published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2005.

The thesis is divided into three parts. The first part looks at the reactivity difference between [Pt(terpy)(OH2)f+ and [Pt(bpma)(OH2)]2+ where terpy is 2,2' :6',2"-terpyridine and bpma is bis(2-pyridylmethyl)amine, towards thiols namely, L-cysteine, DLpenicillamine and glutathione. This is followed by a comparative study of [Pt(bpma)(OH2)]2+ and [pd(bpma)(OH2)f+. Finally the reactivity differences between [Ru(terpy)(bipy)(OH2)f+ and [Ru(terpy)(tmenXOH2)]2+ are reported. Included are the synthesis and characterization ofthe complexes. The substitution behaviour of [pt(terpy)(OH2)]2+and [Pt(bpma)(OH2)f+ was studied as a function of entering thiol concentration and temperature. The reactions between the Ptcomplexes and DL-penicillamine, L-cysteine and glutathione were carried out in a 0.10 mol dm03 aqueous perchloric acid medium using stopped-flow or conventional UV-Vis spectrophotometry as required. The observed pseudo-first-order rate constants for the substitution reactions are given by kobs = k2[thiol] + k 2. The k 2 term represents the reverse solvolysis reaction. This term was found to be zero for Ptn(terpy) which was the most reactive complex. The second-order rate constants, ka; for the three thiols varied between 0.107±0.001 M·l S·l and 0.517±0.025 M"l sol for PtlI(bpma) and 10.7±0.7 M"l S·l to 711.9±18.3 M"l S·l for PtlI(terpy), with glutathione being the strongest nucleophile. Analysis of the activation parameters, Mf' and .1.S", clearly shows that the substitution process is associative in nature. The second study has looked at the substitution of the coordinated water molecule from [Pt(bpma)(OH2)f+ and [pd(bpma)(OH2)f+ by a series of nucleophiles [Nu] viz. TU, DMTU, TMTU and as well as Be", Cl', SCN", and r for the Ptn(bpma) complex. The investigation was conducted under pseudo-first-order conditions as a function of concentration of [Nu] as well as temperature for PtlI(bpma) complex using stopped flow spectrophotometry. Reactions involving PdII(bpma) were done at 10°C. The observed pseudo-first-order rate constants obeyed the equation kobs= k2[Nu]. The second-order rate constants, kz, at 10 "C for the sulfur donor nucleophiles have been found to vary between 70.35 M I sol and 223.06 M I sol for PtII(bpma) and (1.24 ± 0.01) x 105 M I sol to (2.17 ± 0.02) x 105 M-Is-l for PdII(terpy), with DMTV being the strongest nucleophile. The second-order rate constant, ka; at 25 "C fur PtII(terpy) was found to increase in the following order cr < Be" < TMfU < SCN < TV < DMTV < f. This order is in agreement with the polarizability of the nucleophiles, the nucleophilic discrimination factor being 0.38. The temperature studies for PtII(bpma) suggest that the substitution process is associative in nature.n The third part looked at the reactivities of [Ru(terpy)(bipy)(OHz)]z+ and [Ru(terpy)(tmen)(OHz)]z+ where bipy is 2,2'-bipyridine and tmen is N,N,N ',N 'tetramethylethylenediamine with three nucleophiles TV, DMTV and CH3CN. The pKa values for the complexes were found to be 9.99 and 10.27 for [Ru(terpy)(bipy)(OHz)]z+ and [Ru(terpy)(tmen)(OHz)f+, respectively. The substitution of water involving the two complexes was studied under pseudo-first order conditions using UV-Visible Spectrophotometry. The pseudo-first-order rate constant fitted the simple rate law kobs = kz [Nu] + k-z. The k.z term was found to be zero for [Ru(terpy)(bipy)(OHz)f+ but nonzero for [Ru(terpy)(tmen)(OHz)]z+. The values of the second order rate constants (kz) for the three nucleophiles were found to be between (1.08 ± 0.02) x 10-4 M l sol and (15.0 ± 0.27) x 10-4 M-l sol for [Ru(terpy)(bipy)(OHz)]z+ and (0.82 ± 0.04) x 10-4 M-l sol and (21.90 ± 0.69) x 10-4 M-I sol for [Ru(terpy)(tmen)(OHz)]z+. The results suggests that nback donation accounts for the difference in reactivity. / Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 2003.

