Table of Contents
Metal-Based Drugs
Volume 2 (1995), Issue 1, Pages 43-56
http://dx.doi.org/10.1155/MBD.1995.43

Oxygen Radical Scavenger Activity, EPR, NMR, Molecular Mechanics and Extended-Hückel Molecular Orbital Investigation of the Bis(Piroxicam)Copper(II) Complex

1Department of Chemistry, University of Siena, Pian dei Mantellini 44, Siena 1-53100, Italy
2Institute of Reumathology, University of Siena, Via dei Tufi 3, Siena 1-53100, Italy

Received 27 July 1994; Accepted 30 August 1994

Copyright © 1995 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 (1.02·104M) and [CuII(Pir)2(DMF)2] (1.08·105M) /HPir (8.01·105M) 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 (1.00·105M) and [CuII(Pir)2(DMF)2] (1.08·105M)/Hpir (8.01·105M)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. C13 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 dx2y2. 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 piroxicam could be due in part to the formation of [CuII(Pir)2] chelates, which can exert a SOD-like activity.