| Protein tyrosine phosphatases?PTPs?is a kind of enzymes that do not contain metal,exits widely in biological body,together with the protein tyrosine kinases?PTKs?regulate the process of the protein tyrosine phosphorylation.Every step of the biological process is closely related to protein tyrosine phosphorylation level,such as cellular basal metabolism,growth,metabolism,differentiation,migration,apoptosis,immune response,gene transcription and ion channels of openning and so on.It is reported that the abnormal of the protein tyrosine phosphorylation level can lead to many diseases,such as cancer diabetes,immune deficiency disease and cardiovascular disease.Consequently,PTPs have emerged as a new drug targets and the research of PTPs inhibitors also gradually attracted attention.Since professor Rosenberg found anticancer activity of cisplatin,people began to study of platinum metals complexes and synthesis of a series of platinum anticancer drugs.Regardless of the great success of cisplatin,the severe side-effects and the frequent resistance are main drawbacks for its clinical use,which makes people have to find new solutions.In 1984,Gill found palladium complexes have good antitumor activity.Because of palladium?II?and platinum?II?has the similar coordination environment and properties of thermodynamics and kinetics,we hope that can find the discovery of new compounds showing a different spectrum of biological activity,complementary to cisplatin,accompanied by a more favourable toxicological profile.Like platinum?II?complexes,anticancer mechanism of palladium complexes research also focuses on the interaction with DNA.So far,it have not research of interaction palladium complexes with other biological macromolecules to inhibiting tumor cell growth.Due to the activity of a variety of PTPs anomaly has a close relation with the incidence of malignant tumor,so we guess that PTPs signaling pathway is likely to be affected by palladium complexes inhibiting somePTPs to the effect of anti-tumor.So we choosed different ligands,synthesized a series of palladium complexes,explored the inhibitory effect of these complexes against PTPs.The main results are listed as follows:1.With N'-?pyridin-2-ylmethylene?pyrazine-2-carbohydrazide?HL1?,2-hydroxy-N'-?1-?pyridin-2-yl?ethylidene?benzohydrazide?HL2?,2-hydrox y-N'-?1-?pyrazin-2-yl?ethylidene?benzohydrazide?HL3?,N'-??E?-1-?pyrazi n-2-yl?ethylidene?-2-?1-?pyrazin-2-yl?ethylidene?hydrazine-1-carbothiohydr azide?H2L4?,N'-??E?-pyridin-2-ylmethylene?-2-?pyridin-2-ylmethylene?hy drazine-1-carbothiohydrazide?H2L5?,N',2-bis??E?-2-hydroxybenzylidene?hydrazine-1-carbothiohydrazide?H2L6?,2-??1H-imidazol-2-yl?methylene?-N'-??E?-?1H-imidazol-2-yl?methylene?hydrazine-1-carbothiohydrazide?H2L7?,4-???1-carboxy-2-hydroxyethyl?amino?methyl?benzoic acid?H2L8?as ligands,dessignned and synthesized of nine the bivalent palladium co mplexes [Pd?II??L1?Cl]?H2O?1?H2O?,[Pd?II??L2?Cl]?2?,[Pd?II??L3?Cl]?H2O?3?H2O?,[Pd?II??HL4?Cl]?2.5H2O?4?2.5H2O?,[Pd?II??HL5?Cl]?2H2O?CH3OH?5?2H2O?CH3OH?,[Pd?II?2?L5?Cl2]?6?,[Pd?II?2?L6?Cl2]?7?,[Pd?II?2?L7?Cl2]?4H2O?8?4H2O?,[Pd?II??L8?2]?0.5H2O?9?0.5H2O?.There compositions and structions are established by FT-IR and EA.The st ructures of complexes 1,2,3 and 5 are determined by X-ray single c rystallography.And the palladium complex form in solution were also studied by ESI-MS.2.Studied the inhibitory effect of these complexes against PTPs.The experimental results show that the inhibition effect of palladium complexes against PTPs is obviously better than the inhibition effect of metal against PTPs.Compared with the IC50 of complex 1-3,the IC50 of complex 2against TCPTP is 0.12?M,its inhibitroy effect is 1/10-fold and 1/4-fold than complexes 1 and 3.The inhibition effect of palladium complexes 1 and 2against SHP-1 are almost the same,is about 2-fold compared with complex3.Complex 7 of complexes 4-8 is strongest inhibitor against PTP1 B,is about 5-7 fold compared with other complexes.The inhibition effect of palladium complexes 6 and 7 against TCPTP are relatively strong.Theinhibition effect of palladium complexes 4 against SHP-1 is about 3-11 fold compared with other complexes.The inhibition effect of all kinds of palladium complexes are almost the same.The study of PTPs inhibition shows complexes 1-9 are potent inhibitors of PTP1 B,TCPTP,SHP-1 and SHP-2 and they exhibit different inhibitory ability over different PTPs.Complex 1 and 6 is selective inhibitors of TCPTP.Inhibitroy effect of complex 1?the IC50 of 0.12?M?of TCPTP is 4-fold,3-fold and 12-fold stronger than against PTP1 B,SHP-1 and SHP-2.Inhibitory effect of complex 6?the IC50 of 0.24?M?of TCPTP is 5-fold,8-fold and 7-fold stronger than against PTP1 B,SHP-1 and SHP-2.The ligand of complexes 5and 6 are same,but the coordination ratio of metal and ligand of complex 5is 1:1,and the coordination ratio of metal and ligand of complex 6 is 2:1.The results shows the different structure of ligands and different coordination ratio of metal and ligand will lead to the different inhibition effect of PTPs.3.Studied the interaction mechanisms of the complex 6 and PTPs by kinetics data,which shows complex 6 inhibit PTP1 B,TCPTP,SHP-1 and SHP-2 with competitive inhibition mode.The inhibition constant are about3.5,0.57,9.5,5.5?M for PTP1 B,TCPTP,SHP-1 and SHP-2,respectively.All these results illustrate that the different structure of ligands and different coordination ratio of metal and ligand will lead to the different inhibitory effect of PTPs.Therefore,the reasonable choice of ligands and the change on the coordination ratio of metal and ligand may result in screening potent and selective palladium inhibitors of PTPs. |
PDF Full Text Request