A series of novel Bis 2,2':6',2″-terpyridinyl ligands, linked through a flexible alkyl chain situated at the 4' position, were synthesised and characterised by microanalysis, FTIR, NMR, UV-Visible spectroscopy, and MS-ToF. Single crystals of all the ligands were obtained, of which one has been published, one has been submitted for publication and one is in preparation for publication. These ligands were then coordinated to platinum(II) and characterised, including ¹⁹⁵Pt NMR spectroscopy. A detailed kinetic study involving the substituting the chloride co-ligand with the following nucleophiles thiourea, 1,3-dimethyl-thiourea and 1,1,3,3-tetramethyl-thiourea was conducted using stopped-flow techniques. An associative reaction mechanism was suggested for the pendant ligand substitution and the following trend in reactivity was observed: L2-Ptα > L3-Ptβ > L1-Ptχ. UV-Visible absorption spectra were recorded on sequentially diluted solutions of the ligands (in chloroform), and the platinum complexes (in water). These spectra obeyed the Beer-Lambert law. The values of the molar absorption coefficients at the wavelengths of maximum absorption for the ligands followed the trend L1 < L2 < L3, whilst for the complexes the trend was L1-Pt < L3-Pt < L2-Pt. It has been concluded that at low concentrations L2-Pt and L3-Pt undergo intramolecular folding. Variable temperature and variable concentration NMR spectroscopic studies were performed on all three complexes. At higher complex concentrations intermolecular self-association takes place for L2-Pt and L3-Pt but not for L1-Pt. The reactivity of the complexes is predominately determined by their structural conformations in solution. At low concentrations the L1-Pt complex remains in its linear conformational state, whilst the L2-Pt and L3-Pt complexes undergo intramolecular folding with the formation of an axial Pt—Pt bonded and π—π stacked dinuclear platinum terpyridine centre. The latter is believed to be more active in the substitution reaction than the original mononuclear centre. The reasons for the folding and self-association in the L2-Pt and L3-Pt systems are related to the steric crowding and stress in the spacer region of the folded or self-associated complexes. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2012.

Six novel platinum(II) intercalators of the form [Pt(AL)(IL)]Cl2, where AL = ethylenediamine (en), 1R,2R-diaminocyclohexane (R,R-dach), or 1S,2S-diaminocyclohexane (S,S-dach) and IL = 4,7-dihydroxy-1,10-phenanthroline (4,7-dhp) or 4,7-dicarboxy-1,10-phenanthroline (4,7-dcp), were synthesised. All complexes were prepared by the addition of the intercalating ligand followed by the addition of the diamine ancillary ligand. The complexes with 4,7-dhp were soluble in DMSO and were characterised by 1H, 13C, and 195Pt NMR, elemental analysis, UV-vis, ESI-MS, and CD. The complexes with 4,7-dcp were only soluble in a highly acidic solution and, therefore, were characterised only by 1H NMR and elemental analysis. The cytotoxicity of the 4,7-dhp complexes was tested in the L1210 murine leukaemia cell line. [Pt(S,S-dach)(4,7-dhp)]Cl2 showed an IC50 value of > 80 μM. The antitumour and antibacterial activities of all six complexes were tested in vitro using the Kirby-Bauer disc diffusion method with Staphylococcus aureus and Agrobacterium tumefaciens. The 4,7-dhp complexes showed no activity to these bacteria strains. The activities of the 4,7-dcp complexes were not able to be tested due to their solubility only in acidic solutions, which itself inhibits cell growth. The diffusion coefficients of the Pt(II) intercalators of the form [Pt(AL)(IL)]Cl2, where AL = en, R,R-dach, or S,S-dach and IL = phen, 4-mp, 4,7-dmp, 4,7-dhp, 4,7-dcp or 3,4,7,8-tmp and various starting materials used during the synthesis of these complexes were measured using pulsed gradient spin-echo (PGSE) NMR. The diffusion coefficients of both 4,7-dcp and [Pt(4,7-dcp)Cl2] were observed to be lower than other compounds with similar molecular weights indicating dimerisation of the compounds. The binding studies of the systems, [Pt(en)(phen)]Cl2 to (i) BSA, (ii) delipidated BSA, and (iii) d(GTCGAC)2 were studied using a simple two-site binding model with diffusion NMR. The binding of [Pt(en)(phen)]Cl2 – BSA was well described by the model giving the values Kd = 0.0021 ± 0.0002 M and n = 5.85 ± 0.31. On the contrary, the binding of [Pt(en)(phen)]Cl2 – delipidated BSA showed a poor fit to the model. From the poor fit of the data, it was speculated that the transverse relaxation of BSA largely affected the system. The binding of [Pt(en)(phen)]Cl2 – d(GTCGAC)2 showed results where the diffusion coefficient decreases as the concentration of the drug increases but an opposite effect was observed from the point where the drug reached equimolar concentrations to d(GTCGAC)2. It was speculated that the drug undergoes allosteric binding to the biomolecule or that a conformational change occurred as the drug concentration increases in the system. A further study of [Pt(en)(phen)]Cl2 and K2PtCl4 using 195Pt diffusion NMR was conducted giving a diffusion coefficient of 3.08 ± 0.04 × 10-10 m2 s-1 for K2PtCl4. The diffusion coefficient of [Pt(en)(phen)]Cl2, however, were unobtainable due to the short transverse relaxation of the Pt complex. / Master of Science (M.Sc.) (Hons)

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 148-156).