The Inhibitions Against PTPs And The Antitumor Activities Of The Schiff Base Derived Pt(Ⅱ) Complexes

As a critical role making protein phosphorylate dcphosphorylate, protein tyrosine phosphatases (PTPs) exists widely in biological body. The tyrosine phosphorylation process can be regulated by PTPs together with protein tyrosine kinases (PTKs). The abnormalities of tyrosine phosphorylation can lead to disorders of autoimmune and metabolism, resulting in many human diseases, such as diabetes, cancer, obesity and immunodeficiency. So PTPs have been the new drug target due to the close relation to human disease.Platinum-based antitumor drugs have been the target of intense research since cisplatin was discovered as an established antineoplastic agent in the treatment of various cancer cells by Rosenberg in the 1960s. However, the mechanism investigation of antitumor platinum complexes mainly focus on DNA, and few studies on the interaction between PTPs and platinum have been reported.Cisplatin is the significant antitumor agents currently available in the clinic. But severe side-effects and intrinsic or acquired resistance can limit the scope of their application. To overcome these drawbacks, a new target PTP was used in the antitumor investigation based some novel platinum complexes. In this paper, several series of novel mononuclear platinum(Ⅱ) complexes with Schiff base were synthesized and characterized. And the inhibition interaction of the complexes was investigated against PTPs. The main results are listed as follows:based on PTPs targets.1. A series of different Schiff base ligands and the corresponding Pt(Ⅱ) complexes were synthesized and characterized by several methods, such as IR, UV, element analysis and X-ray single crystal diffraction etc. The crystals of a Schiff base ligand and a platinum complex were obtained successfully. In addition, the stability of the Pt(Ⅱ) complexes were studied using UV-vis spectra in DMSO and MOPS buffer containing 10% DMSO, respectively. And the bind ratio between metal ion and ligand of the complex was also studied in solution by UV-vis spectra.2. The inhibitory effects of the Pt(II) complexes with Schiff base ligand against three PTPs were evaluated. The results showed the complexes PtL1-PtL7 are effective PTPs inhibitors (IC50 approximately 0.25～51.85μM), but PtL9-PtL12 hardly inhibited PTPs activity. Of them, PtLl and PtL4 have certain selectivity against SHP-1 and PTP1B, respectively. Furthermore, the stoichiometry and binding constants between the Pt(Ⅱ) complex and PTP1B or TCPTP were investigated by fluorescence spectra.3. The antitumor activity of the Pt(II) complexes on MCF-7 cells was studied in vitro by determining the inhibitory percentage against growth of cancer cell MCF-7 using the method of MTT reduction. The results showed that the complexes can inhibit the proliferation of the cancer cells MCF-7 and the time and concentration dependence of complexes on MCF-7 was shown. The inhibiting activities of the complexes on the cancer cells in the order:PtL5>PtL4>cisplatin>PtL1> PtL6>>tL10. Intriguingly, the Pt(Ⅱ) complexes PtL4 and PtL5 displayed inhibiting activities comparable to or even greater than cisplatin toward MCF-7 cell lines.4. Analysis of the relationship between structure and biological activity of these platinum complexes showed that the structures of the Pt(II) complexes can influence their inhibition activities to PTP1B and MCF-7 cells. Particularly, the existence of the leaving group which attached directly to the metal ions of platinum complexes can obviously improve their inhibition activities. Furthermore, the proper modification of the organic ligand moieties may result in screening potent and selective Platinum-based PTP inhibitors. The results will be the scientific bases for designing some novel antitumor drugs based Pt(II) complexes in future.