Synthesis, Structures And Antitumor Properties Of Pt(Ⅱ)and Pd(Ⅱ) Complexes

The mortality rate of cancer is the second only to Cardiovascular disease,which is also a serious threat to human life and health.The discovery of antitumor drug cisplatin cisPt（NH₃）Cl₂（Cis-DDP）has stimulated the broad interest of scientists,especially inorganic chemists,to find platinum group drugs.Cis-DDP covalently binds to DNA guanine base N7,resulting in the mutations of the genetic code in the tumor tissue,hindering DNA replication,resulting in higher cytostatic activity and anti-cancer effect.Due to renal toxicity,nausea,vomiting,low solubility,high cross-resistance and other shortcomings of platinum drugs,the design and development of low toxicity,high efficacy,good bioavailability and weak cross-resistance of new complex is the hotspots research in the current platinum group anti-tumor complexs.Platinum（Ⅱ）and Palladium（Ⅱ）all are precious group metal elements,belonging to Group V（ⅡI）,with the similar spatial configuration characteristics,and chemical properties.Potential drug molecules are increasingly favored by many scholars.In this paper,we selected Pd（Ⅱ）and Pt（Ⅱ）metal ions with the flexible phenylalkylmalonic dicarboxylic acid,a rigid planar aromatic carboxylic acid,to synthesize three kinds of target complexes（1-10）with antitumor activity under the normal temperature or by hydrothermal method at low temperature.The molecular structure,antitumor activity and its interaction with targeted DNA were systematically explored,and the molecular mechanisms of anti-tumor activity induced by metal complexes was discussed.The main results of this paper are as follows:1.Pyrazine-2,3-dicarboxylic acid and pyridine-2,3-dicarboxylic acid as regulatory ligand were used to react with platinum（Ⅱ）metal ions to prepare two novel complexes Pt（pzdc）₂（H₂O）₂（1）and [Pt（pydc）（H₂O）₂ ]·H₂O（2）.The structures of the two complex were characterized by IR,elementary analysis and X-ray single diffractometer.The cytotoxicity of the complexes to HeLa cells were studied by MTT,compared with the clinical drug cisplatin.The apoptosis of cancer cells were characterized by flow cytometry and cell image.The results showed that the complexes had good inhibitory effects on the tumor cells.The ineraction abilities of the complexes with fish sperm DNA was determined by UV spectroscopy,fluorescence spectroscopy and viscosity method.The cleavage ability of pBR322 plasmid DNA was detected by gel electrophoresis.The binding energys of the complexes were calculated by molecular docking.The results showed that both compounds 1 and 2 have high anti-cancer effect and target DNA mechanism on HeLa cells,and their activity depended on the electron distribution of the atoms of the non-coordinating group of the rigid ligand2.Four palladium complexes 3-6 with molecular folding structures were synthesized by flexible phenylalkyldicarboxylic acid（phenylmalonate= bzm,benzylmalonate= pyem（2-phenyl-ethyl）malonate=pyem,（3-phenylpropyl）malonate= ppym）as the main regulatory ligand and 2,9-dimethyl-1,10-phenanthroline（phen）with large plane features as the rigid ligand,[Pd（pm）（phen）]（3）,[Pd（bzm）（phen）]（4）,[Pd（pyem）（phen）]（5）,[Pd（ppym）（phen）]（6）.The results of UV-vis and fluorescence spectra showed that the complex can interact with DNA.Agarose gel electrophoresis showed that the complexes had cleavage ability to pBR322 plasmid DNA.Cytotoxicity studies showed that the four complexes with good cytotoxic activity against different cell lines tested,especially for HeLa and HL-60 cell lines,and IC50 cytotoxicity of complex 6 was similar to cisplatin.The results showed that the structural properties of the series of complexes had a close relationship with the length of the aliphatic chains.Based on the above results,a new structure-activity relationship between the structure and the interaction ability with the DNA target was established.The activity level is closely related to the length of the flexible carbon chain.3.Four Pd（Ⅱ）and Pt（Ⅱ）complexes（7-10）regulated by the rigid dipyridyl dicarboxylic acid ligands were synthesized and characterizaed by 4,4′-dcbpy = 2,2′-bipyridyl-4,4′-dicarboxylate,5,5′-dcbpy= 2,2′-bipyridyl-5,5′-dicarboxylate and piperazine,Pd（5,5-dcbpy）Pip]·4H₂O（7）,[Pt（5,5-dcbpy）Pip]·3H₂O（8）,[Pd（4,4-dcbpy）-Pip]·4H₂O（9）and [Pt（4,4-dcbpy）Pip]·2H₂O（10）.The UV spectra and fluorescence spectra of the four complexes were studied.The cleavage ability of pBR322 plasmid was analyzed by gel electrophoresis.The antitumor effect and apoptosis effect of complexes 7-10 were determined by MTT assay and flow cytometry,respectively.The results showed that this series of palladium（Ⅱ）and platinum（Ⅱ）complexes can interact with DNA,and they have strong inhibitory ability to KB tumor cells.The activity of the complex depends on the structural characteristics of the metal ions and the position of the non-coordinating carboxyl groups.In sum,we synthesized three series of platinum（Ⅱ）and palladium（Ⅱ）complexes（1-10）with excellent antitumor activity.The interaction of metal complexes with DNA was investigated using UV-Vis spectra and fluorescence measurements.Moreover,the anticancer activity and apoptosis of complexes 1-10 against some human cancer cells was tested by MTT assay,microscope observation,flow cytometry,and the molecular biology technology.The antitumor activity of complexes 1-10 was related to their DNA binding ability with the same order,indicating that the complexes play an antitumor effect mainly by hindering the replication of targeted DNA molecules.In this paper,we studied the aspects of metal ion radius,the regulation of flexible carbon chain,the substituent position non-coordinated of the ligand and the atom species noncoordinated.The experimental results from the molecular structure of the complexs,the anti-tumor cell activity and the mechanism of its targeting DNA,etc.,will supply an important scientific basis for the discovery of inorganic drugs in the future.