Antitumor Mechanism Studies Of Platinum Based Complexes

cisplatin, carboplatin and oxaliplatin are used as antitumor drugs in more than50%chemotherapeutic cases in clinic. However, the applications of platinum based drugs are limited by the side effects and intrinsic or acquired resistance. In recent years, great attention are paid to the antitumor mechanism of platinum based drugs to design new type of platinum compounds and overcome the resistance of cisplatin. In this dissertation, a new kind of platinum compound, ampyplatin, was synthesized based the mechanism of the monofunctional platinum compoud cDPCP. The chemical and biological studies was carried out between ampyplatin and biomoleculars. And the interaction of the fourth metal binding domain of ATP7A (MNK4) and cisplatin was studied and the transfer of platinum from Atoxl to MNK4was verified through several methods.In the first chapter, the mechanism of platinum drugs are reviewed, including the interaction between platinum compounds and their targets DNA, the mechanism of cisplatin resistance.In the second chapter, the studies focus on ampyplatin, the metabolite of monofunctional platinum compounds cDPCP. cDPCP can convert to trans-oriented in the presence of sulfur containning moleculars, resulting the metabolite similar to trans-oriented compounds. The cytotoxicity of ampyplatin was measured. Ampyplatin could be effective uptake and the DNA adducts of ampyplatin are mainly monofunctional. Little of ampyplatin is hydrolyzed due to a fast back reaction. The kinetics of ampyplatin and GMP was monitored and fitted through non-linear fitting to obtain the rate constants.In the third chapter, the interaction between the fourth metal binding domain of ATP7A (MNK4) and cisplatin was studied; and the transfer of platinum from Atox1to MNK4was determined through several methods. The results showed that cisplatin could bind to the copper binding sites on MNK4and the binding of cisplatin induced MNK4aggregate. The transfer of platinum from Atoxl to MNK4indicate that copper transporters play a role in the resistance of platinum based complexes.The transfer of platinum from Atoxl to the second metal binding domain of ATP7B (WLN2) was observed in the fourth chapter. The results showed that different WLN2-Pt adduct could be formed with different reducing agents; the transfer of platinum from Atoxl to WLN2was observed with NMR spectra.In the fifth chapter, the reactions between Pt/Atoxl adducts and DNA were studied. The transfer of Pt from Atoxl to DNA indicated that platinum could be handled to different targets by Atoxl.The interactions between C-terminal of Ctrl (C8) and Cu(Ⅰ) were studied and the transfer of Cu(Ⅰ) from C8to Atoxl was determined in the sixth chapter. The results showed that more than one Cu(Ⅰ) could bind to C8and the dissociation constant of C8with one Cu(Ⅰ) is1.018x10"16M. The transfer of Cu(Ⅰ) to Atox1was identified through NMR and anion exchange chromagraphy.