The oxygen radical scavenger activity (ORSA) of [CuII(Pir)2] (HPir = Piroxicam = 4-hydroxy -2- methyl -N-2- pyridyl -2H- 1,2-benzothiazine -3- carboxamide 1,1-dioxide) was determined by chemiluminescence of samples obtained by mixing human neutrophils (from healthy subjects) and [CuII(Pir)2(DMF)2] (DMF = N,N -dimethylformammide) in DMSO/GLY/PBS (2:1:2, v/v) solution (DMSO = dimethylsulfoxide, GLY = 1,2,3-propantriol, PBS = Dulbecco’s buffer salt solution). The ratio of the residual radicals, for the HPir (1.02·10−4M) and [CuII(Pir)2(DMF)2] (1.08·10−5M)/HPir (8.01·10−−5M) systems was higher than 12 (not stimulated) [excess of piroxicam was added (Cu/Pir molar ratio ≈1:10) in order to have most of the metal complexed as bischelate]. In contrast, the ratio of residual radicals for the CuCl2 (1.00·10−5M) and [CuII(Pir)2(DMF)2] (1.08·10−5M)/Hpir (8.01·10−5M)system was 5. The [CuII(Pir)2] compound is therefore a stronger radical scavenger than either HPir or CuCl2. A molecular mechanics (MM) analysis of the gas phase structures of neutral HPir, its zwitterionic (HPir+-) and anionic (Pir-) forms, and some CuII-piroxicam complexes based on X-ray structures allowed calculation of force constants. The most stable structure for HPir has a ZZZ conformation similar to that found in the CuII (and CdII complexes) in the solid state as well as in the gas phase. The structure is stabilized by a strong H bond which involves the N(amide)-H and O(enolic) groups. The MM simulation for the [CuII(Pir)2(DMF)2] complex showed that two high repulsive intramolecular contacts exist between a pyridyl hydrogen atom of one Pir- molecule with the O donor of the other ligand. These interactions activate a transition toward a pseudo-tetrahedral geometry, in the case the apical ligands are removed. On refluxing a suspension of [CuII(Pir)2(DMF)2] in acetone a brown microcystalline solid with the Cu(Pir)2·0.5DMF stoichiometry was in fact prepared. 13C spin-lattice relaxation rates of neutral, zwitterionic and anionic piroxicam, in DMSO solution are explained by the thermal equilibrium between the three most stable structures of the three forms, thus confirming the high quality of the force field. The EPR spectrum of [CuII(Pir)2(DMF)2] (DMSO/GLY, 2:1, v/v, 298 and 110 K) agrees with a N2O2+O2 pseudo-octahedral coordination geometry. The EPR spectrum of [CuII(Pir)2·0.5DMF agrees with a pseudo-tetrahedral coordination geometry. The parameters extracted from the room temperature spectra of the solution phases are in agreement with the data reported for powder and frozen solutions. The extended-Hückel calculations on minimum energy structures of [CuII(Pir)2(DMF)2] and [CuII(Pir)2] (square planar) revealed that the HOMOs have a relevant character of dx2−y2. On the other hand the HOMO of a computer generated structure for [CuII(Pir)2] (pseudo-tetrahedral) has a relevant character of dxy atomic orbital. A dxy orbital is better suited to allow a dπ-pπ interaction to the O2- anion. Therefore this work shows that the anti-inflammatory activity of pi...

È dall'inizio degli anni '70 che si è compreso come il nostro organismo produca continuamente radicali liberi e li controlli attraverso una serie di meccanismi di difesa antiossidanti. In condizioni fisiologiche alcuni radicali liberi hanno funzioni utili per il nostro organismo. Quando, però, la generazione di sostanze radicaliche supera la capacità delle difese antiossidanti ne risulta uno stress ossidativo che si evidenzia in molte patologie umane e che talvolta dà un contributo significativo alla loro patogenesi. Le reazioni radicaliche sembrano coinvolgere una lunga serie di malattie, da quelle infiammatorie-immunitarie a quelle su base ischemica a carico del sistema nervoso centrale, cardiaco e renale (1,2,3,4,5). Nelle patologie reumatiche, in particolare, è riconosciuto il ruolo dei radicali e della lipoperossidazione nel determinismo della flogosi, di qui l'interesse per lo studio di sostanze capaci di avere un effetto scavenger e antilipoperossidante (6,7,8,9). Inoltre lo studio di sostanze già in uso da tempo come antireumatici ha evidenziato un potere scavenger di queste sui radicali liberi dell'ossigeno (RLO) (10). Ci è così sembrata interessante una nuova classe di sostanze, i "lazaroidi", di cui abbiamo voluto valutare le capacità scavenger sui RLO. Sono stati studiati i seguenti lazaroidi: U74389F e U74500A (21-aminosteroidi) U78517F (aminocromani). Gli aminosteroidi sono un nuovo gruppo di sostanze derivate dai Effetto scavenger dei lazaroidi U78517F, U74389F, U74500A sui radicali liberi dell'ossigeno prodotti da polimorfonucleati umani stimolati e mediante metodo chimico Reumatismo, 2001; 53(3):223-228 Reumatismo, 2001; 53(3):223-228 SUMMARY Authors investigated the scavenger capability of lazaroids, a new group of compounds (21-aminosteroid) that are reported in the literature to have interesting anti-lipid peroxidation properties. Authors tested the degree of scavenger activity related to the oxygen derived free radicals (ODFR) with different methods