A structure for the selenium analogue of the Roussin's black anion, [Fe4S3(NO)7]− had been proposed, on the basis of 15N.N.M.R. spectroscopy results, as being similar to that of the sulphur molecule. X-Ray crystallography was carried out on a crystal of Ph4AS Fe4Se 3(NO)7]− to determine whether this conclusion was correct. The crystal, Mr=1053.67, was triclinic of space group p1̅ with a=13.122 (9), b=13.936 (9), c=9.908 (8)A, α =99.30 (6), β =97.04 (6), γ=71.94 (5)° and Z=2. This structure was refined from diffractometer data to an R value of 0.047 and was found to consist of isolated Ph4As+ cations and [Fe4Se3(NO)7]− anions which exhibit approximate C3v symmetry, and agrees with that deduced from earlier work. It was also found that the capping influences the size of the Fe4 cage. Nitrosation studies of amines by iron sulphur nitrosyl clusters had reached a variety of conflicting conclusions; i.e. that no anaerobic nitrosation occurred and that the formation of solvocomplexes may or may not have been important in the nitrosation mechanism. An investigation was undertaken using tetranuclear, dinuclear and mononuclear iron sulphur nitrosyl complexes in a variety of atmospheres and solvents with amines of different basicities. It was found that tetranuclear clusters do not nitrosate amines readily and that solvocomplex formation is not important in nitrosation by tetranuclear clusters. The cluster does require to be oxidised however. Only morpholine and pyrrolidine, both of which were capable of forming mononuclear solvocomplexes themselves, were nitrosated by dinuclear clusters and it is thought that the formation of solvocomplexes is important to nitrosation by di-iron species, which was found to occur as readily in an atmosphere of nitrogen as in air. These amines were also nitrosated by mononuclear iron complexes and it was found that the dinitrito species [Fe(N0)2(N2)2]- did not nitrosate amines more readily than other monoiron sulphur nitrosyl complexes. Fragmentation and reassembly is thought to be the likely mechanism of conversion of the Roussin's black salt anion, [Fe4S3(NO)7]-, to the cubane-type cluster, although mixed cluster experiments were found to be invalid for these studies because the black salt anion spontaneously converts to the cubane-type cluster on refluxing it in toluene. Experiments done to investigate the likely mechanism of the methylation of [Fe(SH)2(NO)2]- found that reactions with bromopentane, which would cause the sulphur atom to be methylated, and pentanethiol, which would attack the metal atom, both gave the same product. Chapter One summaries the history and development of iron sulphur nitrosyl chemistry and provides an introduction to the biological aspects of this field of work. Chapter Two describes the crystal structure determination of tetraphenylarsonium heptanitrosyl-tri-μ3-seleno tetraferrate (1-). Chapter Three provides an account of a study of the nitrosation of amines by iron sulphur nitrosyl complexes of various nuclearities and suggests mechanisms for and limitations on their nistrosating ability. In Chapter Four is to be found a description of two other lines of research which were undertaken; a study of the mechanism of the conversion of [Fe4S3(NO)7]− to [Fe4s4(no)4] and an investigation of the methylation of [Fe(SH)2(NO)2]−. Chapter Five contains a description of all preparations used during the work.

S-Nitrosothiols (RSNO) are an important class of NO-donor drugs. They have been used clinically and occur naturally where they may have a role in several biological and physiological processes in the human body. The medical importance of S-nitrosothiols has been highlighted recently by several reports which describe the clinical use of GSNO (13) to inhibit platelet aggregation during coronary angioplasty and also to treat a form of preeclampsia, a high blood pressure condition suffered by some pregnant women. We set out to extend the range of compounds of this type by synthesising a novel series of biologically active S-nitrosothiols (1-13) and to look for a correlation between structure, chemical stability, and physiological activity. The situation has been complicated by the recent discovery that the main route for the release of NO from S-nitrosothiols is a copper- catalysed process. A detailed kinetic study of copper ions, and thiols on the stability of the compounds we synthesised has shown that the dominant pathway for the decomposition of S-nitrosothiols in most circumstances is one catalysed by Cu+ ions. We suggest that Cu+ ions are formed by the reaction of Cu2+ ions with thiol, present in the S-nitrosothiols as an impurity. The implications of this discovery for an understanding of the biological action of S-nitrosothiols is suggested. All the new S-nitrosated dipeptides (2-12) examined show less susceptibility to copper (I)- catalysed release of NO than SNAP (1) but are more reactive than GSNO (13). We found that S-nitrosated dipeptides are potent vasodilators and suitable inhibitors of platelet aggregation but are chemically very stable in the absence of copper ions. All thirteen compounds combine the favoured property of chemical stability with a high level of biological activity. We found that copper(I)-chelation induced reduction of the biological activity of S- nitrosothiols in smooth muscle relaxation. The results show that responses to both SNAP and GSNO are reversibly inhibited by neocuproine. We conclude that relaxation of vasodilator smooth muscle by SNAP and GSNO is caused in part by NO released into solution via a Cu+-dependent catalytic reaction, and provide evidence that endogenous Cu+ ions may also contribute to the maintenance of vasodilator 'store' in vivo by catalysing the decomposition of naturally-occurring S-nitrosothiols. A particularly interesting finding recently by Gordge et al. (1995) shows that the inhibition of platelet aggregation activity shown by GSNO is much reduced in the presence of neocuproine and the closely related bathocuproine, both specific Cu+-chelating agent. However, it was shown very recently (Schrammel et al, 1996) that copper ions inhibit basal and NO-stimulated recombinant soluble guanylate cyclase activity and that Cu+ is more effective than Cu2+ in this regard. L-Ascorbic acid (vitamin C) could play a role in the in vivo release of NO from naturally occurring and exogenous S-nitrosothiols and so play a part in smooth muscle relaxation and in inhibition of platelet aggregation. All thirteen compounds examined show the ability to release NO in vitro. The inhibitory effect of Hb, a recognised NO scavenger, was investigated. In smooth muscle, responses to intermediate doses of S-nitrosothiols were significantly inhibited by Hb, though not abolished entirely. In platelet, we found that the inhibitory activity of these S-nitrosothiols was reversed by haemoglobin, indicating the involvement of NO in the process. We found that the solution stability of the S-nitrosothiols did not correlate with relaxation of vascular smooth muscle or inhibition of platelet aggregation, again suggesting that the tissue specificity is a function of the R- group. We conclude that the biological activity of S-nitrosothiols depends upon the release of NO in a process catalysed by Cu(I), and that the decomposition may occur inside or outside the cell, depending upon the structure of RSNO.

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by Kwok Chun-kiu. / Thesis (M.Ph.)--Chinese University of Hong Kong, 1987. / Bibliography: leaves 69-74.

Thesis (Ph. D.)--Drexel University, 2003. / Includes abstract and vita. Includes bibliographical references.