The human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) that subsequently develops remain major health concerns even after three decades since the first cases were reported. Successful therapeutic measures to address HIV/AIDS consist mostly of combinations of drugs targeting viral enzymes including reverse transcriptase (RT), protease (PR) and integrase (IN) as well as entry steps of the viral life cycle. The remarkable benefits (e.g. improved quality of life) derived from the use of these agents are unfortunately limited by toxicity to the host and the development of drug resistant viral strains. Drug resistance limits the repertoire of drug combinations available. Unfortunately, because latent forms of the virus exists, therapy has to be life-long and with new infections occurring every day, resistant strains tend to spread. To circumvent these problems, new drugs that inhibit resistant strains or work against new viral targets have to be developed. The history of gold compounds as potential inhibitors of HIV prompted this study in which twenty seven compounds consisting of gold(I), gold(III) and precursors from five classes were tested for drug-likeness, anti-HIV and immunomodulatory effects using wet lab and in silico methodologies. Cytotoxicity determination was done using viability dyes and flow cytometry. Cell proliferation profiles were monitored using the carboxyflourescein succinimidyl ester dye dilution technology and a real time cell analyser for confirming viability dye findings. The compounds’ effects on viral enzymes was determined using direct enzyme assays and in silico molecular modelling techniques. H and P nuclear magnetic resonance spectroscopy studies for determining stability revealed that the backbone chemical shifts of the compounds were relatively unchanged after one week (-20 and 37 ºC) when dissolved in dimethylsulfoxide. Eight of the gold compounds had drug-like properties comparable to clinically available drugs when in silico predictions were performed. The 50% cytotoxic dose of the compounds in human cells was between 1 and 20 μM (clinically relevant concentrations for gold compounds). Three gold(I) compounds inhibited viral infectivity at non-toxic concentrations and two gold(III) compounds did so at cytostatic (anti-proliferative mechanism that is also antiviral) concentrations. In the immunomodulatory assay, cytokine levels were altered by five compounds with one gold(I) and a gold(III) compound significantly reducing the frequency of CD4+ cells (an anti-viral function) from HIV+ donors (p= 0.005 and 0.027 respectively) when multi-parametric flow cytometry was performed. Inhibition of RT activity was predicted in in silico studies to be through interactions with the ribonuclease (RNase) H site although with poor stereochemical orientation while favourable binding predictions with the IN cofactor binding site were observed for some gold(III) complexes. Compounds predicted to interact with the RNase H site of RT and the IN cofactor site require structural modification to improve drug-likeness and binding affinity. The drug-like compound(s) which inhibited viral infectivity and lowered CD4+ cell frequency have potential for incorporation into virostatic cocktails (combination of cytostatic and directly anti-viral agent). Cytostatic agents are known to be less prone to drug resistance and because they lower CD4+ cell frequency, such compounds can potentially limit HIV immune activation. / Thesis (PhD)--University of Pretoria, 2011. / Biochemistry / unrestricted

Thesis (PhD (Chemistry and Polymer Science))--Stellenbosch University, 2008. / Novel gold(I) trithiophosphite complexes were synthesised by utilising the ligands P(SR)3 (R = Me, Ph) and 1,2-bis(1,3,2-dithiaphospholan-2-ylthio)ethane (2L). Reaction with (tht)AuCl or (tht)AuC6F5 readily yielded the corresponding complexes (RS)3PAuX and 2L(AuX)2 (X = Cl, C6F5) as well as {Au[P(SMe)3]2}CF3SO3. Structural characterisation by X-ray diffraction revealed linear complexes in part associating by Au…Au and/or Au…S contacts, two polymorphs of one compound associating by either Au…S interactions or p-stacking was also obtained. (MeS)3PAuCl and (MeO)3PAuCl were found to be isostructural in the solid state. The complex chloro[tris(4-methylthiazol-2-yl)phosphane]gold, A, was used to probe the electronic influence tris(azol-2-yl)phosphanes exert upon gold(I) by substituting the chloride with various thiolates. In contrast to Ph3PAuCl, only NCS– and PhC(O)S– afforded stable compounds which could be attributed to a weaker donating capability of the tris- (azolyl)phosphane ligand class. The compounds A and chloro[tris(thiazol-2-yl)phosphane]- gold, B, were shown to crystallise in 4 new polymorphs and solvates bringing the total to an exceptional seven. Among the solid-state structures of A the rare instance of a polymorph and a thf solvate not exhibiting aurophilic interactions as opposed to the original structure