Water soluble platinum complexes are a recent area of emphasis of cisplatin chemistry. The water soluble complexes could have a reduced toxicity compared with cisplatin. Oxaliplatin, which has an oxalate leaving group, has previously been shown to have less nephro-toxicity and higher water solubility than cisplatin. [Pt(en)(oxalate)] (en = ethylenediamine) has been prepared from Pt(en)Cl2 and silver oxalate. This complex has been reacted with methionine and N-acetylmethionine at different molar ratios. At high Pt: methionine ratios, chelates with the sulfur and nitrogen atoms of the methionine are dominant; at lower Pt: methionine ratios, a bis-methionine product is formed. The en ligand is displaced by methionine but not N-acetylmethionine.

Η εργασία εστιάζει στην παρασκευή και μελέτη πολυλειτουργικών μαγνητικών νανοσωματιδίων Ιξαμπεπιλόνης, με σκοπό την χορήγησή τους για την αντιμετώπιση του καρκίνου του μαστού. Πραγματοποιήθηκαν φυσικοχημικές μελέτες, μελέτες αποδέσμευσης και κυτταρικές μελέτες. / The aim of the current study is the preparation and the characterization of multifunctional magnetic Ixabepilone nanoparticles, in order to determine their use for the treatment of advanced breast cancer. Physicochemical studies, release studies and cell studies were performed.

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This work is concerned with the design and synthesis of the cheap, late first row transition metal complexes of Schiff base ligand systems. The prepared complexes readily afford systematic variation in order to probe potency and understand the role of metal, chelating ligands and anionic ligands when carrying out their cytotoxic effect. This study has lead to a better understanding of the action of these classes of complex and will be used to direct the design of new anti-cancer metallopharmaceuticals going forward. This thesis details the synthesis of a library of Schiff base macroacyclic ligands and their novel late first row transition metal complexes with varying anionic counterparts. The creation of a library with several degrees of variability provides a wide array of parameters to afford subtle variation in structure and chemistry e.g. denticity, co-ordination mode, chelate hole size, metal centred redox potentials, hydrolysis rates, co-ordinative saturation, lipophilicity, solubility and more. Complexation of the ligands was carried out by the free ligand and a novel macroacyclic metal template approach using the cheap late first row transition metal salts of Cobalt (II), Nickel (II), Copper (II) and Zinc (II) plus one Ru (III) complex. Structural studies of the 80 generated complexes was carried out by vibrational spectroscopy, elemental analysis, mass spectrometry, magnetic susceptibility and NMR. Single crystal X-ray structures have been determined with 20 reported in this thesis. All ligands act as tridentate ligands in all except one case to form monomeric distorted trigonal-bipyramidal, square-pyramidal or octahedral structures. In the case of zinc nitrate, the ligand L2PhMe acts as a tetradentate ligand to give a distorted octahedral structure. Paramagnetic NMR and solution magnetic susceptibility of paramagnetic complexes was achieved by the Evans NMR method and analysis of the solution NMR showed that L2R and L3R ligands display 2-fold symmetry and are likely either tetradentate in solution or a fast exchange between imine N-donar sites is occurring even down to -65°C. The majority of the resulting complexes of L1R were screened against a panel of three cancer cell lines. Several categories of complex were able to afford structure activity relationships. It was discovered that the ligand is indeed essential for activity of the metal salts against the panel of cell lines and it was largely discovered that the variation in 'tail group' and anionic coordinating ligands played little role in providing a dramatic variation in activity of the metal salt. In general all L1R complexes displayed moderate cytotoxicity showing a trend in activity with respect to the metal in the order RuIII≈CoII>CuII≈ZnII>NiII, over a 6 day exposure to the three cell panel RuIII was shown to be the most potent metal of the L1R series providing IC50 values of 4.6 (0.7) and 7.5 (1.2) μM against the DLD-1 and H460 cell lines respectively, which is Ca. 4.6 and 15 times less potent than cisplatin to the same cell panel respectively. RuIII was also discovered to be the only metal to provide an IC50 value from a 1 hour exposure to the DLD-1 cell panel. The value of 20.4 (3.5) μM is a moderate figure but again Ca. 10 fold less potent than cisplatin for the same test. The L2R and L3R complexes could not be screened by the same comprehension due to their low solubilities. However the lone screen that was possible from the very sparingly soluble complex [CuCl2(L3Bui)] gave the most exciting result and most potent complex of this thesis. After a 6 day exposure, [CuCl2(L3Bui)] gave IC50 values of 4.3 (0.1) and 2.9 (0.1) μM against the DLD-1 and H460 cell lines respectively. These values are merely 4 and 6 fold more than Cisplatin to the same cell lines respectively and demonstrates the potential of this class of complex as cytostatic agents. Further studies utilising a semi-quantitative DNA damaging assay, demonstrated that all first row complexes can damage DNA when in the presence of hydrogen peroxide, with the exception of ZnII complexes. CoII appeared to afford the greatest DNA damage with the most intsense bands for double strand breaks and the CuII complex of the ligand L3Bui also demonstrated a greater DNA damage as opposed to its L1Bui analogue.

