PTPs Inhibitory Activity Of Cisplatin And Platinum Complexes With Triazole Schiff Bases

Malignant tumor is a serious threat to human life and health, and there still have been many defects in the treatment of cancer until now. Antineoplastic agents play a significant role in the clinical treatment of cancer, and with the development of the life sciences and technology, the various basic process of signal transduction of malignant cells and the regulation of cell cycle and so on are being progressively clarified, which has become a hot research topic about the new role of molecular targeted drugs. Recent studies have shown that the abnormal activity of PTPs has close relations with the occurrence and development of malignant tumors. So PTP has become a new target for anticancer drug research, and PTPs inhibitors is becoming a new direction for the development of anticancer drugs.Currently, the researches on the inhibitors based metal complexes against PTPs are focused on vanadium, copper and zinc complexes. However, there are few studies about antitumor drugs with the platinum complexes targeted PTPs. Furthermore, It is considering that platinum complexes play an important role in the chemical treatment of malignant tumors and recent studies indicate that platinum complexes may also inhibit tumor cell growth and reproduction by the action of certain proteins. So in this thesis, a series of novel polynuclear platinum complexes were designed, synthesized and characterized, and the inhibition activities of these complexes and cis-platinum against PTPs were explored. The results are as follows:1. The inhibition activities of the clinical platinum drug (such as cis-platinum, carboplatin, oxaliplatin etc.) against PTPs were studied in vitro. The results show that cis-platinum had better inhibitory ability and the IC50 value of PTP1B inhibition was ten times about that of TCPTP, which indicated that cis-platinum could selectively inhibit PTP1B. The mechanism studies show that the cisplatin can inhibits PTP1B through the non-competitive mode and the combined ratio between cisplatin and PTPIB is close to 1:1. Furthermore, the cisplatin can inhibit PTP1B actvity effectively in the cell level which implies that the cisplatin may have a new anti-tumor mechanism.2. Four new triazole Schiff base ligands and the corresponding platinum complexes were synthesized and characterization. The structures of complexes 2,3 and 4 were determined by X-ray crystal analysis. These complexes exhibited the inhibitory effects against PTP1B and TCPTP, which is weaker than that of cis-platinum. Fluorescence titration experiments shows that the possible role of the active site of PTP1B.3. The Structure-activity relationship of the platinum complexes was analyzed, and it was can be found that the presence of platinum coordinated ions will help improve the inhibitory ability of the platinum complex against PTPs, while platinum complexes spatial structures may also influence their inhibitory ability against PTPs. These results provide theoretical guidance for design and synthesis of the antitumor platinum complexes targeting PTPs.