Low-temperature crystal structures of Tetrakis-μ-3,5-diisopropylsalicylatobis-dimethylformamidodicopper(II) and Tetrakis-μ-3,5-diisopropylsalicylatobis-diethyletheratodicopper(II) and their role in modulating polymorphonuclear leukocyte activity in overcoming seizures

Two binuclear copper(II) complexes of 3,5-diisopropylsalicylic acid were characterized by single crystal X-ray diffraction methods and examined for anti-inflammatory activity using activated polymorphonuclear leukocytes and for anticonvulsant activities using electroshock and metrazol models of seizures. These complexes were crystallized from dimethylformamide (DMF) or diethylether. Tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodicopper(II) [Cu(II)(2)(3,5-DIPS)(4)(DMF)(2)] I is in space group P (s) over bar; a=10.393 (2), b=11.258 (2), c=12,734 (2) Angstrom, alpha=96.64 (2), beta=92.95 (2), gamma=94.90 (2)degrees; V=1471.7 (4) Angstrom(3); Z=1. Tetrakis-mu-3,5-diisopropylsalicylatobis-etheratodicopper(II) [Cu(II)(2)(3,5-DIPS)(4)(ether)(2)] II is in space group P (1) over bar; a=10.409 (3), b=11.901 (4), c=12.687 (6) Angstrom, alpha = 91.12 (5), beta = 90.84 (5), gamma = 100.90 (4)degrees; V= 1542 (1) Angstrom(3); Z= 1. The structure of I was determined at 140 K from 4361 unique reflections (1 > 2 sigma(1)) and refined on F-2 to R1= 0.04 and wR2=0.09. The structure of II was determined at 180 K from 4605 unique reflections (1 > 2 sigma(1)) and refined on F-2 to R1 = 0.05 and wR2 = 0.13. Each compound is a crystallographically centrosymmetric binuclear complex with Cu atoms bridged by four 3,5-diisopropylsalicylate ligands related by a symmetry center [Cu-Cu-l: 2.6139 (9) Angstrom in I and 2.613 (1) in II]. The four nearest O atoms around each Cu atom form a nearly rectangular planar arrangement with the square pyramidal coordination completed by the dimethylformamide (or diethylether) oxygen atom occupying an apical position, at a distance of 2.129 (2) Angstrom in I and 2.230 (3) Angstrom in II. Each Cu atom is displaced towards the DMF (or diethylether) ligand, by 0.189 Angstrom in I and 0.184 Angstrom in II, from the plane of the four O atoms. The crystal structures of I and II are essentially similar to each other, except for the DMF or diethylether accommodation. Many disorder phenomena were found in the crystal structure of I. Copper(II),(3,5-DIPS)(4)(DMF)(2) inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism in vitro. This effect was concentration related and significant for concentrations higher than 10 mu g or 0.68 nmol/ml. Copper(II)(2)(3,S-DIPS)(4)(DMF)(2) was more active than the parent ligand, 3,5-DIPS, as has been demonstrated with copper complexes of other non-steroidal anti-inflammatory drugs. The DMF and diethylether ternary complexes of Cu(II)(2)(3,5-DIPS)(4) were found to have anticonvulsant activity in the maximal electroshock model of grand mal epilepsy in doses ranging from 26 to 258 mu mol/kg of body mass following intraperitoneal, subcutaneous, or oral treatment. The DMF ternary complex was also found to be effective in the subcutaneous injection of metrazol model of petit mal epilepsy. We conclude that both ternary copper complexes are lipophilic and bioavailable, capable of facilitating the inflammatory response to brain injury and causing the subsidence of this response in bringing about remission of these disease states. (C) 2000 Elsevier Science S.A. All rights reserved.