Bernard Viossat

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.

Copper(II) complexes of a nonsteroidal anti-inflammatory drug niflumic acid. Synthesis, crystal structure of tetrakis-μ-(2-[3-(trifluoromethyl)phenyl]aminonicotinato)bis(dimethylsulfoxide)dicopper(II) complex at 190 K. Anti-inflammatory properties

Abstract The synthesis and characterization of three complexes with a potent nonsteroidal anti-inflammatory drug niflumic acid {2-[3-(trifluoromethyl)phenyl]aminonicotinic acid} with formula [Cu(niflumato) 2 L] (L=H 2 O, DMSO=dimethylsulfoxide, DMF= N , N -dimethylformamide) were investigated. The crystal and molecular structure of the {Cu(niflumato) 2 (DMSO)} 2 was reported. Crystallographic data are as follows: monoclinic system, space group P 2 1 / n , Z =2, a =11.1318(8), b =17.513(2), c =15.336(1) A, β =103.316(8)°, V =2909.4(4) A 3 . The structure was refined to R =0.030 and w R =0.037 for 3702 reflections with I > σ ( I ). It consists of centrosymmetric binuclear units with the Cu–Cu i (symmetry code i: 1− x , − y , 1− z ) distance between two centrosymmetrically related ions of 2.6272(5) A. Each Cu(II) ion in [Cu 2 (DMSO) 2 (μ-niflumato) 4 ] is coordinated to an apical dimethylsulfoxide O atom on the one hand and to the equatorial carbonyl and carboxylic O atoms of two crystallographically independent niflumate moieties and their centrosymmetric counterparts on the other hand. In spite of the low-temperature (190 K) crystal measurements, one –CF 3 grouping exhibits some disorder. The biological activities of these complexes were compared to that of niflumic acid. Niflumic acid and its various copper complexes significantly inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism, as assessed by chemiluminescence and O − 2 generation measurement. This effect was dose-dependent. All copper complexes exerted a similar inhibiting effect which was always significantly higher than that exerted by the parent drug.

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-dimethylformamidodicop per(II) [Cu(II)2(3,5-DIPS)4(DMF)2] I is in space group P 1; a = 10.393 (2), b = 11.258 (2), c = 12.734 (2) A, alpha = 96.64 (2), beta = 92.95 (2), gamma = 94.90 (2) degrees; V = 1471.7 (4) A3; 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; a = 10.409 (3), b = 11.901 (4), c = 12.687 (6) A, alpha = 91.12 (5), beta = 90.84 (5), gamma = 100.90 (4) degrees; V = 1542 (1) A3; Z = 1. The structure of I was determined at 140 K from 4361 unique reflections (I > 2sigma(1)) and refined on F2 to R1 = 0.04 and wR2 = 0.09. The structure of II was determined at 180 K from 4605 unique reflections (I > 2sigma(I)) and refined on F2 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(i): 2.6139 (9) A 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) A in I and 2.230 (3) A in II. Each Cu atom is displaced towards the DMF (or diethylether) ligand, by 0.189 A in I and 0.184 A 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)2(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 microg or 0.68 nmol/ml. Copper(II)2(3,5-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 micromol/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.

A convenient asymmetric synthesis of thalidomide

Abstract Benzyloxyamine reacted with BOC-glutamic-α-phenyl ester in the presence of carbodiimide to give BOC-amino-N-benzyloxypiperidinedione. Deprotection of the amino group followed by phthaloylation led to N-benzyloxythalidomide which was then converted into thalidomide.

