Cancer is a human tragedy that strikes and kills the lives of our beloved people. With a limited number of effective anticancer drugs from natural resources currently in use, there is a real need for new, safe, cheap and effective anticancer drugs to combat this dreaded and formidable disease. Plants have a long history of use in the treatment of cancer. Several plant-derived anticancer agents including taxol, vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan and etoposide derived from epi- podophyllotoxin are in clinical use all over the world. In this study, two endemic plant species from the Rubiaceae and Asteraceae families, namely Anthospermum hispidulum E.Mey. ex Sond. and Eriocephalus tenuifolius DC. were investigated for their anticancer properties. The organic (methanol/dichloromethane, 1:1 v/v) extracts of both plant species were found to have moderate anticancer activity against a panel of three human cancer cell lines namely, breast MCF7, renal TK10 and melanoma UACC62 at the CSIR anticancer screen. Bioassay-guided fractionation of the organic extracts of Anthospermum hispidulum led to the isolation of an active compound which was characterised as ursolic acid. Another compound, namely scopoletin was also isolated. The compounds isolated here are known compounds, but have not previously been reported as present in the genus Anthospermum. Bioassay-guided fractionation of the organic extracts of Eriocephalus tenuifolius resulted in the isolation of 8-O-isobutanoylcumambrin B as the active constituent. This compound is reported to have been isolated from related plant species; however its biological activity is not known. The compounds pectolinagenin, hispidulin, friedelinol and tetracosanoic acid were also isolated, but did not show any significant anticancer activity. The structures of all compounds isolated in this study were elucidated using nuclear magnetic resonance spectroscopy, mass spectroscopy and also by comparison with data reported in the literature. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.

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.

Solid tumors are commonly subject to hypoxia. Hypoxic cancer cells have undesirable properties such as a high tendency to metastasize and resistance to chemotherapy and radiotherapy. Hypoxia-inducible factors (HIFs) respond to the changes in oxygen levels, orchestrating the transcription of many proteins that are vital for the survival of hypoxic cancer cells. With their parent drug SN-38 as an inhibitor of both topoisomerase 1 and HIF-1, hypoxia-activated SN-38s may have a dual inhibitory effect on hypoxic tumor cells due to hypoxia-targeting and HIF-1 inhibition. To develop hypoxia-activated prodrugs of SN-38; 2-, 3-, and 4-nitrobenzyl SN-38s have been synthesized with good yields (78%, 67% and 68%, respectively). Topoisomerase 1 inhibitory assay on 2- and 4-nitrobenzyl SN-38s and cell viability assay on 2-, 3- and 4-nitrobenzyl SN-38s have been performed. All three derivatives showed less toxicity on K562 cells, which meets the principle of prodrug design. Cyclic voltammetry results suggest that the reduction potentials of these three derivatives may be not high enough for these compounds to be activated. The manner of reduction of three nitrobenzyl SN-38s is quasi-reversible under the testing condition, not against the proposed mechanism of activation. Two new derivatives of SN-38 have been designed to elevate reduction potential and further reduce toxicity. They are to be synthesized and tested for future work. / October 2016

M.B.A. / Please refer to full text to view abstract

A dissertation submitted to the Faculty of Science, University of the Witwatersrand, in fulfilment of the requirement for the degree Master of Science (MSc) in Chemistry. Johannesburg, March 2017. / A series of [Pt(diimine)(Ln-O,S)]Cl complexes, where Ln-O,S represents a series of N,N dialkyl-N’-acylthiourea ligands and diimine represents (1,10-Phenanthroline; 5,6-dimethyl 1,10-phenanthroline or [3,2-d:2’,3’-f]-quinoxaline were successfully synthesised and characterised. A new crystal structure was obtained for N,N-di(2-hydroxy)-N’ benzoylthiourea which revealed an interesting herringbone crystal packing arrangement. The cytotoxicity of the series of complexes was evaluated on H1975 lung cancer cell lines at 50 µM and 5 µM. All the complexes were highly cytotoxic with cell death of 90-98% at 50 µM. However, at 5 µM there were much more variations on cell viability percentages. Although the structure–activity relationship can only be established when the IC50 (the concentration of an inhibitor where the response is reduced by half) values are determined, it is clear that the complexes containing the methyl substituents on the 5 and 6 positions of the phenanthroline moiety were the most cytotoxic with almost 98% cell death at 5 µM. The solubility of the complexes did improve by using N,N-dialkyl-N’-acylthiourea as ancillary ligands, however aqueous solubility remains a major problem. Sulphobutyl-ether-β-cyclodextrin (captisol) and low-molecular-weight surfactant micelles as drug delivery systems were considered in attempt to improve the solubility. DOSY NMR Spectroscopy revealed that there was no inclusion complex formation between the complex and capstiol, although the chemical shift trend suggested that there is at least some interaction. The low-molecular-weight surfactant micelles were considered as an alternative, which showed some promise as a drug delivery system, since the aqueous solubility improved and a colloidal suspension was obtained. / LG2018

