. All complexes show significant cytotoxicity when compared to cisplatin, carboplatin, oxaliplatin as well as the platinum(IV) precursors. This work provides insights into the possibilities of a new generation of platinum(IV) prodrugs for the treatment of cancer.

Date of Award	2024
Original language	English
Awarding Institution	Western Sydney University
Supervisor	Janice Aldrich-Wright (Supervisor), Krishant Deo (Supervisor) & Christopher Gordon (Supervisor)