Minimizing anti-cancer drug toxicity is a major challenge for the pharmaceutical industry. Toxicity is most frequently due to either the direct interaction of the drug on previously unidentified targets or its conversion to metabolites by drug metabolizing enzymes (e.g. CYP450 enzymes) that cause cellular, tissue or organ damage. Pharmacoproteomics is beginning to take a central role in studying changes in protein expression corresponding to drug administration, the results of which, inform about the mode of action, toxicity, and resistance in pre-clinical and clinical stages of drug development. The main aim of this research is to apply comparative proteomics studies on livers from male and female mice xenograft models treated with major anti-cancer drugs (5-flourouracil, paclitaxel, cisplatin, and doxorubicin) and CYP inducer, TCPOBOP, to investigate their effect on protein expression profiles (proteome). Within this thesis, an attention is paid to optimise a highly validated proteomics workflow for biomarker identification. Proteins were extracted from liver microsomes of mice treated in two separate sets; Set A – male (5-fluoruracil, doxorubicin, cisplatin and untreated) or Set B – female (5-fluoruracil, paclitaxel, TCPOBOP and untreated) using cryo-pulverization and sonication method. The extracts were digested with trypsin ii and the resulting peptides labelled with 4-plex iTRAQ reagents. The labelled peptides were subjected for separation in two-dimensions by iso-electric focusing (IEF) and RP-HPLC techniques before analysis by mass spectrometry and database searching for protein identification. Set A and Set B resulted in identification and quantification of 1146 and 1743 proteins, respectively. Moreover, Set A and Set B recovered 26 and 34 cytochrome P450 isoforms, respectively. The microsomal changes after drug treatments were quite similar. However, more changes were observed in the male set. Up-regulation of MUPs showed the greatest distinction in the protein expression patterns in the treated samples comparing to the untreated controls. In Set A, 5-fluoruracil and cisplatin increased the expression of three isoforms (MUP1, 2, and 6), whereas doxorubicin has increased the expression of four isoforms (MUP1, 2, 3, and 6). On the other side, only TCPOBOP in Set B has increased the expression of two isoforms (MUP1 and 6). Our findings showed that the expression of MUP, normally involved in binding and excretion of pheromones, have drug- and sex-specific differences. The mechanism and significance of MUP up-regulation are ambiguous. Therefore, the impact of each therapeutic agent on MUP and xenobiotic enzymes will be discussed.

