Anti-inflammatory compounds as ligands in metal complexes as revealed in x-ray structural studies

The papers which report on the crystal structures of the metal complexes co ntaining anti-inflammatory drugs used to cure humans and other animals are critically reviewed and analyzed to search for the major structural-charact eristics both for the coordination spheres and the ligand moieties. Even th ough this is not an exhaustive review, it appears that metal complexes of n on-steroidal anti-inflammatory drugs (NSAID) only, have been reported thus far. The total number of compounds structurally characterized via diffracti on techniques is small (ca. 20). Five of the complexes contain piroxicam (H (2)pir, 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 studie d are also few in number, Cu(II) being the more frequently encountered; oth er metals are Cd(II), R(II) and Sn(IV). Some of the articles reviewed inclu de the syntheses and the physico-chemical characterizations of other comple xes whose molecular structures are inferred from spectroscopic techniques. Some complexes of H(2)pir with Fe(II), co(II), Ni(II), and Zn(II) and a com plex of ibuprofen (Hibu) with Cu(LI) have been partially characterized in t his way. The preponderance of Cu(II) complexes stems from the long-known an ti-inflammatory superoxide dismutase (SOD) like activity shown by several C u(II) inorganic and coordination compounds. [M-II(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 o xygen radical scavenger activity as measured through the luminescence techn ique by using stimulated human neutrophils from healthy subjects. The perip heral parts of the complex molecules are mostly hydrophobic in character. T he [(PtCl2)-Cl-II(H(2)pir)L] (L: dmso, C2H4) complexes contain the neutral ligand molecule H2pir in the EZE conformation, coordinated through the pyri dyl nitrogen atom only The Pt-N linkage is greatly weakened by the high tra ns influence of the (S) under bar -DMSO and eta (2)-C(2)H(4)ligands The mol ecular structure of the polymeric [Sn-IV(pir)(bu)(2)](n) compound has two n -bu groups and a doubly deprotonated tridentate ph? ligand (ZZE) per Sn cen ter. The donor atoms from pir(2-) are the enolate oxygen and the amidate ni trogen. The pyridyl nitrogen is also weakly bound to the Sn-IV atom. The am idic oxygen atom form a weak link to the Sn-IV atom from a different coordi nation 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 PtC l2 and Sn(bu)(2) reactive moieties. The complexes from the carboxylic acid family usually have the formula [(Cu2L4L)-L-II ' (2)] (L: indo(-); L ': dmf , H2O, nmp, dma dmso. L: tol(-), nap(-); L ': dmso. L: dic(-): L ': ac, dmf ) and [Cu-2(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] coor dination core, in some solution conditions (e.g. biological buffers, HEPES (N-2-hydroxyethylpiperazine-N ' -2-ethanesulfonic acid) and TES (N-tris(hyd roxymethyl-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 carbo xylic acid family molecule conformations have been analyzed (the metal-boun d and the free forms). Molecular orbital investigations at semi-empirical l evels 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 c onformations, charges and energetics; I hope that all laboratories will fin d these methods to be useful in subsequent analyses of drug-metal and drug- enzyme interactions.