| Amino acids are endogenous substance of life and essential physiological activesubstances for organism cell growth. Amino acid Schiff base and their metalcomplexes have a wide application prospect in medicine, catalysis, optics, materialsand other fields, has become the focus in the field of coordination chemistry. Thesynthesis of many novel amino acid Schiff bases and their metal complexes throughthe reaction of various functional groups into the derivatization, and the studies ontheir molecular structures, physicochemical properties and practical application haveimportant significance for the development of coordination chemistry.In this paper, six Schiff base ligands and twenty-eight corresponding metalcomplexes have been synthesized and the single crystals of three coordinationcompounds have been obtained. These complexes have been characterized byelemental analysis, IR spectrum, UV spectrum, fluorescence spectrum, molarconductivity and thermal gravimetric analysis. The suggested structures of the metalcomplexes have been concluded. The spatial structures of three single crystals havebeen detected using the X-ray diffraction analysis. Fluorescence properties of theSchiff base metal complexes and the interaction modes of ternary metal complexesand DNA have been studied. The proliferation inhibitory abilities of all the metalcomplexes on breast cancer cell (MDA-MB-231) and prostate cancer cells (PC-3)have been detected and the complexes which have antitumor activity have beenselected. The reaction mechanisms of the amino acid Schiff base copper ternarycomplexes induce cancer cells apoptosis through inhibiting proteasome activity havebeen discussed using proteasome as reaction target. The main works of the article areas follows:1. The metal complexes with Schiff base ligand （H2L1） derived from2,4-Dihydroxybenzaldehyde and L-Aspartic acid were synthesized. The possible chemical compositions of these complexes are confirmed to be:[M（L1）（H2O）2]·nH2O（M=Cu, Zn, n=2; M=Co, Mn, n=3）,[M（L1）（NO3）（H2O）x]·nH2O （M=La, x=3, n=2）,[M（L1）（Phen）]·nH2O （M=Cu, n=1）。H2L1=C11H11NO6, Phen:1,10-Phenanthroline2. The metal complexes with Schiff base ligand （H2L2） derived from2,4-Dihydroxyacetophenone and L-Aspartic acid were synthesized. The possiblechemical compositions of these complexes are confirmed to be:[M（L2）（H2O）2]·nH2O（M=Cu, n=0; M=Co, n=2; M=Zn, n=3）,[M（L2）（NO3）（H2O）x]·nH2O （M=Sm, x=2,n=2; M=La, x=3, n=3）,[M（L2）（Phen）]·nH2O （M=Cu, n=3）。H2L2=C12H15NO73. The metal complexes with Schiff base ligand （H2L3） derived from2,4-Dihydroxybenzaldehyde and L-Valine were synthesized. The possible chemicalcomposition of these complexes are confirmed to be:[M（L3）（H2O）2]·nH2O （M=Zn,n=1; M=Co, n=2; M=Cu, n=3）,[M（L3）（NO3）（H2O）x]·nH2O （M=Yb, x=2, n=1; M=Er,x=3, n=2）,[M（L3）（Phen）]·nH2O （M=Cu, n=2）。H2L3=C12H15NO44. The metal complexes with Schiff base ligand （H2L4） derived from2,4-Dihydroxyacetophenone and L-Valine were synthesized. The possible chemicalcomposition of these complexes are confirmed to be:[M（L4）（H2O）2]·nH2O （M=Cu,n=1; M=Zn, Co, n=2）,[M（L4）（NO3）（H2O）x]·nH2O （M=Er, x=2, n=3; M=La, x=3,n=2）,[M（L4）（Phen）]·nH2O （M=Cu, n=4）。