Synthesis and antitumor activity of the metformin platinum (IV) complex. Crystal structure of the tetrachloro(metformin)platinum (IV) dimethylsulfoxide solvate

The synthesis of (metformin) tetrachloroplatinum (IV) was investigated (metformin is N,N-dimethylbiguanide). It crystallizes with one dimethylsulfoxide molecule as solvate in the monoclinic system, space group P2(1)/n (No. 14) with Z = 4. The cell dimensions are: a = 13.136(7), b = 9.424(2), c = 14.009(8) A, beta = 111.96(4) degrees, V = 1608.4(2) A3. Of the 4269 independent nonzero reflections collected, 1979 with I > 3 sigma (I) were considered and used in the calculations. The structure was refined to R = 0.043 and wR = 0.045. The platinum coordination is octahedral, built up from four chloride anions and one bidentate chelating ligand via the two imine nitrogen atoms cis position. The distances and angles are typical of six-membered rings that have similar donor atoms. The complex was evaluated in vitro and in vivo on murine P388 leukemia. It was found to be as potent as cis-dichlorodiammine platinum (II), CDDP, in inhibiting the proliferation of the sensitive P388 cells. However the resistant P388/CDDP cells were threefold more sensitive to the compound than to CDDP. The two compounds induced a similar perturbation in the G2+M phases of the cell-cycle. The complex was less active than CDDP in vivo on P388 leukemia when administered i.p. (intra peritoneal) on day 1.

Rapid Assembly of the Polyhydroxylated β-Amino Acid Constituents of Microsclerodermins C, D, and E

A very short and efficient synthesis of protected derivatives of APTO and AETD, the complex polyhydroxylated beta-amino acid residues present in microsclerodermins C, D, and E, is described. The targets are obtained in only five steps, in 23% and 16% overall yields, respectively. The key transformation involves the completely diastereoselective two-carbon homologation of appropriately selected intermediate chiral sulfinimines.

ADDITION OF DIAZOMETHANE TO 3 AND 4-NITROPHTHALODINITRILES

The reaction of two nitrophthalodinitriles with diazomethane is described. If the nitro group is at position 3, only one of the two nitrile functions reacts giving three isomeric N-methyl 1,2,3-triazoles. In contrast, if the nitro group is at position 4, both nitriles react, each producing a 2-N-methyl 1,2,3-triazole. The reactivity was accounted for in terms of electronic densities, which were determined for several nitrile compounds. Interestingly, for 4-nitrophthalodinitrile, original methylation of the aromatic ring at position 5 was also observed. I n t r o d u c t i o n In a previous study (1) on the addition of diazomethane to different nitriles, we showed that the addition reaction requires the presence of an electroattractive group. We describe here the reactivity of the 3and 4-nitrophthalodinitriles 2 and 3, and compare it with the unreactivity of phthalodinitrile 1. The nitrophthalodinitriles were stirred during several days with a solution of diazomethane in diethyl ether. The reaction was followed by thin-layer chromatography. Resu l t s In the case of 3-nitrophthalodinitrile 2, three N-methyl 1,2,3-triazoles 4, 5 and fLderived from the cyano group at position 2 were isolated (cf figure 1).

Crystal structure at 180°K of bis-3,5-diisopropylsalicylatobisdimethylsulfoxidozinc(II) and the inhibition of seizures and polymorphonuclear leukocyte chemiluminescence

