Both trans- and cis-[PtCl(2)(NH(3))(L)] compounds have been synthesized, L representing either the imino
ether HN=C(OMe)Me having a Z or E configuration at the C=N double bond, or the cyclic
ligands N = C(OMe)CH2CH2CH2 and N = C(Me)OCH2CH2 (compounds 1-4 for trans geometry and 5-8 for cis geometry, respectively). The cyclic
ligands mimic the imino
ether ligands but, differently from imino
ethers, cannot undergo change of configuration. In a panel of human
tumor cells, trans compounds inhibit growth much more than
transplatin. Moreover, compound 1 in most cases is less active than 2, and 1 and 2 are less active than 3 and 4, respectively. For cis compounds with imino
ethers, the activity is reduced (5) or unaffected (6) with respect to
cisplatin. Moreover, unlike trans compounds, substitution of cyclic
ligands (7,8) for imino
ethers (5,6) generally decreases the activity. This determines, for compounds with cyclic
ligands, an unusual inversion of the cis geometry requirement for activity of
platinum(II) species. Importantly,1-4 and 5-8 partially circumvent the multifocal
cisplatin resistance of A2780cisR cells, and 1-4 also overcome resistance from reduced uptake of 41McisR cells.
DNA interaction regioselectivity of 1-4 and 5-8 is not substantially modified with respect to
transplatin and
cisplatin. However, both imino
ethers and cyclic
ligands slow down the
DNA interstrand cross-link reaction, ( E)-HN=C(OMe)Me and N = C(Me)OCH2CH2 decreasing also its extent. Therefore,
DNA interaction of 1-4 and 5-8 appears to be characterized by persistent monoadducts (1-4), and by monoadducts and/or intrastrand cross-links structurally different from those of
cisplatin (5-8). This study demonstrates that
ligand configuration modulates the activity of both trans and cis compounds, and supports the development of
platinum drugs based on their coordination chemistry to combat
cisplatin resistance.