were observed. Complex B was shown to crystallise in polymorphs where dimers are associated either by Au…Au or Au…Cl interactions but otherwise exhibit similar arrangements of the ligand, this set of polymorphs is unprecedented amongst gold complexes. An NMR experiment proved that tris(thiazolyl)phosphane complexes are subject to hydrolysis under alkaline conditions. A trimeric gold(I) heterometallacycle, obtained by reacting (tht)AuCl with 4,4-dimethyl-2-(2- thienyl)oxazoline deprotonated at C-5 of the thiophene ring, was structurally characterised. Intramolecular Au…S interactions were found to be present which precluded interaction of the gold atoms with other metal centres such as Me3CNCAuCl or AgNO3. A second solvate obtained additionally exhibits Au…Au interactions. The scope of uncommon bis-imine coordination to AuI was expanded by utilising 1,2-bis(1-imidazolylmethyl)-2,4,6-trimethylbenzene (2L) to synthesise the [Au2(μ-2L)2]2+ cation. The triflate salt forms the first porous crystal structure of gold and the co-crystallised solvent could be partially removed by evacuation at elevated temperatures. Utilising a ditopic phosphite ligand instead of the commonly used ditopic phosphane ligands, a new cationic species of the type [Au2(μ-2L)3]2+ was characterised in the solid state for the first time. Finally, employing 2-phenylthiazole and 1-(thiazol-2-yl)piperidine which can be deprotonated at C-5 of the thiazole ring, Fischer-type pentacarbonyltungsten carbeniate complexes were prepared and structurally characterised. Starting from these complexes, the analogous Fischertype methoxycarbene as well as carbyne complexes could be obtained by alkylation and formal oxide abstraction, respectively. The latter products readily formed dinuclear adducts with AuCl. A Fischer-type methoxycarbene could be transferred to AuI affording the first such gold(I) complex exhibiting Au…Au interactions in the solid state as well as a rare agostic Au…H interaction which was examined by low-temperature 1H NMR measurements. Transfer of the carbeniate ligand derived from 1-(thiazol-2-yl)piperidine to Ph3PAu+ afforded an aurated thiazole product (by an unprecedented loss of CO) which may be represented as a pseudoabnormal azolylidene complex owing to W(CO)5-coordination at a distant nitrogen. The carbeniate originating from 2-phenylthiazole, on the other hand, afforded, by rare W(CO)5- trapping and without CO-loss, a pseudo Fischer-type carbene complex. Carbene transfer to gold was complemented by the first transfers of rNHC ligands from chromium and tungsten to gold(I) affording a novel class of complexes, all of which were structurally characterised. This work bridges the unnatural divide created between Fischer and N-heterocyclic carbene complexes.

Ruthenium-based homogenous catalysis is a broad and extremely useful branch of transition metal catalysis. Surely, the most famous example is olefin metathesis, for which Yves Chauvin, Robert Grubbs and Richard Schrock were awarded the 2005 Chemistry Nobel Prize. Although some of the most well-known catalysts are widely used and considered benchmark catalysts, the research around this topic has not stopped. The modification of known systems to achieve better performance and better understanding of the catalytic mechanism is very important and an example of such modification is reported in this thesis. The newly synthesised catalysts were compared to the parent commercially available catalyst showing better reactivity. Ruthenium catalysis, though, is not limited to olefin metathesis and C-H activation, for example, it has become a useful approach to the functionalisation of organic molecules. In this field, the deuteration of C-H bonds is an interesting transformation, which has many applications. The synthesis of new hydridosilylruthenium complexes and their application in the deuteration of a variety of substrates is reported in this manuscript. The unprecedented synthesis of tetradeuterated Ketoprofene is also reported. Recently, ruthenium-based catalysts have found application in the dehydrogenation of suitable compounds, such as formic acid, ammonia-borane and other hydrogen-rich substances. The driving force behind these discoveries is the use of H2 as an energy vector in place of fossil fuels. A hydrido-ruthenium catalyst was shown to catalyse the decomposition of formic acid in CO2 and H2 and to catalyse the reduction of olefinic substrates. The released CO2 from the reaction did not interfere with the fuel cell due to its inertness. This property makes its employment as C1 source very challenging, although its use would also be extremely attractive because of the abundance of this gas. In these regards, both frustrated Lewis pairs (FLPs) and gold catalysts have shown interesting reactivity in the activation of CO2. A new FLP and a silica supported gold catalyst were synthesised to test them in CO2 activation and the results are reported in this manuscript.

