published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

The substitution kinetics of the complexes: [Pt(terpy)Cl]Cl?2H2O (PtL1), [Pt(tBu3terpy)Cl]ClO4 (PtL2), [Pt{4?-(2???-CH3-Ph)terpy}Cl]BF4 (PtL3), [Pt{4?-(2???-CF3-Ph)terpy}Cl]CF3SO4 (PtL4), [Pt{4?-(2???-CF3-Ph)-6-Ph-bipy}Cl] (PtL5) and [Pt{4?-(2???-CH3-Ph)-6-2??-pyrazinyl-2,2?-bipy}Cl]CF3SO3 (PtL6) with the nucleophiles: imidazole (Im), 1-methylimdazole (MIm), 1,2-dimethylimidazole (DIm), pyrazole (pyz) and 1,2,4-triazole (Trz) were investigated in a methanolic solution of constant ionic strength. Substitution of the chloride ligand from the metal complexes by the nucleophiles was investigated as a function of nucleophile concentration and temperature under pseudo first-order condition using UV/Visible and stopped-flow spectrophotometric techniques. The results obtained indicate that by either changing the substituents on the terpy backbone or by slight modification of the chelate itself leads to changes in the ?-acceptor ability of the chelate. This in turn controls the electrophilicity of the metal centre and hence its reactivity. In the case of PtL3 and PtL4, the ortho substituent on the phenyl ring at the 4?-position on the terpy backbone is either electron-donating or electron-withdrawing respectively. For an electron-donating group (CH3, PtL3) the reactivity of the metal centre is decreased whilst an electron-withdrawing group (CF3, PtL4) lead to a moderate increase in reactivity. Electron-donating groups attached directly to the terpy moiety (tBu3, PtL2) also leads to a decrease in the rate of chloride substitution. Placing a strong ?-donor cis to the leaving group (PtL5) greatly decreases the reactivity of a complex while the addition of a good ?-acceptor group (PtL6) significantly enhances the reactivity. The results obtained for PtL5 and PtL6 indicate that the group present in the cis position activates the metal centre in a different manner than when in the trans position. The experimental results obtained were supported by DFT calculations at the B3LYP/LACVP+** level of theory, with the NBO charges showing a less electrophilic Pt(II) centre when a strong ?-donor cis to the leaving group was present such as in PtL5 and a more electrophilic centre for complexes with good ?-acceptor groups such as with PtL6. Surprisingly, the results indicate that in the case of PtL5, when the metal centre was less electrophilic it also appears to be less selective. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.

Leung Chung Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 142-146). / Abstracts in English and Chinese. / ABSTRACT (ENGISH) --- p.iii / ABSTRACT (CHINESS) --- p.v / ACHKNOWLEDGEMENTS --- p.vii / TABLE OF CONTENTS --- p.viii / Chapter CHAPTER 1 --- Introduction and Background / Chapter 1.1 --- Introduction of Platinum Drugs --- p.1 / Chapter 1.2 --- Mechanism of Action of Cisplatin --- p.3 / Chapter 1.3 --- Structure-Activity Relationships of the Platinum Drug 、 --- p.4 / Chapter 1.4 --- QS AR Parameters --- p.9 / Chapter 1.4.1 --- Chemical Hardness: Descriptor of Chemical Reactivity --- p.9 / Chapter 1.4.2 --- Possible Reaction Pathway of Platinum Drugs --- p.12 / Chapter 1.4.2.1 --- Proposed DNA Binding Pathway of Platinum Drugs --- p.13 / Chapter 1.4.2.1.1 --- Hydrolysis Pathway --- p.13 / Chapter 1.4.2.1.2 --- DNA Binding Pathway Involving the S-containing Biomolecules (Methionine Pathways) --- p.16 / Chapter 1.4.2.1.3 --- Conclusion --- p.21 / Chapter 1.5 --- Thesis Scope --- p.22 / Chapter CHAPTER 2 --- Theory and Methodology / Chapter 2.1 --- Introduction --- p.24 / Chapter 2.2 --- Density Functional Theory (DFT) --- p.24 / Chapter 2.2.1 --- Kohn-Sham Theorem --- p.25 / Chapter 2.2.2 --- Exchange-Correlation Energy Functional --- p.27 / Chapter 2.3 --- Basis Set --- p.27 / Chapter 2.3.1 --- Relativistic Effective Core Potential --- p.27 / Chapter 2.3.2 --- Double-Zeta --- p.28 / Chapter 2.3.3 --- Polarized Basis Set --- p.29 / Chapter 2.4 --- Solvation Model --- p.30 / Chapter 2.4.1 --- Continuum Model --- p.30 / Chapter 2.4.1.1 --- Simple Solvation Model --- p.31 / Chapter 2.4.1.1.1 --- Electrostatic Component --- p.31 / Chapter 2.4.1.1.2 --- Dispersion-Repulsion Interaction --- p.33 / Chapter 2.4.1.1.3 --- Cavitatoin Energy --- p.35 / Chapter 2.4.1.2 --- Polarized Continuum Model --- p.36 / Chapter 2.5 --- Methodology --- p.39 / Chapter 2.5.1 --- Calculation of DFT Global Reactivity Index --- p.39 / Chapter 2.5.1.1 --- Calculation for the Reaction Intermediates --- p.41 / Chapter 2.5.2 --- Calculation of the Reaction Pathways --- p.42 / Chapter CHAPTER 3 --- Results and Discussion / Chapter 3.1 --- Introduction --- p.49 / Chapter 3.2 --- Optimized Structure against Experimental Geometry --- p.49 / Chapter 3.3 --- Kohn-Sham Orbitals --- p.54 / Chapter 3.3.1 --- Location of the HOMO and LUMO --- p.55 / Chapter 3.4 --- Results of the DFT Reactivity Parameter --- p.57 / Chapter 3.5 --- Chemical Structure of the Drugs in the QSAR --- p.64 / Chapter 3.6 --- QSAR Analysis --- p.67 / Chapter 3.6.1 --- The Overall QSAR Plot of the Platinum Drugs --- p.68 / Chapter 3.6.1.1 --- Empirical Applicability of the QSAR on the Platinum(IV) Drugs --- p.70 / Chapter 3.6.1.2 --- Detail QASR Study According to the Type of Platinum Drug --- p.71 / Chapter 3.6.1.2.1 --- QSAR Study of the non-“trans-DACH´ح Platinum Drugs --- p.72 / Chapter 3.6.1.2.1.1 --- "QSAR Equation of the non-""trαns-DACH"" Platinum Drugs" --- p.75 / Chapter 3.6.1.2.2 --- QSAR Analysis for the Pt-trαns-DACH Drugs --- p.77 / Chapter 3.6.1.2.2.1 --- "QSAR Study of trans-S,S-DACH Platinum Drugs" --- p.79 / Chapter 3.6.1.2.2.2 --- "QSAR Study of trans-R,R-DACH Platinum Drugs" --- p.80 / Chapter 3.6.1.3 --- Summary --- p.81 / Chapter 3.7 --- QSAR Study of the Important Intermediates Using Chemical Hardness --- p.82 / Chapter 3.7.1 --- Optimized Structure for the Intermediates --- p.84 / Chapter 3.7.2 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Parent Compounds --- p.90 / Chapter 3.7.3 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Hydrolysis Intermediates --- p.91 / Chapter 3.7.4 --- QSAR of the Dichloride Pt-Drugs Using Chemical Hardness of Cyclic-Methionine Intermediates --- p.93 / Chapter 3.7.5 --- Conclusion --- p.95 / Chapter CHAPTER 4 --- Results and Discussion / Chapter 4.1 --- Introduction --- p.96 / Chapter 4.2 --- Study Scheme --- p.97 / Chapter 4.3 --- Optimized Structures --- p.98 / Chapter 4.4 --- Comments on the Reliability of the Calculation Model --- p.103 / Chapter 4.4.1 --- Reaction Profile in the Gas Phase --- p.104 / Chapter 4.4.2 --- Reaction Profiles Using Simple Solvation Model --- p.105 / Chapter 4.4.2.1 --- Defects of the Simple Solvation Model --- p.107 / Chapter 4.4.3 --- Reaction Profile Using PCM-UAHF Solvation Model --- p.109 / Chapter 4.4.3.1 --- Selection of the Reaction Parameters for the QSAR Study --- p.112 / Chapter 4.5 --- QSAR Study of Platinum Drugs Using the Reaction Parameters (AG and ΔG+) --- p.121 / Chapter 4.5.1 --- QSAR Analysis Using ΔG+(hydrolysis) --- p.121 / Chapter 4.5.2 --- QSAR Analysis Using ΔG(hydrolysis) --- p.123 / Chapter 4.5.3 --- QSAR Analysis Using ΔG+(guanine) --- p.125 / Chapter 4.5.4 --- QSAR Analysis Using ΔG(guanine) --- p.127 / Chapter 4.5.5 --- Further investigation of the Bidentate Pt-drugs DNA Binding --- p.129 / Chapter 4.5.5.1 --- Calculation Model --- p.129 / Chapter 4.5.5.2 --- Bidentate Pt-Drugs Reactions --- p.130 / Chapter 4.5.5.3 --- Selection of the Calculated Model for the QSAR Study --- p.133 / Chapter 4.5.5.4 --- QSAR Analysis Using ΔG+(guanine) for the Platinum Drugs with Bidentate Caboxylate Ligands --- p.136 / Chapter 4.5.5.5 --- QSAR Analysis Using ΔG(guanine) for the Platinum Drugs with Bidentate Carboxylate Ligands --- p.137 / Chapter 4.5.6 --- Conclusion --- p.138 / Chapter CHAPTER 5 --- Conclusion Remarks and Future Works / Chapter 5.1 --- Conclusion --- p.140 / Chapter 5.2 --- Future Works --- p.141 / REFERENCES --- p.142

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 296-314). Also available in print.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 296-314). Also available online.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 258-281). Also available in print.