title: Synthesis, characterization and preliminary cytotoxicity assays of poly(ethylene glycol)-malonato-Pt-DACH conjugates.
abstract: Oxalate 1,2-diaminocyclohexane platinum (oxaliplatin(R)), 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 (4) has been tested against L1210-implanted mice and showed and appreciable increase in cytotoxicity as compared to the reference standard Cl(2)PtDACH.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Universita' degli Studi di Padova, via F. Marzolo, 5-35100, Padua, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Furin
authors.forename: Andrea
authors.initials: A
authors.lastname: Guiotto
authors.forename: Franca
authors.initials: F
authors.lastname: Baccichetti
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pasut
authors.forename: Christine
authors.initials: C
authors.lastname: Deuschel
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertani
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Veronese
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008314:Malonates / Q000737:chemistry; D051379:Mice; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D008314:Malonates; D009944:Organoplatinum Compounds; D011092:Polyethylene Glycols; C030290:malonic acid; C030435:1,2-cyclohexanediamine