Anti-Inflammatory Compounds as Ligands in Metal Complexes as Revealed in X-Ray Structural Studies

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The papers which report on the crystal structures of the metal complexes containing anti-inflammatory drugs used to cure humans and other animals are critically reviewed and analyzed to search for the major structural-characteristics both for the coordination spheres and the ligand moieties. Even though this is not an exhaustive review, it appears that metal complexes of non-steroidal anti-inflammatory drugs (NSAID) only, have been reported thus far. The total number of compounds structurally characterized via diffraction techniques is small (ca. 20). Five of the complexes contain piroxicam (H2pir, see list of abbreviations) and almost fifteen of them are based on drugs from the carboxylic acid family: indomethacin (Hindo), tolmetin (Htol), naproxen (Hnap), diclofenac (Hdic) and aspirin (Hasp). The metals studied are also few in number, Cu(II) being the more frequently encountered; other metals are Cd(II), Pt(II) and Sn(IV). Some of the articles reviewed include the syntheses and the physico-chemical characterizations of other complexes whose molecular structures are inferred from spectroscopic techniques. Some complexes of H2pir with Fe(II), Co(II), Ni(II), and Zn(II) and a complex of ibuprofen (Hibu) with Cu(II) have been partially characterized in this way. The preponderance of Cu(II) complexes stems from the long-known anti-inflammatory superoxide dismutase (SOD) like activity shown by several Cu(II) inorganic and coordination compounds. [MII(Hpir)2(dmf)2] (M: Cu, Cd) are pseudo-octahedral neutral complexes of the monoanionic piroxicam (Hpir−) drug in the ZZZ conformation. The Cu(II) derivatives have a high oxygen radical scavenger activity as measured through the luminescence technique by using stimulated human neutrophils from healthy subjects. The peripheral parts of the complex molecules are mostly hydrophobic in character. The [PtIICl2(H2pir)L] (L: dmso, C2H4) complexes contain the neutral ligand molecule H2pir in the EZE conformation, coordinated through the pyridyl nitrogen atom only. The Pt-N linkage is greatly weakened by the high trans influence of the π-DMSO and π2-C2H4 ligands. The molecular structure of the polymeric [SnIV(pir)(bu)2]n compound has two n-bu groups and a doubly deprotonated tridentate pir2- ligand (ZZE) per Sn center. The donor atoms from pir2- are the enolate oxygen and the amidate nitrogen. The pyridyl nitrogen is also weakly bound to the SnIV atom. The amidic oxygen atom forms a weak link to the SnIV atom from a different coordination unit. The Pt and Sn compound are of potential anti-inflammatory and anti-tumor interest because of the presence of the piroxicam and of the PtCl2 and Sn(bu)2 reactive moieties. The complexes from the carboxylic acid family usually have the formula [CuII 2L4L'2] (L: indo'; L': dmf, H2O, nmp, dma, dmso. L: tol−, nap−; L': dmso. L: dic−; L': ac, dmf) and [Cu2(asp)4], and are neutral binuclear molecules which show a high peripheral hydrophobicity. The indo−, tol−, nap−, dic− and asp− derivatives have a chemical inertness, at least as regards the [Cu2L4] coordination core, in some solution conditions (e.g. biological buffers, HEPES (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid) and TES (N-tris(hydroxymethyl-2-aminoethanesulfonic acid)). The compounds can exert a SOD-like activity once the apical positions on Cu(II) are made free by dissociation of L'. Both the piroxicam and the carboxylic acid family molecule conformations have been analyzed (the metal-bound and the free forms). Molecular orbital investigations at semi-empirical levels have been initiated for some of the ligands in this article, with the aim of searching for fast and easily accessible ways to compute reliable conformations, charges and energetics; I hope that all laboratories will find these methods to be useful in subsequent analyses of drug-metal and drug-enzyme interactions.