Low-temperature (180 K) crystal structure, electron paramagnetic resonance spectroscopy, and propitious anticonvulsant activities of CuII2(aspirinate)4(DMF)2 and other CuII2(aspirinate)4 chelates.
The purpose of this research was to characterize by X-ray crystallography the ternary dimethylformamide (DMF) Cu(II) complex of acetylsalicylic acid (aspirin), in an effort to compare the structure-activity relationships for the anticonvulsant activity of this and other Cu(II)aspirinate chelates. The ternary DMF Cu(II) complex of aspirin was synthesized and crystals grown from a DMF solution were characterized by single crystal X-ray diffraction. This crystalline material was analyzed for anticonvulsant activity in the Maximal Electroshock (MES) Grand Mal and subcutaneous Metrazol (scMET) Petit Mal models of seizure used to detect anticonvulsant activity. The ternary DMF complex was found to be a monomolecular binuclear complex, tetrakis-mu-(acetylsalicylato)bis(dimethylformamido)dicopper(II) [Cu(II)(2)(aspirinate)(4)(DMF)(2)] with the following parameters: monoclinic, space group P2(1)/n, a=12.259 (1), b=10.228 (1), c=16.987 (1) A, beta=92.07 (1) degrees; V=2128.5 (3) A(3); Z=2. The structure was determined at 180 K from 2903 unique reflections (I>1sigma(I)) to the final values of R=0.030 and wR=0.033 using F. This binuclear complex contains four acetylsalicylate bridging ligands which are related to each other in a two by two symmetry center. The four nearest O atoms around each Cu atom form a closely square planar arrangement with the square pyramidal coordination completed by the dimethylformamide oxygen atom occupying an apical position at a distance of 2.154 (1) A. Each Cu atom is displaced towards the DMF ligand by 0.187 A from the plane of the four O atoms. Electron paramagnetic resonance (EPR) spectra of [Cu(II)(2)(aspirinate)(4)(DMF)(2)] crystals show a strong antiferromagnetic coupling of the copper atoms, similar to that observed with other binuclear copper(II)salicylate compounds. Studies used to detect anticonvulsant activity revealed that [Cu(II)(2)(aspirinate)(4)(DMF)(2)] was an effective anticonvulsant in the MES model of seizure but ineffective against scMET-induced seizures. The monomolecular ternary binuclear [Cu(II)(2)(aspirinate)(4)(DMF)(2)] complex is more effective in inhibiting MES-induced seizures than other binuclear or mononuclear Cu(II) chelates of aspirin including: binuclear polymeric [Cu(II)(2)(aspirinate)(4)], [Cu(II)(2)(aspirinate)(4)(H(2)O)], which is anticipated to be less polymeric, and monomolecular ternary [Cu(II)(2)(aspirinate)(4)(DMSO)(2)] and [Cu(II)(aspirinate)(2)(Pyr)(2)]. These and other chelates appear to be more effective in the scMET model of seizure than [Cu(II)(2)(aspirinate)(4)(DMF)(2)]. These structure-activity relationships support the potential efficacy of Cu chelates of aspirin in treating epilepsies.
Viossat
Bernard
B
Laboratoire de Chimie Générale, Faculté de Médecine et de Pharmacie, Poitiers, France.
Daran
Jean Claude
JC
Savouret
Grégoire
G
Morgant
Georges
G
Greenaway
Frederick T
FT
Dung
Nguyen Huy
NH
Pham-Tran
Van Anh
VA
Sorenson
John R J
JR
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D001241:Aspirin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D003080:Cold Temperature; D003300:Copper / Q000737:chemistry*; D003460:Crystallization; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D004578:Electron Spin Resonance Spectroscopy; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013696:Temperature
D000927:Anticonvulsants; D009942:Organometallic Compounds; C027058:tetrakis-mu-acetylsalicylato-dicopper(II); D003300:Copper; D001241:Aspirin