M.Sc. (Chemistry) / Please refer to full text to view abstract

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Gold(I)phosphines, nucleoside analogues, and azole derivatives have been identified as promising anticancer compounds. The clinical use of these individual compounds is, however, limited due to non-selectivity associated with adverse effects and developed resistance. This study investigated seven novel gold compounds that contain either a nucleoside analogue or an azole, bound via a gold nitrogen bond, which have been designed and synthesized by Dr. Horvath under the supervision of Prof. Raubenheimer from the University of Stellenbosch. The novel compounds are divided into purinecontaining/ nucleoside analogue compounds (UH 86.2, UH 75.1, UH 58.1, UH 145.1) and azole-containing compounds (UH 107.1, UH 126.1, UH 127.1). The anticancer effects of these novel compounds were compared with that of previously described anticancer compounds [Au(dppe)2]Cl and cisplatin. The octanol/water partition coefficients (PC) of the compounds were measured in order to determine whether a correlation between the lipophilicity of the structures and the cytotoxic potency and selectivity exists. This might provide further insight for structural alterations of the compounds in order to improve their anticancer activity. The results from octanol/water PC determinations, revealed that the purine-containing compounds (UH 86.2, UH 75.1, UH 58.1, and UH 145.1), as well as the azole-containing compound, UH 127.1, exhibited hydrophilic properties, while the azole-containing compounds, UH 107.1 and UH 126.1 are lipophilic. In contrast to results by Berners-Price et al. (1999), that reported a direct proportionality between lipophilicity and cytotoxicity, for the current study, involving HeLa cells, CoLo cells, normal resting and PHA stimulated lymphocytes, no correlation was observed. For the Jurkat cell line, however, an increase in lipophilicity for the series of compounds studied was accompanied by an increase in cytotoxicity. The reason for the exception is not yet fully understood. The in vitro tumour specificity of each compound was established with cytotoxicity assays on various cancer cell lines and normal cell cultures. The cancer cell lines included human cervical cancer (HeLa) cells, human colon cancer (CoLo) cells, and human lymphocytic leukaemia (Jurkat) cells. The normal cell cultures included human resting lymphocytes and human phytohemaglutin (PHA) stimulated lymphocytes. From this data, the four most promising novel compounds were identified. Additional tests were performed by adding these four compounds to cancer cells including human breast cancer (MCF-7) cells, and cisplatin sensitive and resistant human ovarian cancer (A2780 and A2780cis) cells as well as normal chicken embryo fibroblasts. The tumour specificity of each compound was determined from the results obtained via the cytotoxicity assays. The compound is more selective the higher the tumour specificity. Cisplatin exhibited the highest tumour specificity, and [Au(dppe)2]Cl, the lowest. The two most promising novelcompounds were identified as UH 126.1 and UH 127.1, which was evidenced by their high tumour specificities. Further experiments were conducted with these two azolecontaining compounds by using Jurkat cells. The possible mechanism by which the novel compounds induce cytotoxicity was investigated with flow cytometric analysis. The effects of the compounds on the cell death pathway, the mitochondrial membrane potential and the cell cycle were determined. These results indicated that the novel compounds, UH 126.1 and UH 127.1 initiate the apoptotic cell death pathway rather than the necrotic cell death pathway. According to results, UH 126.1 and UH 127.1 influenced the status of the mitochondrial membrane potential (MMP) non-selectively and only at high concentrations. Although involvement of mitochondria in the mechanism of action cannot be excluded, results indicated that it is most likely not the primary target. After investigating the effects of the two novel azole-containing compounds on the cell cycle in Jurkat cells, it was detected that these compounds induce cell accumulation in the G1 phase of the cell cycle. It was concluded that UH 126.1 and UH 127.1 might interfere with the cell cycle indirectly, possibly by inhibition of cyclin-dependent kinases and/or other enzymes necessary for DNA replication. In an acute in vivo toxicity test during this study, results revealed drug induced adverse effects (such as significant weight loss, piloerection and diarrhoea), in the mice that received 3 and 6ìmol/kg of both UH 126.1 and UH 127.1. Evidence also revealed signs of nephrotoxicity and epatotoxicity. Due to minimal adverse effects observed in the groups that received UH 126.1 and UH 127.1 at the concentration of 1,5ìmol/kg, this is the suggested maximum tolerated dose (MTD) for these compounds. Further dose-range studies with UH 126.1 and UH 127.1 are, however, needed in order to evaluate clinicalefficacy. Copyright / Dissertation (MSc)--University of Pretoria, 2009. / Pharmacology / unrestricted

Various gold complexes were computationally investigated, to probe their photophysical, geometric, and bonding properties. The geometry of AuI complexes (ground state singlet) is very sensitive to the electronic nature of the ligands: σ-donors gave a two-coordinate, linear shape; however, σ-acceptors yielded a three-coordinate, trigonal planar geometry. Doublet AuIIL3 complexes distort to T-shape, and are thus ground state models of the corresponding triplet AuIL3. The disproportionation of AuIIL3 to AuIL3 and AuIIIL3 is endothermic for all ligands investigated, however, σ-donors are better experimental targets for AuII complexes. For dimeric AuI complexes, only one gold center in the optimized triplet exciton displays a Jahn-Teller distortion, and the Au---Au distance is reduced versus the ground state distance (i.e., two reasons for large Stokes' shifts).

