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

Abstract

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.

Synthesis, characterization and cytotoxic activity of substituted benzyl iminoether Pt(II) complexes of the type cis- and trans-[PtCl2{E-N(H)C(OMe)CH2–C6H4–p–R}2] (R=Me, OMe, F). X-ray structure of trans-[PtCl2{E-N(H)C(OMe)CH2–C6H4–p–F}2]

“…These results well agree with those we had recently obtained with some unsubstituted benzyliminoether derivatives [15]. Moreover, the most promising derivatives 1a and 5a elicited a biological activity comparable and even better than that of cis-[PtCl 2 {E-N(H)@ C(OMe)CH 2 Ph} 2 ] [15], thus indicating that suitable functionalizations of the benzyl moiety could represent an useful tool to obtain more interesting benzyliminoether platinum derivatives.…”

“…A downfield shift is expected for the protons which come close to platinum [36,37]: the alkoxide protons (R 0 ) in the Z configuration and the nitrile protons (R) in the E configuration. Since the E isomer is found to be more stable both in solution and in the solid state and is not susceptible to further isomerization to the Z isomer, the synthesis of imino ethers were performed using a solvent richer in methanol and prolonging the reaction time up to 1 day in order to obtain E isomers, similarly to what previously observed [15].…”

“…In a recent work, in order to evaluate the influence of the lipophilicity of the iminoether ligands on the biological activity of [PtCl 2 (iminoether) 2 ] complexes, we have explored the effect of the introduction of a phenyl ring into the iminoether ligand structure, by determining the in vitro and in vivo antitumor activity of a series of complexes of the type cis-and trans-[PtCl 2 {E-N(H)@C(OMe)CH 2 Ph} 2 ] [15]. The most effective derivative appeared to be cis-[PtCl 2 {E-N(H)@C(OMe)CH 2 Ph} 2 ], which showed a cytotoxic potency from about 4-to 40-fold higher than the corresponding trans species.…”

“…The compound proved to be able to overcome acquired and intrinsic cisplatin resistance and to induce cell death by triggering the caspasedependent apoptotic pathways. Moreover, studies performed in vivo, on two experimental tumor models, revealed that the new iminoether complex owns a remarkable antitumor activity in spite of a very low toxicity toward the host in comparison with cisplatin [15].…”

Gold(III)‐dithiocarbamato anticancer agents: Activity, toxicology and histopathological studies in rodents

“…In our study, a median LD of 30 mg kg À1 was detected for the investigated gold(III)-dithiocarbamato derivative, $2.6-fold higher than cisplatin, previously tested under the same experimental conditions (LD 50 ¼ 11.4 mg kg À1 ). 32 Consequently, AUL12 turned out to be significantly less toxic than the reference drug in terms of acute toxicity.…”