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Platinum-based anticancer drugs such as cisplatin, carboplatin and nedaplatin have been widely used in the chemotherapy of a variety of solid tumours for several decades. However, the development of both inherent and acquired resistance has greatly limited the efficacy of all of these drugs. Several mechanisms were proposed to explain the cellular resistance to these platinum drugs, including decreased drug accumulation. Previously, it was suggested that cisplatin enters cells via passive diffusion, followed by intracellular hydrolysis and activation prior to targeting DNA. However, recent in vivo and in vitro studies confirmed that transporters and carriers involved in copper homeostasis play important roles on the transport as well as cellular resistance to the platinum drugs. CTR1, a major plasma-membrane transporter involved in intracellular copper(I) homeostasis, was found to facilitate the uptake of several platinum drugs although the molecular mechanism remains unclear. The extracellular N-terminal domain of human CTR1 (hCTR1) with two methionine(Met)-rich and two histidine(His)-rich motifs has been proved to be essential for the uptake of both copper and platinum drugs by the transporter. In this thesis, the extracellular domain of hCTR1 (hCTR1_N, residues 1-55) was overexpressed and the role of the Met- and His-rich motifs on cisplatin binding was examined by either mutagenesis or chemical modification. Cisplatin was found to directly and rapidly bind to the Met residues of hCTR1_N by the formation of monofunctional cisplatin-thioether adducts. The kinetics of the binding process was found to correlate with the number of Met residues, indicating that all Met residues are exposed to solvents and capable for cisplatin binding. Such a non-sequence-specific binding may increase the likelihood of capturing the anticancer drug in extracellular fluid by the N-terminus of hCTR1. The effect of hCTR_N on the binding and activation of second-generation platinum anticancer drugs, e.g. carboplatin and nedaplatin, were subsequently investigated. hCTR1_N was found to significantly facilitate the activation of these platinum drugs by the formation of ring-opened monofunctional Pt-thioether species through Met residues. Although the activities of platinum drugs against hCTR1_N are significantly different, their monofunctional protein-bound species demonstrated great similarity in both structure and kinetic aspects, suggesting the uptake of these platinum drugs by hCTR1 might follow the same mechanism. The formation of active ring-opened species of carboplatin and nedaplatin by chloride/bicarbonate was observed, indicating these nucleophiles may play a critical role in the pre-activation of the drugs prior to their reaching cellular targets. Pt-thioether species were proposed as intermediates for the platination of other biomolecules. The monofunctional cisplatin adduct of hCTR1_N was proved to further transfer its active platinum species to either cysteine- or guaninecontaining biomolecules which mimic the C-ternimus of hCTR1 and DNA. Methionine residues of hCTR1 may therefore serve as key residues for the activation and transport of platinum anticancer drugs in the form of monofunctional Pt-thioether species through the pole of trimeric hCTR1 and eventually to their final target – DNA. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

A series of alkynylplatinum(II) polypyridine complexes with 4,4′,4′′-tricarboxy-2,2′:6′,2′′-terpyridine and 4,4′-dicarboxy-2,2′-bipyridine as TiO2 anchoring functionalities, has been successfully synthesized. Their photophysical, electrochemical and luminescence properties have been extensively studied. The excited state properties were probed using nanosecond transient absorption spectroscopy. [Pt(tctpy)(C≡C-Th-BTD-Th)][NnBu4]2 displayed a long-lived transient signal which was tentatively assigned to result from the formation of a charge-separated state, which could be alternatively described as a [Pt(tctpy)???(C≡C-Th-BTD-Th)+?] state, with the charge recombination rate constant determined to be 2.9 × 105 s?1. The excited state redox potentials for the oxidation process were determined and the data confirmed the ability of the complexes to inject an electron into the conduction band of TiO2. The majority of the complexes were found to sensitize the nanocrystalline TiO2 and exhibit photovoltaic properties, which have been characterized by current-voltage measurements under illumination of air mass (AM) 1.5G sunlight (100 mW cm–2). A new class of molecular dyads comprising metalloporphyrin-linked alkynylplatinum(II) polypyridine complexes was synthesized and characterized. Their photophysical, electrochemical and luminescence properties have been studied in detail. The excited state properties were probed using nanosecond transient absorption spectroscopy which indicated the formation of a charge-separated state involving the porphyrin radical anion, [Por??