Oxygen Radical Scavenger Activity, EPR, NMR, MolecularMechanics and Extended‐Hückel Molecular Orbital Investigationof the Bis(Piroxicam)Copper(II) Complex

Abstract

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...

Mononuclear metal complexes with Piroxicam: Synthesis, structure and biological activity

“…Iron(II), cobalt(II), nickel(II) and zinc(II) almost certainly behave similarly to cadmium(II) [56,58,59]. A number of transition-metal complexes of piroxicam have been reported earlier [56][57][58][59][60][61][62], though by screening the literature, no studies concerning the synthesis, characterization and biological study of piroxicam complexes with transition metal ions, such as VO 2+ , MoO 2þ 2 , Mn 2+ , UO 2þ 2 and Fe 3+ are reported.…”

“…Even though it is a potentially tetradentate ligand, it is known to react as a monodentate ligand through the pyridyl nitrogen towards Pt(II) [55], as a bidentate chelating ligand via the pyridyl nitrogen and the amide oxygen towards Cu(II) and Cd(II) [56] and as a singly deprotonated tridentate ligand through the enolic oxygen, the pyridyl and the amide nitrogen atoms in the Sn(IV) complex [57]. Iron(II), cobalt(II), nickel(II) and zinc(II) almost certainly behave similarly to cadmium(II) [56,58,59]. A number of transition-metal complexes of piroxicam have been reported earlier [56][57][58][59][60][61][62], though by screening the literature, no studies concerning the synthesis, characterization and biological study of piroxicam complexes with transition metal ions, such as VO 2+ , MoO 2þ 2 , Mn 2+ , UO 2þ 2 and Fe 3+ are reported.…”

Unusual coordinating behavior by three non-steroidal anti-inflammatory drugs from the oxicam family towards copper(II). Synthesis, X-ray structure for copper(II)–isoxicam, –meloxicam and –cinnoxicam-derivative complexes, and cytotoxic activity for a copper(II)–piroxicam complex

“…The importance of copper(II) complexes with non-steroidal anti-inflammatory drugs (NSAIDs) as ligands has been stressed in several articles and in review papers in the last 15 years [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…Schematic structures for selected drugs, and for the ligands MBT (3-(methoxycarbonyl)-2-methyl-2H-1,2-benzothiazin-4-olate 1,1-dioxide) and PPA (3- characterized over the years [9][10][11][12][13][14][15][16][17][18][19]. Some of these metal compounds have been proposed as potential anti-inflammatory and/or anti-cancer drugs.…”

Synthesis, and Electrochemical and Density Functional Studies of New Copper(II)‐ and Manganese(II) Oxicam Drugs. Redox Potentials and MOs Compatible with SOD‐like Activity and Unusual Six‐membered Rings of Water Molecules Bridging Complex Units

“…[26,27] Based on results from the present work as well as on the data in Ref [17], complexes 1, 2 and 3 can be considered as good candidates for in vitro cytotoxic measurements, and possibly for in vivo anti-cancer tests as well as anti-inflammatory tests.…”