C h a p t e r 25 Nitric
Oxide—Nucleophile as
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Ligands
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Structural Aspects of the Coordinated "NONOate" Functional Group in Novel Mixed-Ligand, Non-Nitrosyl Metal Complexes 1
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Danae Christodoulou , David A. Wink , Clifford F. George , Joseph E. Saavedra , and Larry K. Keefer 1
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Chemistry Section, Laboratory of Comparative Carcinogenesis, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, MD 21702 Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375 2
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"NONOates" are unusual N-nitroso compounds containing the anionic N O2 functional group that have been recently shown to display versatile pharmacological activity (1). Their biological effects are attributable to their ability to release the multifaceted bioregulatory agent (2), nitric oxide (NO), when dissolved in physiological media (3). In comprehensively exploring the structural characteristics and reactivity of this functional group, we are investigating the coordination chemistry of X-N O2 ions in which X is a secondary amine residue such as Et N. These X-N O2 compounds should exhibit ligand properties if the oxygen atoms of the N O2 group are in the Z -configuration. This type of structure would resemble the reported [O S-N O ] (4) and [Ο-N O ] (5) structures, which contain cis oxygens. One also would expect that coordination of the anions to metal centers would affect the stability, solubility and reactivity of the derivative molecules. In addition, the unique properties of metal ions, such asredoxactivity, ligand exchange properties or expansion of the coordination sphere, could be exploited to modulate the ligands' pharmacological activity. Thus metal derivatives of biologically active compounds could be useful in tissue targeting via potential interactions of vacant coordination sites on the metal center with ligand residues of biopolymers such as sulfhydryl, carboxyl or amino. In addition, metal complexes of various nuclearity and ligand content provide a discrete way of aggregating the drug (increasing the number of NO molecules per molecule of complex) in a single compound (equation 1). Longhi and Drago (6)reportedevidence for interaction of the Et2N-N202 ion with certain metal ions, namely Co *, Fe and Cu . We have further investigated the interactions of this ion with different metal centers, in nonaqueous solutions, under conditions that prolong the half-lives of starting materials and products. Ligand substitution, or the use of an isolated complex as a synthon, generated a series of these complexes. This suggests lability of the products in solution. However, in some cases self assembly led to thermodynamically stable products suggesting self organization in the interaction of X-N2O2- ligands with metal ions. In the case of Cu + we have crystallized mixed-ligand complexes of various nuclearity, according to the general scheme of equation 1. 2Et N-N 0 * + xCu • yL Cu (L) (Et2N-N 02)2 (1) 2
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L = OMe , OEt", MeOH, OAc" This chapter not subject to U.S. copyright Published 1994 American Chemical Society
In Nitrosamines and Related N-Nitroso Compounds; Loeppky, Richard N., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
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NITROSAMINES AND RELATED ΛΓ-NITROSO COMPOUNDS
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Among these copper complexes, we have isolated the mononuclear Cu(MeOH)(Et2N-N202)2 (Fig. 1), previously prepared (6) via a different route, and have determined its crystal structure by X-ray diffraction analysis. Structure determinations on this and other metal complexes demonstrate the planar, bidentate chelate nature of the N2O2" functional group. In the N2O2" group, the N-N linkage has double bond character, in contrast to the (Et2)N-N linkage which is a single bond (structure in Fig. 1). The N - 0 distances are equivalent with single bond character, both oxygens are functionalized and interact with the metal center. These compounds are novel examples of metal complexes having nitric oxide as a ligand, oxygen bound rather than in the form of a classical metal nitrosyl, LnM-NO. MeOH
Figure 1. Mononuclear C u f M e O H X E t ^ - ^ O ^ .
Solution studies of the complexes in aqueous, nonaqueous and biological media suggest potential applications in NONOate biology. Coordination of the anions to a metal center in general prolonged the life of the derivative in nonaqueous medium, whereas the free ligand was more stable in aqueous solution. In the latter solutions, the behavior of the metal complexes was similar to that of the free ligand, suggesting that nitric oxide release is controlled primarily by the hydrolysis of the ligand. The amount of nitric oxide produced by these complexes is generally proportional to the number of NONOate ligands present Presumably this accounts for the increased vasorelaxant effects observed for these compounds in isolated rabbit aorta. In conclusion, aminoNONOates contain an N2O2" functional group best described as a bidentate chelating ligand since the oxygens are found in the Z-configuration and both interact with metal ions as demonstrated by crystallographic studies on select copper complexes. These molecules illustrate how biologically active NONOate ligands can coexist with other biologically relevant ligands in mixed-ligand complexes. Metal complexes of this kind suggest possibilities of modulating the reactivity as well as pharmacology of the X-N2O2" anions upon coordination. References (1) Keefer, L. K.; Wink, D. Α.; Maragos, C. M.; Morley, D.; Diodati, J. G. In The Biology of Nitric Oxide, Moncada, S.; Marietta, Μ. Α.; Hibbs, J. B. Jr.; Higgs, E. A. (eds), Portland Press, Colchester, UK, in press. (2) Moncada, S.; Palmer, R. M. J.; Higgs, E. A. Pharmacol. Rev. 1991, 43, 109-142. (3) Maragos, C. M.; Morley, D.; Wink, D. Α.; Dunams, T. M.; Saavedra, J. E.; Hoffman, Α.; Bove, Α. Α.; Isaac, L.; Hrabie, J. Α.; Keefer, L. K. J. Med. Chem. 1991, 34, 3242-3247. (4) (a) Cox, E. G.; Jeffrey, G. Α.; Stadler, H. P. Nature 1948, 162, 770-771. (b) Cox, E. G.; Jeffrey, G. Α.; Stadler, H. P. J. Chem. Soc. 1949, 1783-1793. (c) Jeffrey, G. Α.; Stadler, H. P. J. Chem. Soc. 1951, 1467-1474. (5) Hope, H.; Sequeira, M. R. Inorg.Chem.1973, 12, 286-288. (6) Longhi, R.; Drago, R. S. Inorg. Chem. 1963, 2, 85-88. R E C E I V E D January 31, 1994
In Nitrosamines and Related N-Nitroso Compounds; Loeppky, Richard N., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
