Synthesis And Antitumor Activities Of Platinum Complexes With N-heterocyclic Schiff Base Ligands

With the development of molecular science and technology,most researchers have focused on the antitumor drugs targeted at biomolecules.Protein tyrosine phosphatases?PTPs?,as a large family,play essential roles in intracellular signal transduction.The dysregulation of PTPs activities contributes to the phathogenesis of several human diseases including cancer,diabetes,and immune disorders.So far,at least 37 PTPs have been implicated in human cancers.Therefore,PTPs have been promising targets for antitumor drug discovery.Cisplatin,as the significant antitumor agent,has been successfully applied in the clinic.Its application was restricted due to the poor targeting and severe side-effects.To develop new highly effective and low-toxicity antitumor drugs,it is imperative to design new platinum complexes and investigate their antitumor mechanis.Herein,PTPs were chosen as molecular targets to design and synthesize some platinum complexes with antitumor activties.Recent studies have shown that PTP1B and TCPTP overexpressed in many cancer patients,and their inhibitors also exhibited good antitumor activities.Our group's previous research indicated that the dinuclear platinum complexes with the triazole Schiff base ligands 1-4 could inhibit the recombinant of PTP1B and TCPTP.In this paper,we further studied the antitumor activities of these binuclear platinum complexes and their antitumor mechanism at the cellular level.Moreover,a series of new platinum complexes were designed and synthesized to improve the inhibition of platinum complexes against PTPs.The inhibitory effects of the complexes on PTP1B and TCPTP and the antitumor activity at the cellular level were preliminarily studied in this thesis.The main contents and results are listed as follows:1.The antiproliferative potential of complexes 1-4 and cisplatin against four human cancer cell lines?MCF-7,HepG2,SMCC-7721 and A549?were evaluated by MTT assay,and the cell morphology of complex 3 treated HepG2 cells at different intervals was observed by fluorescent inverted microscope.The results displayed that these complexes could inhibit the cellular growth against MCF7,HepG2 and SMCC-7721 except for A549 cell lines.The cytotoxicity of complex 3 is significantly higher than those of other three complexes against HepG2 cell lines.Notably,Complex 3 showed a comparable inhibitory potency(IC₅₀=5.5?M)to that of cisplatin and better selectivity against HepG2 cells.The kind of selective cytotoxicities of these complexes to different cancer cells could have been caused by their different steric configuration,which might be affected on the alkyl length of substituted in triazole.The cytotoxic activities of the complexes were also shown to be dose and time-dependent.2.The main distribution of complex 3 in HepG2 cells was observed by laser scanning confocal microscopy.DNA binding action and intracellular phosphatase or proteasome inhibition of the complex 3 was evaluated in this paper,respectively.Unlike the anticancer mechanism of cisplatin,complex 3do not strongly bind to DNA,and the confocal microscopy imaging displayed that 3 mainly distributed in the cytoplasm.Further studies revealed that the 3can inhibit intracellular phosphatases activities,while hardly influence proteasome activities.The results indicated that 3 might enter into cytoplasm to interact with some phosphatases and interfere with cellular signaling pathways,leading to the inhibition of cellular growth.3.A series of novel Schiff base Pt?II?and Pt???complexes?5-16?have been synthesized and characterized.The inhibitory effects of these platinum complexes against recombinant PTP1B and TCPTP in vitro were evaluated.The experimental results showed that the IC₅₀0 values of complex 5-14 were micromol order of magnitude.Furthermore,it was found that the Pt?II?and Pt?IV?complexes with the same ligand had similar inhibitory abilities against PTP1B and TCPTP.Compared to the PTPs inhibition of Pd?II?complexes with the same ligands,Pt?II?complexe showed lower inhibitory activity.In addition,the inhibitory activity of these platinum complexes on the two recombinant PTPs was mainly affected by the structure of ligands and the type of metal ions,while hardly related to the valence state of metal ions.Finally,the antitumor activity of complexe 5?6?11 on HepG2 cells was studied in vitro by determining the inhibitory percentage against growth of the cells by MTT assay.The results showed that complexes 5 and 6 had strong inhibitory effect on cancer cell proliferation,while the dinuclear platinum complex 11 had weaker inhibitory effect.These results indicated that the valence state of platinum in the complex had little effect on the antiproliferation of cancer cells,and we can improve the antitumor activity of the platinum complexes by changing their coordination structures.These results will provide the scientific basis for designing some novel platinum antitumor drugs targeted at PTPs in future.