Synthesis,Characterization And Biological Evaluation Of Non-steroidal Anti-inflammatory Drug Diclofenac Complexes

Non-steroidal anti-inflammatory drugs(NSAIDs)are among the most frequently used medicinal drugs.They are utilized primarily as analgesics,antiinflammatories and antipyretics.The most common side effects associated with NSAID administration are gastrointestinal,cardiovascular,renal,and hepatic side effects.Metal complexes drugs has been an important research content of bioinorganic chemistry.Using coordination chemistry method,integrate the non steroidal anti-inflammatory drugs with metal ions maybe a good means of drug design.There are many reports that the enhanced anti-inflammatory activity and reduced gastrointestinal(GI)toxicity of anti-inflammatory drug complex compared with the parent constituents.Seven novel complexes with diclofenac(dicl)as the primary ligand and nitrogen donor small molecular as the secondary ligand were synthesized.The complexes were characterized by C,H,N elemental analysis,UV-Vis,FT-IR and single crystal X-ray diffraction.It was found that the seven complexes were mononuclear structures.Complex 1[Cu(dicl)2(dap)].H2O crystallizes in triclinic space group P-1,a= 8.6297(14),b=14.254(2),c=16.375(3)A,a=112.708(4),?=95.733(5),?=105.806(4)°,V=1739.4(5)A3,each copper ion is four-coordinated with two O atoms from two diclofenacs and two N atoms from one 1,3-propanediamine,thus forming a[CuO2N2]chromophore.Complex 2[Cu(dicl)2(im)2]crystallizes in monoclinic space group C2/c,a=25.815(3),b=7.9833(10),c=21.366(2)A,a=90,?=119.232(3),?=90°,V=3842.5(8)A3,each copper ion is four-coordinated with two O atoms of two diclofenacs and two N atoms of two imidazoles,thus forming a[CuO2N2]chromophore.Complex 3[Cu(dicl)2(bipy)2]crystallizes in monoclinic space group C2/c,a=25.0787(17),b=11.3779(7),c=27.4385(16)A,a=90,?=98.362(3),? =90°,V=7746.2(8)A3,each copper ion is four-coordinated with two O atoms of two diclofenacs and two N atoms of one 2,2'-bipyridine,thus forming a[CuO2N2]chromophore.Complex 4[Zn(dicl)2(tmeda)2]crystallizes in monoclinic space group C2/c,a=24.5279(11),b=7.3686(3),c=19.8738(8)A,a=90,?=99.343(1),? =90°,V=3544.3(3)A3,each zinc ion is six-coordinated with four O atoms of two diclofenacs and two N atoms of one N,N,N',N'-tetramethylethylenediamine,thus forming a[ZnO4N2]chromophore.Complex 5[Zn(dicl)2(phen)]crystallizes in monoclinic space group C2/c,a=26.5122(18),b=12.8673(9),c=11.4305(7)A,a=90,?=110.822(2),? =90°,V=3644.7(4)A3,each zinc ion is six-coordinated with four O atoms of two diclofenac and two N atoms of one 1,10-phenanthrolin,thus forming a[ZnO4N2]chromophore.Complex 6[Zn(dicl)2(dap)]crystallizes in triclinic space group P-1,a-11.0756(5),b=12.7419(7),c=14.0693(7)A,a=69.065(1),?=78.253(1),?=65.037(1)°,V=1677.94(15)A3,each zinc ion is four-coordinated with two O atoms of two diclofenacs and two N atoms of one 1,3-propanediamine thus forming a[ZnO2N2]chromophore.Complex 7[Zn(dicl)2(bipy)]crystallizes in monoclinic space group C2/c,a=27.254(3),b=11.8771(12),c=11.8328(12)A,a=90,?=112.337(3),?=90°,V=3542.9(6)A3,each zinc ion is six coordinated with four O atoms of two diclofenacs and two N atoms of one 2,2'-bipyridine,thus forming a[ZnO4N2]chromophore.The anti-inflammatory,analgesia,gastric toxicity,urease inhibitory activity and in vitro cytotoxic activity of the seven complexes were tested.We observed the anti-inflammation activity by carrageenan-induced rat paw edema method.The analgesia activity was observed by acetic acid induced writhing tests.Cytotoxic activity was determined by MTT method.Gastric toxicity was determined by gastric ulcer index(UI)in rats which were orally administered the complexes.Compared with the uncoordinated diclofenac,all the complexes showed stronger anti-inflammatory and cytotoxic activity and similar analgesia activity.Complex 1-3 have strong inhibitory activity against jack bean urease,complex 4-7 have no inhibitory activity against jack bean urease at 50 ?M.The complexes induce apoptosis of HepG2 cell lines.We investigated the anti-inflammatory effects of the 7 complexes in LPS-induced RAW 264.7 macrophages.The seven complexes up-regulates the expressions of the pro-inflammatory PGE2,IL-10,IL-6,and NO of the supernatant of LPS-induced RAW 264.7.The interaction of the complexes with human or bovine serum albumins has been studied by fluorescence spectroscopy,which revealing their good binding affinity to the albumins with high binding constant values.The interaction of the complexes with ctDNA has been studied by ultraviolet spectrum,which revealing that complex 5 probably bind to ctDNA by intercalation.