Ph.D. / Ligands bis(pyrazolyl)acetic acid (L1) and bis(3,5-dimethylpyrazolyl)acetic acid (L2) were synthesised by reacting pyrazoles and dibromoacetic acid under phase transfer conditions, by using benzyltriethylammonium chloride as the catalyst. Ligands L1 and L2 were characterised by a combination of 1H, 13C{1H} NMR, IR spectroscopy and microanalysis. Esterification of L1 and L2 led to formation of bis(pyrazolyl)ethyl acetate (L3) and bis(3,5-dimethylpyrazolyl)ethyl acetate (L4). Ligands L3 and L4 were also characterised by a combination of 1H, 13C{1H} NMR, IR spectroscopy and microanalysis. Subsequently, new pyrazolyl palladium(II) and platinum(II) compounds, [PdCl2(L1)] (1), [PdCl2(L2)] (2), [PtCl2(L1)] (3a) and [PtCl2(L2)] (4) were prepared by reacting bis(pyrazolyl)acetic acid ligands (L1-L2) with K2[PdCl4] or K2[PtCl4] respectively. The structures of complex 1 and 2 reveal distorted square planar geometries. The bond angles of N-Pd-N, N-Pd-Cl, N-Pd-Cl, for 1 and 2 are between 85.8(3)o and 90.81(4)o). The platinum compound, K2[Pt4Cl8(L1)2(deprotonated-L1)2].2H2O (3b), crystallised from aqueous solutions containing 3a when such solutions were left to stand overnight. Each platinum coordination environment consists of two cis-Cl ligands and one K2-N^N(L1) unit (L1 = bis(pyrazolyl)acetic acid), with two ligand moieties in 3b that are deprotonated with two K+ counter ions. Reaction of bis(pyrazolyl)acetic acid ligands (L1-L2) with [HAuCl4].4H2O gave gold(III) complexes [AuCl2(L1)]Cl (5a) and [AuCl2(L2)]Cl (6a). The spectroscopic, mass spectroscopy and microanalysis data were used to confirm the formation of the desired complexes. However, attempts to crystallise 5a and 6a led to formation of [AuCl2(pz)(pzH)] (5b) and [AuCl2(3,5-Me2pz)(3,5-Me2pzH)] (6b). This was confirmed by the structural characterisation of 5b, which has a distorted square-planar geometry. When complexes 1-6a were screened for their anti-tumour activity against CHO-22 cells, they showed no appreciable biological activities against CHO-22 cells. Substitution reactions of complexes 1-6a with L-cysteine performed to probe any relationship between the observed antitumour activities and the rates of ligand substitution of these complexes were inconclusive. Dithiocarbamate ligands L5-L8 were synthesised as potassium salts by introducing a CS2 group in positions 1 of pyrazole, 3,5-dimethylpyrazole, indazole and imidazole. The reaction of L5-L8 with [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)] and [Au2Cl2(dpph)], led to isolation of complexes [Au(L)(PPh3)] (13-16), [Au2(L)2(dppe)] (17a-19), [Au2(L)2(dppp)] (20-22) and [Au2(L)2(dpph)] (23-25) (dppe = bis(diphenylphosphino)ethane, dppp = bis(diphenylphosphino)propane, dpph = bis(diphenylphosphino)hexane; L = anions of L5-L8). The mononuclear molecular structure of 15 features a near linear geometry with a P(1)-Au(1)-S(1) angle of 175.36(2) o. The binuclear gold(I) complexes 20-22 and 23-25 have two P-Au-S moieties as evident in the solid state structure of 25. Attempts to crystallise complex 17a led to the formation of a gold(I) cluster complex [Au18S8(dppe)6]2+ (17b) as confirmed by X-ray crystallography. Cluster 17b features weak Au···Au interactions (2.9263(7)-3.1395(7) Å). Complexes 13-16 and 20-25 were tested in vitro for anticancer activity on HeLa cells. The activities of gold(I) complexes 13-16 were comparable to that of cisplatin. Dinuclear gold(I) complexes 20-25 also showed appreciable antitumour activity against HeLa cells. However, the dpph gold(I) compounds (23-25) were highly active, with 24 showing the highest activity against HeLa cells (IC50 = 0.1 μM). The tumour specificity (TS) factors for 23 and 24 were 31.0 and 70.5, respectively.

