Studies On The Synthesis, Characterization And Bioactivities Of2,3-indolinedione Schiff Base Complexes

2,3-indolinedione, also called isatin, is a kind of widespread ocean organisms andendogenous active compounds in the natural body. It is also a very importantpharmaceutical intermediates.2,3–indolinedione can be used to synthesize indirubinwhich has anti-cancer effect. It also has important biological activity in antibacterial,anti atherosclerosis, assimilating cholesterol, anticancer, early warning aboutParkinson’s disease, and regulate the brain hormone balance. Since the20th century,cancer has become one of the main disease for serious harm human health. How tolooking for high efficiency and low side effects anti-cancer drugs has been the scienceresearch focus. In recent years, a large number of transition metal complexes havecertain biological activities.2,3-indolinedione is applied to the synthesis of schiffbase complexes and application research to develop more potential anticancer drugs.Because2,3-indolinedione derivatives has its unique biological activity and theschiff base complexes also has so many features, this paper select amino compoundswhich have different structure and small marine active molecules2,3-indolinedioneto synthesize six series of schiff base ligand and more than30kinds of complexes.four kinds of single crystals were cultivated and determined through X-ray singlecrystal diffraction. The possible chemstrical structure were determined throughelemental analysis, IR, UV spectra, molar conductivity, TG-DTG analysis and soon..Fluorescence properties of ligands and their complexes have been studied and thecomplexes which have good fluorescrnce properties have been chosen. The inhibitionand inducing apoptosis on breast cancer cells of complexes have been also studied bytargeting the cellular proteasome. The details of work are as follow:(1) The ligand and6transition metal complexes derived from2,3-indolinedioneand2-amino-4-methyl phenol were synthetized. The compositions of the complexes are determind to be [ML1(CH3COO)· H2O](M=Cu、Zn、Ni、Mn、Co、Cd，all of them are divalent metal ions; HL1: C15H11N2O2).(2) The ligand and6transition metal complexes derived from2,3-indolinedioneand2-amino-5-methyl phenol were synthetized. The compositions of thecomplexes are determind to be [ML2(CH3COO)]·2H2O (M=Cu、Zn、Ni、Mn、Co、Cd，all of them are divalent metal ions; HL2：C15H11N2O2).(3) The ligand and5transition metal complexes derived from2,3-indolinedioneand2-methoxy-5-amino phenol were synthetized. The compositions of thecomplexes are determind to be [ML3(CH3COO)]· H2O (M=Cu、Zn、Ni、Mn、Cd，all of them are divalent metal ions; HL3：C15H11O3N2).(4) The ligand and5transition metal complexes derived from2,3-indolinedioneand p-aminosalicylic acid were synthetized. The compositions of thecomplexes are determind to be [ML4(CH3COO)]·3H2O (M=Cu、Zn、Ni、Co、Cd，all of them are divalent metal ions; HL4：C15H9O4N2).(5) The ligand and5transition metal complexes derived from2,3-indolinedioneand L-phenylalanine were synthetized. The compositions of the complexes aredetermind to be [ML5(CH3COO)]·3H2O (M=Cu、Zn、Co，all of them aredivalent metal ions; HL5：C17H13O3N2)；[ML5(CH3COO)]·2H2O (M=Ni、Cd，both of them are divalent metal ions).(6) The ligand and5transition metal complexes derived from2,3-indolinedioneand L-tryptophan synthetized. The compositions of the complexes aredetermind to be [ML6(CH3COO)]·2H2O (M=Cu、Co、Cd，all of them aredivalent metal ions; HL6：C19H14O3N3)；[ML6(CH3COO)]·3H2O (M=Ni，Zn，both of them are divalent metal ions)(7) Both Achar differential and Coats-Redfern integral method were used to dealtwith non isothermal kinetics of thermal decomposition for part of thecomplexes.The pyrolysis reaction mechanism, kinetics of thermaldecomposition equation, the corresponding kinetic parameters, activation entropy change△S≠and gibbs free energy change≠△Gof the complexes insome step were obtained. The part results are as follows:The thermal decomposition kinetic function of complexCuL1(CH3COO)· H2O in step3may be definded as f(α)=1/4(1-α)[-ln(1-α)]-3，and the kinetic equation of thermal decomposition may be definded as dα/dt=A·e-E/RT·f(α)=A·e-E/RT1/4(1-α)[-ln(1-α)]-3，E=972.04kJ·mol-1, lnA=197.51，r=0.9989，△S≠=54.57J·mol-1·K-1≠，△G=940.84kJ·mol-1.The thermal decomposition kinetic function of complex[CdL2(CH3COO)]·2H2O in step3may be definded asf(α)=1/4(1-α)[-ln(1-α)]-3，and the kinetic equation of thermal decompositionmay be definded as dα/dt=A·e-E/RT·f(α)=A·e-E/RT1/4(1-α)[-ln(1-α)]-3，E=972.04kJ·mol-1, lnA=197.51≠，r=0.9989，△S≠=54.57J·mol-1·K-1，△G=940.84kJ·mol-1.The thermal decomposition kinetic function of complex[CuL3(CH3COO)]· H2O in step2may be definded as f(α)=(1-α)2，and thekinetic equation of thermal decomposition may be definded as：dα/dt=A·e-E/RT·f(α)=A·e-E/RT·(1-α)2，E=972.04kJ·mol-1, lnA=197.51，r=0.9989，△S≠=54.57J·mol-1·K-1，△G≠=940.84kJ·mol-1.The TG-DTG analysis data of [ZnL5(CH3COO)]·3H2O、[CoL4(CH3COO)]·3H2O�'�[CuL6(CH3COO)]·2H2O the complexes wereomitted.