D. Giordano

In vitro and in vivo antitumour activity and cellular pharmacological properties of new platinum–iminoether complexes with different configuration at the iminoether ligands

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.

Anti-leukaemic action of RuCl2(DMSO)4 isomers and prevention of brain involvement on P388 leukaemia and on P388/DDP subline

Two ruthenium(II) complexes, characterised by the presence of dimethylsulphoxide ligands, were investigated in comparison to cisplatin on mouse P388 leukaemia and on a subline made resistant to cisplatin (P388/DDP). Both cis- and trans-RuCl2(DMSO)4 significantly prolonged the survival time of leukaemic mice, independently of the tumour line used. Unlike cisplatin, the prolongation of life-span of tumour-bearing hosts caused by ruthenium complexes was not supported by a parallel inhibition of the number of tumour cells in the treated hosts, as evidenced by tumour cell count in the peritoneal cavity and by vivo-vivo bioassays of blood samples and of whole brains. Thus, cis- and trans-RuCl2(DMSO)4 appear capable of preventing leukaemic spread into the central nervous system also when the number of tumour cells in the peritoneal cavity and in the blood stream is as high as in untreated controls. When the drug-induced DNA damage was investigated by modifying double stranded DNA and identifying the lesions able to inhibit DNA synthesis in vitro, trans-RuCl2(DMSO)4 and, to a lesser extent, cis-RuCl2(DMSO)4 formed blocking lesions at the same sites of cisplatin; nevertheless, the mechanism of antitumour activity of ruthenium complexes appears to be different from that of cisplatin for the absence of any relationship between cytotoxicity and prevention of leukaemic dissemination into the central nervous system. These data indicate that the activity of cis- and trans-RuCl2(DMSO)4 on the P388 leukaemia is characterised by the lack of cross-resistance with cisplatin and by the alteration of the metastasising behaviour of leukaemic cells which lose their natural capacity to invade the central nervous system.

Platinum complexes with imino ethers or cyclic ligands mimicking imino ethers: synthesis, in vitro antitumour activity, and DNA interaction properties

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Mutagenic activity of some platinum complexes with monodentate and bidentate amines

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Increased Procoagulant Activity of Peripheral Blood Monocytes in Human and Experimental Obstructive Jaundice

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Synthesis, chemical and biological properties of &{Pt[S(CH2)3Cl]2}6 and Pt[C6H3(oCH2CH CH2)(p-CH3)]2

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