Low-temperature crystal structures of Tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodicopper(II) and Tetrakis-mu-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 ch aracterized by single crystal X-ray diffraction methods and examined for an ti-inflammatory activity using activated polymorphonuclear leukocytes and f or anticonvulsant activities using electroshock and metrazol models of seiz ures. These complexes were crystallized from dimethylformamide (DMF) or die thylether. Tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodicopp er(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=9 2.95 (2), gamma=94.90 (2)degrees; V=1471.7 (4) Angstrom(3); Z=1. Tetrakis-m u-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 = 100.9 0 (4)degrees; V= 1542 (1) Angstrom(3); Z= 1. The structure of I was determi ned 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 fr om 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 bi nuclear complex with Cu atoms bridged by four 3,5-diisopropylsalicylate lig ands 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 compl eted by the dimethylformamide (or diethylether) oxygen atom occupying an ap ical position, at a distance of 2.129 (2) Angstrom in I and 2.230 (3) Angst rom in II. Each Cu atom is displaced towards the DMF (or diethylether) liga nd, 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 disorde r phenomena were found in the crystal structure of I. Copper(II),(3,5-DIPS) (4)(DMF)(2) inhibited polymorphonuclear leukocyte (PMNL) oxidative metaboli sm in vitro. This effect was concentration related and significant for conc entrations 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 demon strated with copper complexes of other non-steroidal anti-inflammatory drug s. The DMF and diethylether ternary complexes of Cu(II)(2)(3,5-DIPS)(4) wer e found to have anticonvulsant activity in the maximal electroshock model o f grand mal epilepsy in doses ranging from 26 to 258 mu mol/kg of body mass following intraperitoneal, subcutaneous, or oral treatment. The DMF ternar y complex was also found to be effective in the subcutaneous injection of m etrazol model of petit mal epilepsy. We conclude that both ternary copper c omplexes are lipophilic and bioavailable, capable of facilitating the infla mmatory response to brain injury and causing the subsidence of this respons e in bringing about remission of these disease states. (C) 2000 Elsevier Sc ience S.A. All rights reserved.