H2L4=C13H17NO45. The single crystals of ternary copper complexes with Schiff base ligand （H2L5）derived from O-vanillin and L-Methionine were obtained. The chemical compositionsof these complexes are confirmed to be:[Cu（L5）（Phen）]·9H2O,[Cu（L5）（Bpy）]·3H2O.H2L5=C13H17NO4S, Bpy:2,2’-BipyridineThe crystal of [Cu（L5）（Phen）]·9H2O belongs to the monoclinic crystal system,space group C2with the cell parameter a=22.510（2）, b=21.479（2）, c=14.8300（17）, α=90°, β=92.7460（10）°, γ=90°, V=7162.0（13）3, F（000）=2888. The ligand acts asa doubly deprotonated, tridentate form to coordinate with copper atom to formparatactic five-member and six-member chelated ring. In the ligand, the carbonyloxygen atom and Imine nitrogen atom coordinate with copper atom to formfive-member chelated ring, the phenol hydroxyl oxygen atom and Imine nitrogenatom coordinate with copper atom to form six-member chelated ring, the nitrogen atom of1,10-Phenanthroline coordinate with copper atom to form other five-memberchelated ring. The Cu atoms exhibit five-coordinate distorted square-pyramidconfigurations.The crystal of [Cu（L5）（Bpy）]·3H2O belongs to the monoclinic crystal system,space group P21/c with the cell parameter a=11.0970（11）, b=19.101（2）, c=13.2031（12）, α=90°, β=114.1490（10）°, γ=90°, V=2553.7（4）3, F（000）=1156. Thecoordination mode of ligand in [Cu（L5）（Bpy）]·3H2O is similar with [Cu（L5）（Phen）]·9H2O, except for the use of2,2’-bipyridineinstead of1,10-phenanthroline tocoordinate with copper atom to form five-member chelated ring. Both coppercomplexes are linked into one-dimensional chain structure through O-H…O hydrogenbonds, and the chains to form two-dimensional network also by hydrogen bonds.6. The ternary copper complexes with Schiff base ligand （H2L6） derived from2-hydroxy-1-naphthaldehyde and L-Valine were synthesized. The possible chemicalcompositions of these complexes are confirmed to be:[Cu（L6）（Phen）]·3H2O,[Cu（L6）（Bpy）]·3H2O. H2L6=C16H19NO4. The crystals of [Cu（L6）（Bpy）]·3H2O were otained.The crystal of [Cu（L6）（Bpy）]·3H2O belongs to the triclinic crystal system, spacegroup P-1with the cell parameter a=9.2950（10）, b=9.7861（11）, c=14.3819（15）,α=79.9710（10）°, β=74.7180（10）°, γ=85.745（2）°, V=1242.1（2）3, F（000）=566. Theoxygen atom and nitrogen atom of the ligand coordinate with copper atom to formfive-member and six-member chelated ring. The complexes are linked into ladderform two-dimensional network structure through O-H…O hydrogen bonds.7. A combination of Achar differential and Coats-Redfern method was used toprocess non-isothermal decomposition of kinetics of part of the complexes. Thethermal decomposition reaction mechanism, correspondent kinetic parameters,activation entropy change△S≠and gibbs free energy change△G≠of the complexes.Among them, the thermal decomposition kinetic functions of related steps of complex3a conforms to the reaction equation: f（α）=（1-α）2; complexes2e and3d conforms tothe reaction equation: f（α）=1/3（1-α）[-ln（1-α）]-2; complexes2f,4e and5d conforms tothe reaction equation: f（α）=1/4（1-α）[-ln（1-α）]-3; complexes2f,4e and5d conforms tothe reaction equation: f（α）=1/2（1-α）3. 8. Fluorescence spectra of these complexes were detected and the related fluorescence properties were studied. The experimental results show that compared with thecorresponding ligand, the excitation and emission peaks of complexes [Cu（L1）（H2O）2]·2H2O,[Zn（L1）（H2O）2]·2H2O have shifted to blue for some degree and thefluorescence intensity enhanced obviously. The excitation and emission peaks ofcomplexes [Zn（L2）（H2O）2]·3H2O,[La（L2）（NO3）（H2O）3]·3H2O have shifted to redslightly and the fluores cence intensity Weakened for a little. The excitation andemission peaks of complexes [Zn（L3）（H2O）2]·H2O,[Er（L3）（NO3）（H2O）3]·2H2O,[Zn（L4）（H2O）2]·2H2O,[Co（L4）（H2O）2]·2H2O have shifted to blue for some degree andthe intensity weakened