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Bothtrans- andcis-[PtCl2(NH3)(L)] compounds have been synthesized, L representing either the imino ether HN=C(OMe)Me having aZorEconfiguration at the C=N double bond, or the cyclic ligandsand(compounds1-4fortransgeometry and5-8forcisgeometry, 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,transcompounds inhibit growth much more than transplatin. Moreover, compound1in most cases is less active than2, and1and2are less active than3and4, respectively. Forciscompounds with imino ethers, the activity is reduced (5) or unaffected (6) with respect to cisplatin. Moreover, unliketranscompounds, 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 thecisgeometry requirement for activity of platinum(II) species. Importantly,1-4and5-8partially circumvent the multifocal cisplatin resistance of A2780cisR cells, and1-4also overcome resistance from reduced uptake of 41McisR cells. DNA interaction regioselectivity of1-4and5-8is 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 anddecreasing also its extent. Therefore, DNA interaction of1-4and5-8appears 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 bothtransandciscompounds, and supports the development of platinum drugs based on their coordination chemistry to combat cisplatin resistance. [ABSTRACT FROM AUTHOR]