Investigating biologically inert platinum(IV)-glutamine complexes to maximise their selectivity and utility in personalised cancer therapy

Abstract

This project is aimed at studying the targeted delivery of biologically inert platinum(IV)-glutamine complexes into cancer cells by exploiting their overexpression of glutamine transporter, ASCT2. It addresses the limitations of current platinum(II) drugs in clinics. Biologically inert bis(amino acid)platinum(II) complexes were synthesised as precursors. The transport of modified glutamine compounds via ASCT2 was concurrently investigated to elucidate if the modification of glutamine impacted its transport. trans-[Pt(L-alanine)2] and trans-[Pt(L-glycine)2] were synthesised but determined as unsuitable precursors due to their poor solubility in many solvents which hindered their oxidation. A synthetic procedure using cis-[PtCl2(DMSO)2] as a starting material was developed to synthesise cis-bis(amino acid)platinum(II) complexes with greater solubility. A series of experiments were conducted in different reaction conditions with L-isoleucine, L-tryptophan, and L-alanine to design an optimal procedure. cis-[Pt(L-alanine)2] was synthesised in high purity when cis-[PtCl2(DMSO)2] was reacted with 2 equivalents of L-alanine and base in methanol. A modified glutamine compound was synthesised by attaching a 2-(2-aminoethoxy)ethanol linker to the α-carboxylic acid of L-glutamine (compound 1). Compound 1 and L-theanine were applied to Xenopus laevis oocytes expressing ASCT2. Two-electrode voltage clamp electrophysiology was used to measure substrate-elicited currents over a range of membrane potentials. Compound 1 is neither a substrate nor an inhibitor of ASCT2 while L-theanine was identified as an inhibitor. This revealed that the modification of glutamine prevents it from acting as a substrate of ASCT2. This suggests that ASCT2 may not be a suitable target for the delivery of platinum(IV)-glutamine complexes. The synthesis of cis-[Pt(L-alanine)2] revealed that cis-[PtCl2(DMSO)2] can be utilised as a starting material to synthesise cis-bis(amino acid)platinum(II) complexes.