slightly.9. The interaction modes between the ternery amino acid Schiff base coppercomplexes and DNA was studied by UV-Vis spectrium, fluorescent spectrium andviscosity method. The results show that when1,10-philippines was added as thesecond ligand, complexes [Cu（L1）（Phen）]·H2O,[Cu（L2）（Phen）]·3H2O,[Cu（L3）（Phen）]·2H2O,[Cu（L5）（Phen）]·9H2O can interact with CT-DNA as the insert mode, and[Cu（L4）（Phen）]·4H2O can interact with CT-DNA as the partly insert mode. When2,2’-bipyridyl was added as the second ligand, complex [Cu（L5）（Bpy）]·3H2O caninteract with CT-DNA as electrostatic mode. Comparison of [Cu（L5）（Phen）]·9H2Owith [Cu（L5）（Bpy）]·3H2O indicate that the complexes with better coplanar propertiesare more favorable to interact with DNA as the insert mode, and have better DNAbinding ability.10. Antitumor activity and action mechanism of the complexes as the proteasomeinhibitor is studied. In vitro antitumor drug tests of28kinds of amino acids are carriedout using MTT method, from which some ternary complexes with antitumor activitieslike [Cu（L1）（Phen）]·H2O,[Cu（L2）（Phen）]·3H2O,[Cu（L3）（Phen）]·2H2O,[Cu（L4）（Phen）]·4H2O,[Cu（L5）（Phen）]·9H2O and [Cu（L6）（Phen）]·3H2O are screened out.Inhibition activities to proteasome in tumor cells of the complexes that have beenscreened out are tested to determine whether proteasome is the target or not. Therelevance between proteasome activity and tumor cells apoptosis induction isinvestigated using concentration experiments and kinetics experiments. Morphologies of the apoptotic cells are determined by the cell morphological changes testingtechnique. The results show that the above mentioned ternary complexes can inhibitthe proteasome activity of human breast cancer cells (MDA-MB-231) and prostatecancer cells (PC-3) in concentration-dependent and time-dependent mode.Antitumor activities of some ternary copper complexes using different secondligands are analyzed and compared. It is found that the complexes using1,10-Phenanthroline as the second ligands demonstrate dramatic antitomor activities while thecomplexes using2,2’-bipyridyl as the second ligands demonstrate weak antitomoractivities. For example, the ternary Cu（II） complexes derived from o-Vani llin,L-Methionine and1,10-Phenanthroline as well as2-Hydroxy-1-naphthaldehyde,L-Valine and1,10-Phenanthroline can effectively inhibit the proliferation of breastcancer cells. In contrast, the ternary Cu（II） complexes derived from o-Vanillin,L-Methionine and2,2’-bipyridyl as well as2-Hydroxy-1-naphthaldehyde, L-Valineand2,2’-bipyridyl exhibit weak antitumor activities. This indicates that the secondligands play key roles to the antitumor activities of the ternary complexes.The mechanism of the complexes as proteasome inhibitor to induce the tumorcells apoptosis is discussed, according to the experimental results combined withmolecular simulation and docking technology. The results show that when1,10-Phenanthroline serve as second ligands, the obtained complexes can smoothly reach the β6target of20S proteasome. Then the copper ions can form covalent bonds with β6target and the bioactive radicals can form several hydrogen bonds with the residues inβ6target. These covalent bonds and hydrogen bonds can fix the complexes on β6target to block the protein molecules to go through β5target that has chymotrypsin-like avtiveity. Thus, the activity chymotrypsin-like in20S proteasome will beinhibited and the cell apoptosis will occur. |
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