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 trarzs-[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 mu M, respectively), whereas isomer 2 showed a lower activity (IC50 = 14.3 mu M). Both I 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 I 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. (C) 1999 Elsevier Science Inc. All rights reserved.