Dimethylsulfoxide (DMSO) formed a ternary complex when mixed with a Zn-3, 5-diisopropylsalicylate complex of unknown structure. The structure of this new ternary complex was characterized in an initial effort to understand the nature of this compound. Since the original complex is known to have anticonvulsant activity, the new ternary complex was also examined for anticonvulsant activity. The original complex was examined for inhibition of the polymorphonuclear leukocyte (PMNL) respiratory burst in an effort to mechanistically account for zinc complex mediated anticonvulsant activity. Dissolving the structurally unknown complex in DMSO gave crystals of a characterizable complex with an empirical formula C30H46O8S2Zn. Crystallographic data: P 1, Z = 2, a = 8.06(1), b = 12.452(2), c = 17.951(2) A, alpha = 74.42(l), beta = 77.07(1), gamma = 89.50(1) degree. The structure was refined to R = 0.03, RW = 0.04 for 3815 independent reflections with I > 2 sigma(I). This complex is mononuclear, with two 3,5-diisopropylsalicylate ligands and two bonded DMSO ligands, Zn(II)(3,5-DIPS)2(DMSO)2, Zn(II) is coordinate covalently bonded to four O atoms in a strongly distorted tetrahedral arrangement. Each DMSO ligates via its sulfoxide O atom while each 3,5-diisopropylsalicylate ligand is monodentate The non-ligating carbonyl O atom of each 3,5-DIPS is free except for an intramolecular hydrogen bond from the hydroxy group of the same ligand. Both 3,5-DIPS acid and Zn(II)(3,5-DIPS)2(DMSO)2 were examined for anticonvulsant activity in the Maximal Electroshock (MES) and Metrazol (MET) models of seizures and found to prevent both types of seizures. The Zn complex was qualitatively and quantitatively more effective than treatment with the free ligand. The influence of a Zn 3,5-DIPS complex and of the ligand 3,5-DIPS on PMNL oxidative metabolism was also studied to help understand the mechanism of anticonvulsant activity of these compounds. A dose-related and significant decrease in chemiluminescent (CL) response to opsonized Zymosan was observed, and the Zn complex was significantly more effective than the free ligand. It is concluded that mononuclear Zn complexes have anticonvulsant activity in Grand Mal and Petit Mal models of seizure possibly due to inhibition of the synthesis of superoxide or down-regulation of Nitric Oxide Synthase in activated phagocytic cells of the central nervous system.

Oxidation of arylamidoximes by hydrogen peroxide and horseradish peroxidase in water: Easy preparation and X-ray structure of O-(arylimidoyl)arylamidoximes

Abstract The oxidation of arylamidoximes X-C 6 H 4 C(NH 2 )NOH (X = H, Me, Cl, NO 2 , MeO) by H 2 O 2 in the presence of horseradish peroxidase under mild conditions (phosphate buffer pH 7.4, room temperature) yields the corresponding O-(arylimidoyl)arylamidoximes in 30–70% yields. The structure of one of them is established by an X-ray analysis.

Isostructural cobalt(II) and zinc(II) complexes of the N,N-bis(carboxymethyl)-β-alaninato(3−) ion. Crystal structure of the cobalt(II) derivative, [Co(H2O)6][Co2L2(H2O)2]·4H2O

Abstract Homonuclear compounds [M(H 2 O) 6 [M 2 L 2 (H 2 O) 2 ]·4H 2 O (M(II)Co(II) or Zn(II), L 3− =anion of N , N -bis(carboxymethyl)-β-alanine or ((2-carboxyethyl)imino)diacetic acid) have been synthesized and characterized by chemical analysis, magnetic susceptibility data and/or IR spectra, thermal analysis and X-ray diffraction method. They are isostructural and crystallize in the triclinic system, space group P 1 with Z =1. The crystal structure was determined for the cobalt(II) compound ( a =8.732(7)- b =9.751(6), c =9.918(5) A, α=99.96(4), β=110.88(5), γ=103.79(5), V =734.6A 3 , D meas =1.80 g cm −3 , D exp =1.80 g cm −3 ,μ=1.767 mm − (MoKα)). Final R =0.034 and R w =0.043 for 3145 independent observed reflections. This compound consists of both centrosymmetric hexaaquocobalt(II) cations (Co(1)-OW(1)=2.046(2), (Co(1)-OW(2)=2.077(2), Co(1)-OW(3)=2.119(2) A) and anions [Co 2 L 2 (H 2 O ) 2 ] 2− , and non-coordinated water molecules. In the homodinuclear chelate anions, each cobalt(II) atom is bonded to one water molecule (Co( 2 )-OW(4)=2.098(2) A) and one tetradentate chelating ligand L 3− (Co(2)−N=2.134(2), Co(2)−O(5)=2.113(2), Co(2)−O(13)=2.081 (2), Co(2)-O(23)=2.101(2) A). The dimer has an imposed C i symmetry. One carboxylate oxygen atom from the β-alanine arm acts as a bridge between the two cobalt atoms so completing the octahedral coordination of cobalt. The values of the distances Co(2)−Co(2 i ) and the angle at the oxygen atom Co(2)−O(5)−Co(2 i ) are 3.2934(7) A and 103.5(1) o respectively.