Thesis (MSc (Chemistry and Polymer Science))--University of Stellenbosch, 2007. / A comprehensive, comparative structural study of gold(I), gold(II) and gold(III) compounds with the general formula [Aux(C6F5)y(tht)z] (tht = tetrahydrothiophene) was performed. The series of compounds included the unprecedented dinucleur gold(II) compound, tetrakis(pentafluorophenyl)bis(tetrahydrothiophene)digold(II), which could be prepared in a rational manner. This very unique compound represents the first example of an unbridged dinucleur gold(II) compound in which the gold(II) centres are not stabilised by chelating ligands. Formation of this compound was postulated to have taken place by radical pentafluorophenyl (pfp) ligand migration along with AuII–AuII bond formation. It may therefore be regarded as a rare example of labile behaviour by a generally inert pfp ligand. In addition to this compound, the crystal and molecular structures of the wellknown gold(I) and gold(III) precursor compounds, (pentafluorophenyl)(tetrahydrothiophene) gold(I) and tris(pentafluorophenyl)(tetrahydrothiophene)gold(III) were carried out and are described for the first time. The latter underwent a unique mononuclear ligand rearrangement (metathesis or disproportionation) reaction in solution to yield the novel rearrangement product, bis(pentafluorophenyl)bis(tetrahydrothiophene)gold(III)tetrakis- (pentafluorophenyl)gold(III). In all the complexes, the Au–C and Au–S bond lengths displayed a variation which appears to be dependent on the oxidation state of the central gold atom. Both of these bond types were found to descrease in the order Au(II) > Au(III) > Au(I)...

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Ph.D. / Chapter 1 presents a brief overview on the development of platinum, ruthenium and gold anti-cancer complexes. The clinical success of cisplatin has been a tremendous impetus for the design of metal-based antitumor drugs. Its mechanism of action is therefore briefly discussed, as well as the toxic side effects of its clinical use and the cellular resistance to the drug. It is its side effects and drug resistance that have stimulated the development of cisplatin analogues and other metal based anti-cancer agents. Compounds showing most promise are ruthenium complexes which are structurally different but have the same stability and show similar modes of binding to DNA. The last part of the introduction deals with the development of gold(I) and gold(III) complexes, the main topics of the research described in this thesis. Chapter 2 reports on the attempted preparation of dppf and dippf gold(III) complexes. However, the reaction of these diphosphines with H[AuCl4] and Na[AuCl4] all led to isolation of gold(I) complexes (dppf)Au2X2 (X = Cl (1), Br (3)) and (dippf)Au2X2 (X = Cl (2), Br (4)). In an attempt to oxidize the gold(I) complexes, (dppf)Au2Br2 (3) and (dippf)Au2Br2 (4) were reacted with excess bromine yielding two new complexes (C5H4Br3)(PR2)AuBr (R = Ph, 5; R = i-Pr, 6). This bromination reaction could be extended to the ligands and bromination of the free diphosphinoferrocene ligands produced the expected brominated cyclopentenes (C5H4Br3)(PR2) (R = Ph, 7; R = i-Pr, 8) in good yields. However, these could not be complexed to gold due to reduced basicity of 7 and 8. When the bromination was performed under wet aerobic conditions the oxidized pseudo-centrosymmetric product, [doppf][FeBr4] (9) {doppf = 1,1’-bis(oxodiphenylphosphino)ferrocene, was obtained as the major product. Solid-state structures of 1, 2, 4, 6, and 9 were established by means of single-crystal X-ray crystallography. Chapter 3 reports on the use of chiral Josiphos and Walphos diphosphine ligands to form palladium, platinum and gold complexes. The platinum complexes were prepared by reacting the ligands with [PtCl2(cod)] while the palladium complexes were prepared