This work is concerned with the design and synthesis of the cheap, late first row transition metal complexes of Schiff base ligand systems. The prepared complexes readily afford systematic variation in order to probe potency and understand the role of metal, chelating ligands and anionic ligands when carrying out their cytotoxic effect. This study has lead to a better understanding of the action of these classes of complex and will be used to direct the design of new anti-cancer metallopharmaceuticals going forward. This thesis details the synthesis of a library of Schiff base macroacyclic ligands and their novel late first row transition metal complexes with varying anionic counterparts. The creation of a library with several degrees of variability provides a wide array of parameters to afford subtle variation in structure and chemistry e.g. denticity, co-ordination mode, chelate hole size, metal centred redox potentials, hydrolysis rates, co-ordinative saturation, lipophilicity, solubility and more. Complexation of the ligands was carried out by the free ligand and a novel macroacyclic metal template approach using the cheap late first row transition metal salts of Cobalt (II), Nickel (II), Copper (II) and Zinc (II) plus one Ru (III) complex. Structural studies of the 80 generated complexes was carried out by vibrational spectroscopy, elemental analysis, mass spectrometry, magnetic susceptibility and NMR. Single crystal X-ray structures have been determined with 20 reported in this thesis. All ligands act as tridentate ligands in all except one case to form monomeric distorted trigonal-bipyramidal, square-pyramidal or octahedral structures. In the case of zinc nitrate, the ligand L2PhMe acts as a tetradentate ligand to give a distorted octahedral structure. Paramagnetic NMR and solution magnetic susceptibility of paramagnetic complexes was achieved by the Evans NMR method and analysis of the solution NMR showed that L2R and L3R ligands display 2-fold symmetry and are likely either tetradentate in solution or a fast exchange between imine N-donar sites is occurring even down to -65°C. The majority of the resulting complexes of L1R were screened against a panel of three cancer cell lines. Several categories of complex were able to afford structure activity relationships. It was discovered that the ligand is indeed essential for activity of the metal salts against the panel of cell lines and it was largely discovered that the variation in ¿tail group¿ and anionic coordinating ligands played little role in providing a dramatic variation in activity of the metal salt. In general all L1R complexes displayed moderate cytotoxicity showing a trend in activity with respect to the metal in the order RuIII¿CoII>CuII¿ZnII>NiII, over a 6 day exposure to the three cell panel RuIII was shown to be the most potent metal of the L1R series providing IC50 values of 4.6 (0.7) and 7.5 (1.2) ¿M against the DLD-1 and H460 cell lines respectively, which is Ca. 4.6 and 15 iii times less potent than cisplatin to the same cell panel respectively. RuIII was also discovered to be the only metal to provide an IC50 value from a 1 hour exposure to the DLD-1 cell panel. The value of 20.4 (3.5) ¿M is a moderate figure but again Ca. 10 fold less potent than cisplatin for the same test. The L2R and L3R complexes could not be screened by the same comprehension due to their low solubilities. However the lone screen that was possible from the very sparingly soluble complex [CuCl2(L3Bui)] gave the most exciting result and most potent complex of this thesis. After a 6 day exposure, [CuCl2(L3Bui)] gave IC50 values of 4.3 (0.1) and 2.9 (0.1) ¿M against the DLD-1 and H460 cell lines respectively. These values are merely 4 and 6 fold more than Cisplatin to the same cell lines respectively and demonstrates the potential of this class of complex as cytostatic agents. Further studies utilising a semi-quantitative DNA damaging assay, demonstrated that all first row complexes can damage DNA when in the presence of hydrogen peroxide, with the exception of ZnII complexes. CoII appeared to afford the greatest DNA damage with the most intsense bands for double strand breaks and the CuII complex of the ligand L3Bui also demonstrated a greater DNA damage as opposed to its L1Bui analogue.

Minimizing anti-cancer drug toxicity is a major challenge for the pharmaceutical industry. Toxicity is most frequently due to either the direct interaction of the drug on previously unidentified targets or its conversion to metabolites by drug metabolizing enzymes (e.g. CYP450 enzymes) that cause cellular, tissue or organ damage. Pharmacoproteomics is beginning to take a central role in studying changes in protein expression corresponding to drug administration, the results of which, inform about the mode of action, toxicity, and resistance in pre-clinical and clinical stages of drug development. The main aim of this research is to apply comparative proteomics studies on livers from male and female mice xenograft models treated with major anti-cancer drugs (5-flourouracil, paclitaxel, cisplatin, and doxorubicin) and CYP inducer, TCPOBOP, to investigate their effect on protein expression profiles (proteome). Within this thesis, an attention is paid to optimise a highly validated proteomics