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy of Science. Johannesburg, 2013 / Chemotherapy, while representing a vital component of cancer treatment modalities, has so far not fulfilled basic expectations with unsatisfactory cure rates and frequent relapse due to limited effectiveness of the therapeutic drugs, severe side effects and resistance problems. The platinumcontaining drugs used in present clinical practice are no exception to this generalized finding. While highly effective against a small number of malignancies, they generally share in the deficiencies of other anticancer agents. To address this issue, intense research is being undertaken to develop novel platinum-compounds offering enhanced therapeutic effectiveness. To accomplish this, several new avenues of development are being pursued world-wide, and one of these involving the binding of monomeric anticancer drug systems to water-soluble, biocompatible and biodegradable polymeric carriers, was utilized in the current research. As part of the ongoing research, this dissertation demonstrates the preparation of several water-soluble polymeric carriers bearing pre-synthesized monomers aimed to anchor the platinum drug. The monomers of interest were aspartic acid, p-aminobenzoic acid and p-aminosalicylic acid derivatives; while the water-soluble carriers were polyaspartamides, prepared by an aminolytic ring-opening process of polysuccinimide. The platination agents were conjugated to the polymer backbone both via amine and via leaving-group ligands, such as dihydroxylato, dicarboxylato and carboxylatohydroxylato. In order to demonstrate the multidrug-binding capacity of the carriers, platinum complexes were co-conjugated to polymeric conjugates containing ferrocene. The in vitro studies against a human breast cancer (MCF-7) cell line showed IC50 values ranging from 48.92 μg.mL-1 to 281.37 μg.mL-1 for the platinum conjugates, 13.18 μg.mL-1 to 149.67 μg.mL-1 for ferrocene conjugates and 6.22 μg.mL-1 to 83.86 μg.mL-1 for platinum/ferrocene co-conjugates; and these values were on average 4 fold more active than the parent drug. The results of these preliminary tests provide proof of the principle that polymer-drug conjugates can play a role in future cancer therapy.

This research is part of a long-term project aimed at elucidating important structural features, of both ligands and metals, that are needed to produce effective anti-cancer agents. The specific goal is the synthesis of organotin polymers containing amino acids, in this case the diamino acid diglycine. The desired materials were synthesized with percent yields ranging from 32-99%. The products were synthesized employing the interfacial polymerization technique. The polymers were then characterized utilizing the following physical characterization techniques: light scattering photometry (LS), Infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR), and matrix assisted laser desorption mass spectroscopy (MALDI). Physical characterization showed evidence of formation of desired adducts in addition to data that was consistent with the formation of materials containing multiple repeat units. The materials were then analyzed for biological activity. The synthesized materials displayed the ability to inhibit tested cancer cell lines. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

This thesis details my investigations of marine cyanobacterial natural products that resulted in the discovery of eighteen new secondary metabolites. Isolation and characterization of these unique molecules were carried out using different chromatographic techniques and by careful analyses of 1D and 2D NMR data, respectively. Preliminary bioassays of the crude organic extract of the marine cyanobacterium Lyngbya semiplena collected from Papua New Guinea in 1999, showed good activity in the brine shrimp toxicity model at 10 ppm. Guided by this assay, seven new anandamide-like fatty acid amides, semiplenamides A to G, together with four cyclic depsipeptides, wewakpeptins A to D, were identified. Due to the structural resemblance of the novel ethanolamide derivatives (semiplenamide A-G) with anandamide, (N-arachidonoyl-ethanolamine), an endogenous agonist of cannabinoid receptors compounds, semiplenamide A-G were tested on the well characterized proteins of the endocannabinoid system: 1) the "central" cannabinoid CB₁ receptors; 2) the anandamide membrane transporter (AMT), which is responsible for anandamide cellular uptake; and 3) the fatty acid amide hydrolase (FAAH), which catalyses anandamide hydrolysis. Three showed modest potency in displacing radiolabeled anandamide from the cannabinoid receptor (CB₁), and one was a modest inhibitor of the anandamide membrane transporter (AMT). The wewakpeptins were tested for cytotoxicity to NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells. Intriguingly, wewakpeptin A and B were approximately 10-fold more toxic than C and D to these cell lines. Lyngbya majuscula has been recognized as a chemically and biologically rich strain. Five new lyngbyabellin analogs, lyngbyabellins E-I, along with the known compound dolabellin, originally isolated from sea hare Dolabella auricularia, were identified from a 2002 Papua New Guinea collection of the marine cyanobacterium Lyngbya majuscula. The lyngbyabellins were tested for cytotoxicity to NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells and had LC₅₀ values between 0.2 and 4.8 μM. Intriguingly, lyngbyabellin E and H appeared to be more active against the H460 cell line with LC₅₀ values of 0.4 μM and 0.2 μM, respectively, compared to LC₅₀ values of 1.2 and 1.4 μM in the neuro-2a cell line. Lynbyabellin I was the most toxic to neuro-2a cells (LC₅₀ 0.7 μM), whereas lyngbyabellin G, was the least cytotoxic of all compounds to either cell line. On the basis of this limited screening, it appears that lung tumor cell toxicity is enhanced in the cyclic representatives, and overall potency is increased in those containing an elaborated side chain. Additionally, two new cytotoxins, aurilides B and C, which are closely related to aurilide, originally isolated from the sea hare Dolabella auricularia, have been identified from the same extract where the lyngbyabellins E-I were isolated. Aurilides B and C were tested for cytotoxicity to NCI-H460 human lung tumor and neuro-2a mouse neuroblastoma cells. Interestingly, aurilide B was approximately 4-fold more toxic than C to these cell lines. The LC₅₀ for Aurilide B was 0.01 μM and 0.04 μM for neuro-2a and H460 cells, respectively, and 0.05 μM and 0.13 μM, respectively, for aurilide C. Aurilide B was evaluated in the NCI 60 cell line panel and found to exhibit a high level of growth inhibition in leukemia, renal, and prostate cancer cell lines with a GI₅₀ less than 10 nM. Aurilide B showed net tumor cell killing activity in the NCI's hollow fiber assay, an in vivo model for assessing a chemical's anticancer activity. / Graduation date: 2006

Graduation date: 1994