from [PdCl2(NCMe)2]. The complexes obtained had the general formula [MCl2(P-P)], where M = Pd, Pt, and P-P = Josiphos or Walphos ligand, and were obtained in good yields. The X-ray structures of a palladium(II) and a platinum(II) complex of the same Josiphos ligand were determined. The Josiphos complexes 12 and 14 show good solubility in common solvents. Furthermore, the complexes remained soluble and stable in a 40:60 water:DMSO mixture. The Walphos complexes 13 and 15 rapidly precipitated under the same conditions. In line with this limited solubility 13 and 15 showed minimal cytotoxic effects when compared to their Josiphos counterparts 12 and 14 whose cytotoxic effects (in terms of IC50 values ) were six to seven times less than cisplatin. Reaction of the Walphos ligand and H[AuCl4] in a 1:1 ratio gave a dinuclear gold(I) complex 18 while the same reaction with Josiphos gave a mixture of intractable materials. However a 1:1 reaction of the Josiphos with AuCl(tht) gave a mononuclear three-coordinate gold(I) complex 16. A P^N chiral ligand comprising of a diphenylphosphine and a pyrazole moiety was also prepared and was complexed with AuCl(tht) to give a phosphine bound gold(I) complex 19. The structure of this complex was determined by X-ray studies. From the studies it became evident that apart from increasing the basicity of compound the pyrazolyl moiety remains dangling and the complex shows bond parameters similar to those observed with monophosphine ferrocenyl complexes. Chapter 4 reports on the bidentate and monodentate gold(III) complexes based on the (pyrazolylmethyl)pyridine ligands together with their platinum(II) complexes. The denticity of the complexes depended on the position of the pyrazolyl moiety relative to the pyridine nitrogen. When ortho-substituted ligands were reacted in a 1:1 ratio with H[AuCl4] in a mixture of water and ethanol at room temperature, bidentate cationic complexes of the general formula [AuCl2(PyCH2R2pz)][X], where R = Me (20), X = AuCl4-; R = Ph (21), X = Cl-; t-Bu (22), X= Cl- and p-tol (23), X = AuCl4-, were obtained. When para-substituted ligands were used under same reaction conditions, neutral monodentate complexes [AuCl3(PyCH2R2pz)], where R = Me (24) and R = Ph (25), were obtained. Platinum(II) complexes were obtained using K2[PtCl4] in a mixture of water and ethanol under reflux, and affords neutral complexes of the type [PtCl2(PyCH2R2pz)], where R = Me (27), Ph (28), t-Bu (29) and p-tol (30). When acetone was used instead of ethanol monoacetonylplatinum(II) complex (29a) was formed and on prolonged heating formation of the diacetonyl complex (28b) was observed. Both the platinum and the gold complexes were evaluated for their anti-cancer potency. The gold(III) complexes were devoid of any activity while the platinum complex 30 showed activity 8 times lower than cisplatin. The structures of 23, 25, 28, 29 and 29a were determined from single-crystal X-ray diffraction studies. In Chapter 5, tridentate complexes based on bis(pyrazolylethyl)amine are reported. These were prepared with the aim of improving water-solubility and cytotoxicity of the resulting complexes. New synthetic methods for preparation of the ligands NH(CH2CH2pz)2 (R = Me (L7), H (L8), t-Bu (L9)) under mild reaction conditions were developed albeit the yields obtained were generally low. The reaction of these ligands with H[AuCl4] gave corresponding tridentate dicationic gold(III) complexes [NH(CH2CH2pz)2][X]2 (R = Me (31), H (32), X = AuCl4 , and R = t-Bu (33), X = Cl-). Despite the ligands stabilizing the gold(III) ion, they showed no solubility in water. In an attempt to make the ligand system water soluble, a thiocarbamate analogue with pyrazolyl groups replaced by hydroxyl groups was prepared. However the resulting gold(III) complex [Au{CS2N(CH2CH2OH)2}2][AuCl2] (34) was found to be only soluble in DMSO.