title: In vitro and in vivo antitumour activity and cellular pharmacological properties of new platinum-iminoether complexes with different configuration at the iminoether ligands.
abstract: In order to widen our knowledge on antitumour trans-[PtCl2(iminoether)2] complexes, we have synthesised two new derivatives, trans-[PtCl2¿E-HN = C(OEt)Me¿2] (1) and trans-[PtCl2¿Z-HN = C(OEt)Me¿2] (2), which differ in the configuration of the iminoether ligands. Isomer 1 showed an in vitro cytotoxicity similar to that of cisplatin in a panel of human tumour cell lines (mean IC50 = 8 and 7.7 microM, respectively), whereas isomer 2 showed a lower activity (IC50 = 14.3 microM). Both 1 and 2 isomers overcame cisplatin resistance of ovarian cancer cell line A2780/Cp8. In agreement with the n-octanol/saline partition ratios, intracellular platinum content (and DNA platination) after a 2-h exposure to equimolar drug concentrations was in the order 1 > 2 >> cisplatin, thus indicating that substitution of imminoethers for ammines determines a major lipophilicity and cellular uptake of the platinum drug. Both 1 and 2 showed a major toxic effect towards an excision repair-defective Drosophila strain, thus indicating cellular DNA as cytotoxic target. Finally, both 1 and 2 were active in vivo against the murine P388 system, but, contrary to the in vitro activity, isomer 2 was slightly more active than 1. On the whole, the results confirm the antitumour activity of trans-[PtCl2(iminoether)2] complexes, and indicate that the configuration of the iminoether ligands may affect the pharmacological properties of this class of complexes.
authors.affiliation: Dipartimento Scienze Biomediche e Oncologia Umana, Università di Bari, Italy. mauro.coluccia@dimo.uniba.it
authors.forename: M
authors.initials: M
authors.lastname: Coluccia
authors.forename: A
authors.initials: A
authors.lastname: Nassi
authors.forename: A
authors.initials: A
authors.lastname: Boccarelli
authors.forename: D
authors.initials: D
authors.lastname: Giordano
authors.forename: N
authors.initials: N
authors.lastname: Cardellicchio
authors.forename: D
authors.initials: D
authors.lastname: Locker
authors.forename: M
authors.initials: M
authors.lastname: Leng
authors.forename: M
authors.initials: M
authors.lastname: Sivo
authors.forename: F P
authors.initials: FP
authors.lastname: Intini
authors.forename: G
authors.initials: G
authors.lastname: Natile
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004273:DNA, Neoplasm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004330:Drosophila / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007097:Imines / Q000737:chemistry; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008815:Mice, Inbred Strains; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007097:Imines; D009944:Organoplatinum Compounds; C403610:dichlorobis(1-ethoxyethanimine)platinum(II); D002945:Cisplatin