Synthesis Of New Pyrazolic Metal Complexes And Study Of Their Antitumor Effects Against Liver Cancer Cell Lines

Pyrazole unit exists in the structure of many natural compounds and synthetic drugs.Pyrazolic compounds with a variety of biological activities,such as antibacterial?anti-inflammatory and anti-tumor activity,have been widely using in pesticide,medicine,etc.Pyrazolic compounds can coordinate with a variety of metals and form complexes that have the strong antitumor activity.Recently,the study of pyrazolic compounds and their coordinated complexes are gradually becoming a popular topic.In this research,we had designed and synthesized a series of pyrazolic compounds and obtained metal complexes.The structures of pyrazolic compounds and coordinated complexes have been characterized by using nuclear magnetic resonance(NMR),infrared spectrum,X-ray diffraction,et al.These coordinated complexes were studied morphology and cytotoxicity effect on Hep3B?HepG2 and Huh7 cell lines.The results showed that complexes have certain anti-tumor activity.1.In this research,we prepared six pyrazolic compounds via organic synthesis: 5-methyl-3-hydroxy pyrazole(Hmpo),5-phenyl-3-hydroxy pyrazole(Hppo),5-trifluoromethylphenol-3-hydroxy pyrazole(Hfpo),5-chloromethyl-3-hydroxy pyrazole(Hcpo),5-propyl-3-hydroxy pyrazole(Hbpo)and 5-isopropyl-3-hydroxy pyrazole(Hipo).The compounds were characterized with HNMR,CNMR and MS.Using hydro-thermal synthesis method,the pyrazolic compounds were reacted with metal salts to form a series of Cu and Zn complexes.Five of the complexes were obtained in crystallized form: [Cu8(mpo)4(hmpo)4(Me3CCOO)8(EtO)4](Cu-Hmpo),[Cu8(mpo)8(Me3CCOO)4(Me3CCOOH)4(EtO)CO2](Cu-Hppo),[Cu8(bpo)8(Me3CCOOH)4(Me3CCOO)4(EtO)4](Cu-Hbpo),[Cu8(ipo)8(Me3CCOOH)4(Me3CCOO)4(EtO)4](Cu-Hipo)and [Zn(Hppo)2(ppo)]Cl(Zn-Hppo).The crystallized complexes were characterized with infrared spectra,elemental analysis and X-ray single crystal diffraction.Copper complexes are octanuclear complexes and copper atoms coordinate with five atoms and form a pyramid structure.Zinc complex is mononuclear complex and zinc atom is adopting tetrahedron coordination.2.In this research,the crystallized coordinated complexes were tested the effect of cytotoxicity and cellular morphology against liver cancer cell lines HepG2,Hep3 B and Huh7.The experiments were carried out by MTT method to detect the cytotoxicity of five coordinated complex,six pyrazolic compounds,two metal salts and one positive control(5-fluorouracil).The results showed that the coordinated complexes have better anti tumor effects than pyrazole ligands and metal salts.And some metal complexes are stronger than 5-fluorouracil.The best suppression effect to Hep3 B cell is Zn-Hppo with IC50 9.88 � 0.76 ?g/mL.The best suppression effect to HepG2 cell is Cu-Hipo with IC50 5.90 � 2.24 ?g/mL.The best suppression effect to Huh7 cell is Cu-Hipo with IC50 7.77 � 1.14 ?g/mL.The metal complexes can damage cells integrity and form a large number of cell debris with the increasing concentration and the extension of time.This study shows that the coordination ability of pyrazole ligand is related to the nature of the substituents on the pyrazolic nucleus.We found that the stronger capacity of donor electron of the substituents have stronger coordination ability,and are more likely to form crystal complexes.The research shows that the anti-tumor activities of the complexes are stronger than ligands and metal salts on liver cancer cells.Some of the complexes are stronger than 5-fluorouracil.This study provides a new data for drug development on anti-tumor activity.