workflow for biomarker identification. Proteins were extracted from liver microsomes of mice treated in two separate sets; Set A – male (5-fluoruracil, doxorubicin, cisplatin and untreated) or Set B – female (5-fluoruracil, paclitaxel, TCPOBOP and untreated) using cryo-pulverization and sonication method. The extracts were digested with trypsin ii and the resulting peptides labelled with 4-plex iTRAQ reagents. The labelled peptides were subjected for separation in two-dimensions by iso-electric focusing (IEF) and RP-HPLC techniques before analysis by mass spectrometry and database searching for protein identification. Set A and Set B resulted in identification and quantification of 1146 and 1743 proteins, respectively. Moreover, Set A and Set B recovered 26 and 34 cytochrome P450 isoforms, respectively. The microsomal changes after drug treatments were quite similar. However, more changes were observed in the male set. Up-regulation of MUPs showed the greatest distinction in the protein expression patterns in the treated samples comparing to the untreated controls. In Set A, 5-fluoruracil and cisplatin increased the expression of three isoforms (MUP1, 2, and 6), whereas doxorubicin has increased the expression of four isoforms (MUP1, 2, 3, and 6). On the other side, only TCPOBOP in Set B has increased the expression of two isoforms (MUP1 and 6). Our findings showed that the expression of MUP, normally involved in binding and excretion of pheromones, have drug- and sex-specific differences. The mechanism and significance of MUP up-regulation are ambiguous. Therefore, the impact of each therapeutic agent on MUP and xenobiotic enzymes will be discussed.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / Our research work is divided into three chapters. In the first chapter, synthesis of substituted phenolic compounds including halogenated di- and trihydroxybenzenes, aminophenols, and substituted di-tert-butylphenols, their redox potential, laccase oxidation, and mosquito anti-larval activities are discussed. The synthesized substituted phenols were found to be the substrates but not the inhibitors of laccase. An inverse correlation between the oxidation potential and the laccase oxidation efficiency of halogenated hydroxybenzenes and aminophenols was established. However, substituted di-tert-butylphenols were found to have anti-larval activities in mosquitoes resulting in the death of the larvae just before reaching pupation. Among the di-tert-butyl phenols studied, water insoluble, 2,4-di-tert-butyl-6-(3-methyl-2-butenyl)phenol (16), 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylpropanal oxime (14), and 6,8-di-tert-butyl-2,2-dimethyl-3,4-dihydro-2H-chromene (17) caused the mortility of 98%, 93%, and 92% of Anopheles gambiae larvae in the concentration of 182 nM, 3.4 µM, and 3.7 µM, respectively. In particular, compound 16 had similar anti-larval activities as compared to MON-0585, an anti-larval agent reported by Monsanto in the 70’s. In the second chapter, inhibition of protein kinase C (PKC) phosphorylation by substituted quinolines (PQs) is inverstigated. PQ compounds such as N-(3-aminopropyl)-6-methoxy-4-methyl-5-(3-(trifluormethyl)phenoxy)quinolin-8-amine (PQ1), N-(furan-2-ylmethyl)-6-methoxy-4-methyl)-5-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (PQ11), and 6-methoxy-4-methyl-N-(quinolin-4-ylmethyl)-5-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (PQ15) were found to inhibit PKC phosphorylation with IC50 values of 35 nM, 42.3 nM, and 216.3 nM respectively, among which PQ1 and PQ11 were found to be potent PKC inhibitors as comparable to that of staurosporine (IC50 = 33 nM). In chapter three, the tissue distribution of PQ1 and PQ11 in normal C57BL/6J mice and the effect of PQ1 on the normal tissues of mice were investigated. Substituted quinolines, PQ1 and PQ11 were distributed in the tissues in concentrations that were more than 40 folds of their effective dose. PQ1 and PQ11 were also found to penetrate the blood brain barrier and collect in the tissue in significant amounts. The administration of PQ1 and PQ11 had no effect in the normal behavior of the animals indicating no short term adverse effects. PQ1 was found to increase the expression of survivin, an anti-apoptotic factor and decrease the expression of cleaved caspase-3 and caspase-8, pro-apoptotic proteins. These studies suggests that PQ1 might have anti-apoptotic activities in normal cells, in contrast to the role of PQ1 in cancer cells where it has demonstrated to induce apoptosis. The study also indicated that PQ11 was better metabolized from the tissues over time as compared to PQ1.

Nanoparticles were synthesized and modified for target drug delivery. The research involved the aqueous synthesis of near infrared (NIR) sensitive Au-Au₂S nanoparticles. An anti-cancer drug (<i>cis-platin</i>) was subsequently adsorbed onto the Au-Au₂S nanoparticle surface via the 11-mercaptoundecanoic acid layers. The results showed that the degree of adsorption of cis-platin onto Au-Au₂S nanoparticles was controlled by the pH value of solution, and the rate of drug release was sensitive to NIR irradiation. The results of the synthesis, drug-release properties and nanoparticle-cell interactions will be discussed. / Singapore-MIT Alliance (SMA)