Synthesis and pharmacochemical study of new Cu(II) complexes with thiophen-2-yl saturated and alpha,beta-unsaturated substituted carboxylic acids.
Copper complexes with thiophen-2-yl saturated and alpha,beta-unsaturated carboxylic acids as ligands were prepared, characterized and pharmacochemically studied. The available evidence supports a dimeric structure for the complexes of the general formula [Cu2(L)4(MeOH)2] where L are the anions of thiophene 2-carboxylic acid (HL1), 2-(thiophen-2-yl)-acetic acid (HL2), 3-thiophen-2-yl-acrylic acid (HL3), 2-phenyl-3-thiophen-2-yl-acrylic acid (HL4) respectively. The crystal structure of [Cu2(L1)4(MeOH)2] (2) was determined while preliminary X-ray analysis of the copper complex with L4 isolated from MeOH/DMSO solution proved to contain three crystallographically independent dimers of the formula [Cu2(L4)4(MeOH)(dmso)][Cu2(L4)4(MeOH)2][Cu2(L4)4(dmso)2].8MeOH (9). Since lipophilicity is a significant physicochemical property determining distribution, bioavailability, metabolic activity and elimination, we tried to measure experimentally their lipophilicity from RPTLC method. The copper complexes and the ligands (thiophen-2-yl saturated and alpha,beta-unsaturated carboxylic acids) were tested in vitro on: (a) soybean lipoxygenase inhibition, (b) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, (c) the HO* mediated oxidation of DMSO, (d) inhibition of lipid peroxidation, (e) scavenging of superoxide anion radicals and in vivo for the inhibition of carrageenin-induced rat paw edema. The compounds have shown important antioxidant activity, significant anti-inflammatory activity and potent inhibition of soybean lipoxygenase as a result of their physichochemical features. Complex [Cu2(L1)4(MeOH)2] (2) presents the higher in vivo activity (77.4%) followed by complex [Cu2(L2)4(MeOH)2] (4) (51%). Both complexes are more potent anti-inflammatory agents compared to their respective ligands. Moreover we have performed in vitro studies upon their effect on dsDNA, using adsorptive transfer stripping voltammetry and a dsDNA modified carbon paste electrode. Our conclusions were mainly based upon the effect of the studied compounds on the oxidation signal of guanine and adenine. From the given data it seems that complexes show similarities in their behaviour.
Panagoulis
D
D
Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Pontiki
E
E
Skeva
E
E
Raptopoulou
C
C
Girousi
S
S
Hadjipavlou-Litina
D
D
Dendrinou-Samara
C
C
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015374:Biosensing Techniques; D002264:Carboxylic Acids; D002351:Carrageenan; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D005609:Free Radicals / Q000737:chemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008084:Lipoxygenase / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013025:Glycine max / Q000201:enzymology; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002264:Carboxylic Acids; D005609:Free Radicals; D016859:Lipoxygenase Inhibitors; D013876:Thiophenes; D013481:Superoxides; C550746:2-thiophene carboxylic acid; D003300:Copper; D002351:Carrageenan; D004247:DNA; D008084:Lipoxygenase