Balb/c normal mice were used to study the effects of gold sodium thiomalate (GST) on intact, nonadherent, and adherent mononuclear spleen cells. The three populations were tested for the following aspects: in vitro effects of GST on the mitogen-triggered DNA synthesis; intracellular levels of cyclic AMP; and chemotaxis ability. These studies showed that GST inhibited the proliferative responses of all three populations as the concentration of GST increased. Cyclic AMP levels in the nonadherent population increased as the GST concentration increased. GST had a biphasic effect on the adherent population. At concentrations of 5 and 10 jag/ml, GST suppressed the cyclic AMP levels, and at concentration of 50 pg/ml it enhanced the cyclic AMP levels. GST had no effect on the cyclic AMP levels in the intact mononuclear spleen cells. GST appeared to have an inhibitory effect on the chemotaxis ability of all three populations of spleen cells.

Recently, the Parkin group has synthesized tris[(1-isopropylbenzimidazol-2-yl)dimethylsilyl]methane, [Tismᴾʳⁱᴮᵉⁿᶻ]H, a bulky tetradentate tripodal ligand, which upon deprotonation can coordinate to metal centers via three nitrogen donor atoms and a carbon bridgehead to form metal atrane compounds. The [Tismᴾʳⁱᴮᵉⁿᶻ] ligand has been previously shown to stabilize metal hydride complexes, for example [Tismᴾʳⁱᴮᵉⁿᶻ]MgH [Tismᴾʳⁱᴮᵉⁿᶻ]ZnH. However, no attempts had been previously made to employ this ligand to stabilize heavier Group 12 analogues of these complexes, namely the cadmium and mercury hydride derivatives. In addition, all [Tismᴾʳⁱᴮᵉⁿᶻ] complexes previously reported have employed metals in the first or second oxidation states. In this work, an investigation is undertaken to use the [Tismᴾʳⁱᴮᵉⁿᶻ] ligand to stabilize rare examples of cadmium and mercury hydrides, as well as survey how this ligand binds to Group 13 and transition metals in a variety of oxidation states. In Chapter 1, a series of [Tismᴾʳⁱᴮᵉⁿᶻ] cadmium complexes are reported, including the novel cadmium hydride species [Tismᴾʳᴮᵉⁿᶻ]CdH, which is only the third terminal cadmium hydride species to be structurally characterized by X-ray diffraction. The reactivity of this complex has been probed, revealing the first detailed report of reactivity for a Cd-H bond, as well as the first comparison in relative reactivity between an analogous Cd-H and Zn-H bond. This reactivity of [Tismᴾʳⁱᴮᵉⁿᶻ]CdH includes the ability to insert CO₂ and CS₂, and the resulting cadmium formate and dithioformate complexes have been characterized and discussed, with the latter being the first structurally characterized example of a cadmium dithioformate complex. In addition, [Tismᴾʳⁱᴮᵉⁿᶻ]CdH can undergo hydride extraction to yield the ion pair {[Tismᴾʳⁱᴮᵉⁿᶻ]Cd}[HB(C6F5)₃], a rare example of trigonal monopyramidal cadmium complex. Finally, [Tismᴾʳⁱᴮᵉⁿᶻ]CdMe was synthesized, revealing a different coordination mode of the [Tismᴾʳⁱᴮᵉⁿᶻ] ligand than in the analogous [Tismᴾʳⁱᴮᵉⁿᶻ]ZnMe. In Chapter 2, a series of [Tismᴾʳⁱᴮᵉⁿᶻ] mercury complexes are reported and compared with their cadmium analogues. This comparison revealed several notable differences between [Tismᴾʳⁱᴮᵉⁿᶻ] mercury and cadmium complexes, most notably that the M-O-Si bond angle in [Tismᴾʳⁱᴮᵉⁿᶻ]HgOSiPh₃ is bent, as opposed to the linear [Tismᴾʳⁱᴮᵉⁿᶻ]CdOPh₃ derivative. The synthesis and characterization of [Tismᴾʳⁱᴮᵉⁿᶻ]HgH, the first mercury hydride complex to be structurally characterized by X-ray diffraction, is also reported. This complex has been crystallized in both the κ⁴ and κ³-coordination mode of the [Tismᴾʳⁱᴮᵉⁿᶻ] ligand, representing the first example of a [Tismᴾʳⁱᴮᵉⁿᶻ] compound to be structurally characterized in two coordination modes. In Chapter 3, the synthesis of Group 13 and transition metal [Tismᴾʳⁱᴮᵉⁿᶻ] complexes are reported. These compounds include the first examples of [Tismᴾʳⁱᴮᵉⁿᶻ]M(III) complexes, which reveal that trivalent Group 13 [Tismᴾʳⁱᴮᵉⁿᶻ]M halide