Synthesis, characterization and preliminary cytotoxicity assays of poly(ethylene glycol)-malonato-Pt-DACH conjugates

Oxalate 1,2 – diaminocyclohexane platinum (oxaliplatin), a successfully employed platinum compound belonging to the family of Pt-DACH complexes, has been conjugated to different molecular weight poly(ethylene glycols) (PEG) by means of peptide spacers and a malonic acid bidentate residue. Tri- and tetrapeptidic substrates of lysosomal enzymes were used in order to increase the release of Pt-DACH complex inside the cell following endocytosis and enzymatic degradation of the peptide spacer. Other aminoacids (e.g. norleucine) have been also employed. 1H NMR of some conjugates was performed as characterisation of the product, while 195Pt-NMR analysis was carried out to detect the rearrangement of the platinum complex from the Pt(O,O) to the Pt(O,N) form. The compound PEG(5000)-Nle-malonato-Pt-DACH has been tested against L1210-implanted mice and showed an appreciable increase in cytotoxicity as compared to the reference standard dichloroPtDACH.