The biological activity of cis and truns complexes of formula [PtCl,( HN=C(OMe)Me ) J has been investigated. The iminoether ligands can have either E or Z configuration about the C=N double bond, therefore EE, EZ and ZZ isomers are obtainable. Substitution of iminoether with EE configuration for amine leads to unexpectedly high antitumour activity for the complex with tram geometry which turns out to be more active than the cis congener in the P388 leukaemia system. The same frans-EE complex shows an activity comparable to that of cisplatin in reducing the primary tumour mass and lung metastases in mice bearing Lewis lung carcinoma, thus representing a tram platinum complex active on both limphoproliferative and solid metastasizing murine tumours. Also the cytotoxicity, the inhibition of DNA synthesis and the mutagenic activity, which are greater for the cis- with respect to the fruns-isomer in the amine complexes, are instead greater for the trans- than for the cisisomer in the case of iminoether compounds. Binding to calf thymus DNA is slower for iminoether complexes than it is for amine complexes, however after 24 h reaction time the level of binding is similar for both types of complexes. Tram-EE, like trans-DDP, does not give the DNA conformational alterations (terbium fluorescence) typical of antitumour-active cis-platinum compounds, but, under strictly analogous experimental conditions, shows a greatly reduced DNA interstrand cross-linking ability (heat denaturation/renaturation assay) with respect to either trans-DDP or cis-EE and cis-DDP. The data in hand point to a new tram platinum antitumour complex with a mechanism of action different from that of cis-DDP and classical analogues.

Platinum (II) complexes containing iminoethers: a trans platinum antitumour agent

COLUCCIA, Mauro;BOCCARELLI, Angelina;MARIGGIO', Maria Addolorata;INTINI, Francesco Paolo;NATILE, Giovanni
1995

Abstract

The biological activity of cis and truns complexes of formula [PtCl,( HN=C(OMe)Me ) J has been investigated. The iminoether ligands can have either E or Z configuration about the C=N double bond, therefore EE, EZ and ZZ isomers are obtainable. Substitution of iminoether with EE configuration for amine leads to unexpectedly high antitumour activity for the complex with tram geometry which turns out to be more active than the cis congener in the P388 leukaemia system. The same frans-EE complex shows an activity comparable to that of cisplatin in reducing the primary tumour mass and lung metastases in mice bearing Lewis lung carcinoma, thus representing a tram platinum complex active on both limphoproliferative and solid metastasizing murine tumours. Also the cytotoxicity, the inhibition of DNA synthesis and the mutagenic activity, which are greater for the cis- with respect to the fruns-isomer in the amine complexes, are instead greater for the trans- than for the cisisomer in the case of iminoether compounds. Binding to calf thymus DNA is slower for iminoether complexes than it is for amine complexes, however after 24 h reaction time the level of binding is similar for both types of complexes. Tram-EE, like trans-DDP, does not give the DNA conformational alterations (terbium fluorescence) typical of antitumour-active cis-platinum compounds, but, under strictly analogous experimental conditions, shows a greatly reduced DNA interstrand cross-linking ability (heat denaturation/renaturation assay) with respect to either trans-DDP or cis-EE and cis-DDP. The data in hand point to a new tram platinum antitumour complex with a mechanism of action different from that of cis-DDP and classical analogues.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/132618
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