(8) The fluorescence spectra of ligands and part of their metal based complexeswere measured. Meanwhile, the related fluorescence properties were studied.The results show that the complexes such as [NiL1(CH3COO)·H2O],[CdL1(CH3COO)·H2O],[CuL2(CH3COO)]·2H2O,[ZnL2(CH3COO)]·2H2O,[NiL2(CH3COO)]·2H2O,[CdL2(CH3COO)]·2H2O,[CuL3(CH3COO)]· H2O,[ZnL3(CH3COO)]· H2O,[CuL4(CH3COO)]·3H2O,[ZnL4(CH3COO)]·3H2O,[CoL4(CH3COO)]·3H2O,[CdL4(CH3COO)]·3H2O, [NiL5(CH3COO)]·2H2O,[ZnL6(CH3COO)]·3H2O,[CoL6(CH3COO)]·3H2O have good fluorescence properties. Comparing withthe with the corresponding ligands which almost have little fluorescenceintensity, their fluorescence intensity of these complexes enhancedsignificantly. Besides, excitation and emission peaks have shifted to somerange.(9) Four single crystals were cultivated. They are2,3–indolinedione–2-amino-4-methyl phenol (a, the same as L1),2,3–indolinedione–2-amino-5-methyl phenol (b, the same as L2), PMBP–2-methoxy-5-aminophenol(c), PMBP–2-methoxy-5-amino phenol (d), respectively. The resultsof characterization show that the structure of compound a is similar to b andthe structure of c is similar to d. The proton transferation have taken place inthe compounds c and d to become their tautomer. Proton transferred from N ofpyrazole ketones ring to N atom of Schiff base C=N double bond. The X-raycrystallography shows that: The legend a is in monoclinic system, P-1spacegroup, molecular formula: C24H21N3O3, Unit cell parameter: a=12.6211(11)，b=8.7100(7)，c=11.2835(10)，α=90，β=90.7800(10)，γ=90，V=1240.28(18)3，F(000)=528，Dc=1.351g/cm3, R1=0.0391，wR2=0.0919for I＞2σ(I).The legend c is in triclinic system, P2(1)/c space group, molecular formula:C15H11N2O2, Unit cell parameter: a=8.8111(9)，b=11.4716(12)，c=11.4947(14)，α=115.376(2)，β=99.5470(10)，γ=97.6320(10)，V=1007.74(19)3，F(000)=420，Dc=1.316g/cm3, R1=0.0643，wR2=0.1479forI＞2σ(I).The crystal data for compound b and d are omitted. The study of legends arecalculated by using the density functional method the frontier orbital energyand distribution, molecular electrostatic potential (MEP), NBO chargedistribution and stabilization energy E2analysis, to explore the molecularorbitals and the relationship between activity and active site of the molecules. (10) The anticancer activity of metal complexes were studied using protease fortargets in this paper. The complexes were sifted from32complexes using3-[4,5-dimethyltiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT method)in human breast cancer, to research proliferation inhibition of the MDA-MB-231breast cancer cell. The result showed that there are three complexes [CdL3(CH3COO)]· H2O (C1),[CoL4(CH3COO)]·3H2O (C3) and [ZnL6(CH3COO)]·3H2O (C5) which can inhibit the vicious proliferation of humanbreast cancer cells. In order to study the relationship between chemicalstructure and antitumor activity, three complexes CdL2(CH3COO)·2H2O（C2）、CoL2(CH3COO)·2H2O（C4）and [ZnL5(CH3COO)·3H2O（C6）which have similar chemical structure with complexes C1, C3and C5to studied on chymotrypsin-like (CT-like) activity of six complexes. Furtherstudy is carried on the application of protein immunoblot technique (Westernblot) to study the expression of apoptosis related proteins and morphology ofcell apoptosis. The results show that the above three complexes inhibit thevicious proliferation of human breast cancer cells through the inhibition of theproteasome activity. Forthermore, this paper preliminary discusses therelationship between the chemical structure and antitumor activity of metalcomplexes. The conclusion that the schiff base complexes with the specialstructure which is the benzene ring connected with electron-withdrawingfunctional groups maybe have excellent proliferation inhibiting activity fortumor cell is presented. It plays a guiding role for designing and synthetisingnew metal complexes for anti-cancer drugs.