compounds form charged ion pairs, whereas trivalent transition metal chloride compounds form six-coordinate octahedral complexes. The investigation into Group 13 [Tismᴾʳᴮᵉⁿᶻ] complexes also led to the structural characterization of [Tismᴾʳⁱᴮᵉⁿᶻ]In→InI₃, the first example of a [Tismᴾʳⁱᴮᵉⁿᶻ] compound with a metal-metal bond. A series of [Tismᴾʳⁱᴮᵉⁿᶻ]MCl (M = Mn, Fe, Co, Cu) complexes are reported and their metrical data compared, along with an investigation into the reactivity of [Tismᴾʳⁱᴮᵉⁿᶻ]NiBr, which led to spectroscopic evidence for a [Tismᴾʳⁱᴮᵉⁿᶻ]NiH complex. Finally, the gold complex [κ1-Tismᴾʳⁱᴮᵉⁿᶻ]AuPPh₃ is reported, which adopts a novel κ1-coordination of the [Tismᴾʳⁱᴮᵉⁿᶻ] ligand.

Bibliography: leaves 211-260 / xvii, 260 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 1986

Reactive oxygen species (ROS) such as superoxide radical anion (O2•¯), hydroxylradical (OH•), hydrogen peroxide (H2O2) and peroxynitrite (ONOO-) that are produced during the metabolism of oxygen under oxidative stress in aerobic organisms destroy several key biomolecules and lead to a number of disease states. Mammalian systems possess several effective defense mechanisms including antioxidant enzymes to detoxify these ROS. The selenocysteine-containing Glutathione peroxidase (GPx) is particularly an efficient enzyme in the detoxification of H2O2 and other hydroperoxides by using glutathione (GSH) as cofactor. The chemistry at the active siteof GPx has been extensively investigated with the help of synthetic selenium compounds. Although the anti-inflammatory compound ebselen(2-phenyl-1,2-benzoisoselenazol-3(2H)-one) is undergoing phase III clinical trial as antioxidant, the chemistry of ebselen is still not understood. The present study on a number of ebselen derivatives with various N-substitutions reveals that the substitution at the N atom is important for the antioxidant activity. This study also suggests that the nature for thiol cofactor has a dramatic effect on the GPx activity of ebselen derivatives. It has been shown that ebselen exhibits very poor catalytic activity in the presence of aromatic thiols mainly due to strong Se….O nonbonded interactions that lead to extensive thiol exchange reactions in the selenenyl sulfide intermediate. To prevent the se….O interactions, a series of tertiary amide-based diselenides have been synthesized along with their secondary amide counterparts. Detailed structure-activity correlation studies reveal that the GPx-like activity of the sec-amide-based compounds can be significantly enhanced by the substitution at the free-NH group of sec-amide functionality. The N,N-dialkylbenzylamine-based diselenides exhibit their catalytic activities via the generation of selenols which was confirmed by the reaction with anti-arthritic gold(I) compounds. Interestingly, the replacement of the hydrogen atom at the 6th position of the benzene ring of N,N-dialkylbenzylamine-based diselenides by a methoxy group prevents the thiol exchange reactions mainly be weakening the Se…N interactions and thus enhances the GPx activity. On the other hand, the catalytic activity of the tert-amine-based diselenides can also be increased by replacing the tert-amino groups with the corresponding sec-amine moieties. It has been observed that the basic amino group in the amine-based diselenides deprotonates the selenol and also the thiol cofactor, which is crucial for the higher catalytic activities of the amine-based compounds. Peroxynitrite (PN, ONOO), a strong nitrating agent, is known to inactivate a number of proteins, enzymes and other biomolecules by nitration of tyrosine residues. In this study, we have shown that the commonly used antithyroid drugs and their analogues inhibit protein tyrosine nitration. This study reveals that antithyroid agents having PN scavenging activity may be beneficial of hyperthyroidism as these compounds may protect the thyroid gland from nitrative or nitrosative stress.