－(C≡C)Pt+?]. The excited state redox potentials for the oxidation process were also determined with the data supporting the capability of the complexes to inject an electron into the conduction band of TiO2. The majority of the complexes were found to sensitize the nanocrystalline TiO2 and exhibit photovoltaic properties, as characterized by current-voltage measurements under illumination of air mass (AM) 1.5G sunlight (100 mW cm–2). A series of organic materials consisting of a triphenylamine-based donor with oligothiophene or oligothienylenevinylene based-conjugated linker and dicyanovinyl, tricyanovinyl or cyanacrylic acid groups as acceptor, was synthesized and characterized. Their photophysical, electrochemical, thermal and luminescence properties were studied. Transient absorption spectra of TPA-OTV-DCN in dichloromethane solution on the pico- to nanosecond timescale were recorded after femtosecond laser excitation at 400 nm. A transient signal at ca. 700 nm was tentatively assigned to result from the formation of a charge-separated [(TPA-OTV)+??DCN??] state with the charge recombination rate constant determined to be 5.3 × 109 s?1. The energy levels of the LUMOs of TPA-OTV1-DCN, TPA-OTV2-DCN, TPA-OTV3-DCN TPA-TAZ1-DCN, TPA-TAZ2-DCN and TPA-o-4Th-DCN were calculated to be of ca. ?3.9 eV, establishing the formation of a downhill driving force for the energetically favorable electron transfer process involving the injection of an electron into the LUMO of the C60 acceptor. The majority of the compounds were found to exhibit photovoltaic properties. The photovoltaic responses were characterized by current-voltage measurements under illumination of air mass (AM) 1.5G sunlight (100 mW cm–2). / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Benzimidazole and its derivatives have attracted many organic chemists due to their interesting biological activities. These include activities against viruses such as, HIV, RNA, herpes (HSV-1), influenza, and cytomegalovirus (HCMV); antimicrobial and antitumor activities. Even though a lot of research has been conducted on the synthesis of benzimidazoles, factors such as, drug resistance present a need for synthesis of more structural analogues of these compounds. In chapter three, the synthesis of 2-aryl-1Hbenzimidazoles (46a-c) and 2-aryl-1-arylmethyl-1H-benzimidazoles (49a-d) is described. The yields for these products ranged from 44-79 % and 62-72 %, respectively. The synthesis of novel bisbenzimidazole derivatives is described in chapter four. Direct condensation of 3,3'-diaminobenzidine (1 mmol) with 2-thiophenecarboxyaldehyde (2 mmol) afforded 2, 2’-di-2-thienyl-5,5-Bi-1H-benzimidazole (52) in 65 % yield. Except in the case of 2-furancarboxyaldehyde, the acid catalyzed condensation of 3,3'- diaminobenzidine (1 equivalent) and heteroaromatic aldehydes (4 equivalents) gave novel bisbenzimidazoles where the aldehyde added three times to 3,3'-diaminobenzidine. The four times addition product, 1,2-di-2-furanylmethyl-2,2-di-2-furanyl benzimidazole (53) was obtained in 53 % yield. On the other hand, the three times addition product, 1,2-di-2- pyrrolylmethyl-2,2-di-2-pyrrolyl (54); 1,2-di-2-thienylmethyl-2,2-di-2-thienyl (55); and 1,2-di-2-pyridylmethyl-2,2-di-2-pyridyl benzimidazoles (56) were obtained in 85, 12 and 10 %, respectively. Full characterization of bisbenzimidazoles (54-56) was achieved by 1H, 13C NMR and LCMS spectra. Although benzimidazoles have been proven to be active against various cancers, their use as ligands for platinum (II) has been reported to enhance this activity. Three new benzimidazole Pt (II) complexes were synthesized. N, N, N-bound Pt (II) complexes of 2- quinolyl-1-quinolylmethyl-1H-benzimidazole (60) and 2-pyridyl-1-pyridylmethyl-1Hbenzimidazole (63) were obtained in excellent yields of 82 and 72 %, respectively. S, Nbound Pt (II) complex of 2-thienyl-1-thienylmethyl-1H-benzimidazole (64) was isolated in 63 % yield. From 195Pt NMR spectra analysis, it was concluded that the method reported by Morgan and Burstall is more efficient for the synthesis of these complexes. In addition to 195Pt NMR, platination was also confirmed using 1H and 13C NMR spectra. / Thesis (PhD.)-University of KwaZulu-Natal, Pietermaritzburg, 2010.