Design and development of unconventional platinum(IV) prodrugs as potent anticancer agents

Abstract

In this work, methods were developed to synthesise lipophilic derivatives of the aforementioned [PtIV(HL)(AL)(OH)2]2+ type complexes. Two series of platinum(IV) complexes were synthesised, comprising of either PHEN and SSDACH (PHENSS(IV)) or 56Me2PHEN and SSDACH (56MESS(IV)). Conjugation of the axial ligands to the complexes was achieved by using anhydride forms of the chosen ligands. Reaction conditions were modified to afford the respective mono- and di-substituted species, [PtIV(HL)(AL)(OH)(R)]2+ and [PtIV(HL)(AL)(R)2]2+ (R = increasingly lipophilic carboxylate ligand(s)). Characterisation of complexes was achieved using multinuclear (1H and 195Pt) nuclear magnetic resonance (NMR) spectroscopy, ultraviolet (UV) spectroscopy, circular dichroism (CD) spectroscopy, electrospray ionisation mass spectrometry (ESI-MS) and high-performance liquid chromatography (HPLC). In certain instances, synchrotron radiation circular dichroism (SRCD) was used and where applicable, X-ray crystallography. The work presented herein will contribute to the advancement in the synthetic methodology of this class of platinum complexes and also to those that have been reported. The developed methods will allow a wider range of ligands to be incorporated to the platinum prodrugs, which will help enhance their functionality. It is envisioned that these findings will lead to the development of new drug candidates as platinum-based chemotherapeutic agents.

Date of Award	2020
Original language	English