Synthesis,Inhibitions Against PTPs And The Antitumor Activities Of The Nitrogen Heterocy Platinum Complexes

Platinum complexes were widely used for the treatment of many solid tumor types.And the development of the novel antitumor agents based the platinum complexes also have attracted much attention.In the last decades,DNA has been implicated as the main target for traditional platinum drugs.However,some studies showed the platinum complexes could inhibit the growth and reproduction of tumor cell through specific combinition to certain proteins and enzymes,which would lead to a major shift of the design concept of the antitumor drugs.Several specific moleculars,which are closely related to the development of tumor cells,have recently appeared to be involved in the compounds' overall pharmacological and toxicological profiles,including growth factors,protein kinase and protein tyrosine phosphatase(PTPs).Of them,protein tyrosine phosphatase has aroused wide concern.In view of the important role of platinum complexes in the chemotherapy of malignant tumor,a series of tridentate platinum complexes were synthesized and characterized acting as inhibitors of PTPs in this paper.The inhibition of the complexes against Protein Tyrosine Phosphates 1B(PTP1B)and T cell Protein Tyrosine Phosphates(TCPTP)and the antitumor activity of complexes on MCF-7 cells in vitro were investigated.It is expected that platinum complexes inhibiting selectively and efficiently against specific PTP were screen out.The main results are listed as follows:1.A series of tridentate ligands including nitrogen atoms were selected and their Pt(II)and Pt(IV)complexes 1-6 were synthesized accordingly.Their structures were characterized by several methods such as IR,UV,element analysis and X-ray single crystal diffraction.Besides the solution properties of the platinum complexes were also studied by UV-vis spectra.2.The inhibitory effects of the platinum complexes against PTP1B and TCPTP in vitro were evaluated.The influence of the ligand with different structure and metal ion of different valent on the inhibitory effect aginst PTPwere analysed.The results showed that both Pt(?)and Pt(?)complexescould inhibit the activities of PTP1B and TCPTP,and they indicated higherinhibitory activities and selectivities against TCPTP.For the same ligand,Pt(?)complex showed higher inhibitory activity than Pt(?)complex aginstPTP IB.Complex 2 was screen out as an inhibitors which had certainselectivity against TCPTP.Furthermore,the interaction between the platinumcomplexes and PTP1B or TCPTP by the fluorescence method wasinvestigated.And the results show that their binding ratio approximates 1:1.On the basis of the results,we inferred that these platinum complexes mightbind to the active side of PTP IB and TCPTP.3.The antitumor activity of the platinum complexes on cancercells(MCF-7)was preliminary studied in vitro by determining the inhibitorypercentage against growth of MCF-7 cells using MTT assay..The resultsshow that all the complexes can inhibit the proliferation of MCF-7 cells.Ofthem,complexes 2 and 4 exhibites better inhibiting abilities than othercomplexes,which indicates that different valence of metal and the differentligands will influece the activities.4.In addition,a novel binuclear platinum(II)complex was synthesizedunexpectedly and its crystal structure was obtained and analyzed.X-raysingle crystal diffraction analysis shows that the complex features paddlewheel constituted by two Pt(II)ions and four ligands,which are similar to thedinuclear Pt(II)complexes synthesized previously in our group.Beside,theinhibition of the binuclear complexes against PTP1B and TCPTP wereinvestigated.The results showed the binuclear platinum(II)complexindicated weaker inhibitory effects than the those of the platinum complexeswith the tridentate ligand.In conclusion,the valence of platinum atom and the different structure ofligands in the platinum complexes have an effect on the inhibitory abilityagainst PTPs and anti-cancer activity.Therefore,the proper modification of the organic ligand moieties may result in screening potent and selective platinum-based PTPIB or TCPTP inhibitors.