Amino acids as chelating ligands for platinum: enhanced stability in aqueous environment promoted by biocompatible molecules

Platinum (II) based chemotherapeutics are a cornerstone in the treatment of many malignancies. However, their severe toxicity and dose-limiting side-effects have rooted efforts in the medicinal inorganic community to develop better drug candidates with higher selectivity for tumor tissues and less problematic side effects. In the current study, we developed a cytotoxic platinum (II) complex based on a Zeise’s salt substructure containing the nonsteroidal anti-inflammatory drug (NSAID) acetylsalicylic acid (ASA) as a ligand. Since the original complex displayed high reactivity against sulfur-containing biomolecules, the structure was optimized regarding its stability. Amino acids L-alanine, β-alanine and L-histidine were used as biocompatible chelating ligands to achieve this aim. Differences in the coordination sphere caused pronounced changes in the stability profiles of the Zeise-type precursor complexes 1-3. Of the tested systems, coordination with LAla through N in trans position to ethylene (N-trans) showed the most promising results and was employed to stabilize the previously published complex 5. The stability profiles of all complexes were evaluated by capillary electrophoresis and the biological activity was investigated in vitro in various tumor cell lines. To investigate the effect of the NSAID ligand on the mode-of-action, inhibition of cyclooxygenase enzymes was also tested. Platinum (II) complex 4 containing both the ASA and the Ala ligand showed improved stability and higher cytotoxicity, outperforming both 5 and 1, exhibiting a cytotoxic activity at 25 µM comparable to the reference drug cisplatin.