Cisplatinum and Transplatinum Complexes with Benzyliminoether Ligands; Synthesis, Characterization, Structure−Activity Relationships, and In Vitro and In Vivo Antitumor Efficacy

New benzyliminoether derivatives [PtCl2{N(H)C(OMe)CH2Ph}2] of cis (1a, 1b) and trans (2a, 2b) geometry
were prepared and characterized by means of elemental analysis, multinuclear NMR and FT-IR techniques,
and X-ray crystallography; this latter was carried out for 1b. The cytotoxic properties of these new platinum(II) complexes were evaluated in terms of cell growth inhibition against a panel of different types of human
cancer cell lines. cis-[PtCl2{E-N(H)C(OMe)CH2Ph}2] (1a) was significantly more potent than cisplatin
against all tumor cell lines tested, showing IC50 values from about 2- to 17-fold lower than the reference
compound. Chemosensitivity tests performed on cisplatin-sensitive and -resistant cell lines have demonstrated
that complex 1a is able to overcome cisplatin resistance. Analyzing the mechanism by which complex 1a
led to cell death, we have found that it induced apoptosis in a dose-dependent manner, accompanied by the
activation of caspase-3. The in vivo studies carried out using two transplantable tumor models (L1210 leukemia
and Lewis lung carcinoma) showed that derivative 1a induced a remarkable antitumor activity in both tumor
models, as measured by prolonged survival and reduced tumor mass compared to control groups.