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An in vitro assessment of pharmacodynamic interactions between selected herbal extracts and anticancer chemotherapeutic agents

  • Authors: Hwehwe, Nyashadzashe , Swanepoel, Bresler
  • Date: 2024-04
  • Subjects: Chemotherapy , Herbs -- Therapeutic use , Antineoplastic agents
  • Language: English
  • Type: Master's theses , text
  • Identifier: http://hdl.handle.net/10948/63506 , vital:73383
  • Description: Cancer is a disease caused by uncontrolled growth and spreading of abnormal cells to distant body parts. Approximately 19.3 million and 10 million new cancer cases and cancer deaths, respectively were recorded in 2020. Despite advancements in prevention and therapeutic strategies, cancer remains a global health problem. Cancer patients are increasingly seeking complementary and alternative medicines, of which herbal medicines are the most common form of CAM used by patients. Numerous in vitro and in vivo studies of herbal medicines in cancer have shown that they have antioxidant and anticancer (antitumor and anti-proliferative) properties. While concurrent use with conventional cancer treatments may improve treatment efficacy, alleviate chemotherapy-related side effects, boost the immune system, or impede drug resistance, it can also prompt drug-herbal interactions, and this may affect the pharmacodynamics and pharmacokinetics of the chemotherapeutic drug. This study aimed to determine relevant pharmacodynamic interactions with chemotherapeutic drugs and investigate such interactions' mechanisms. The objectives of the study were to screen the cytotoxicity effects of drug compounds, herbal extracts, and drug-herb combinations, to determine the ability of treatments to induce apoptosis, and to determine the most beneficial treatment. The cytotoxic effects of cisplatin in HeLa cells, tamoxifen in MCF7 cells, 5-fluorouracil in Caco-2 cells, and grapeseed, green tea, fermented rooibos, and green rooibos in all the listed cell lines were evaluated individually and in combination using the bis-Benzamide H 33342 trihydrochloride/propidium iodide (Hoechst 33342/PI) dual staining method. CompuSyn 1.0 Software was used to quantify synergism and antagonism. The mechanism of apoptosis induction of the different synergetic combinations, drug compounds, and herbal extracts was illustrated by quantitative fluorescence image analysis, specifically cell cycle analysis, phosphatidylserine translocation, mitochondrial membrane potential analysis, caspase 3 activation, and reactive oxygen species production using the relevant contrast dyes. Grapeseed displayed cytotoxicity towards MCF7 and HeLa cells (IC50 57.98 and 83.28 μg/mL, respectively). Green tea was only cytotoxic against HeLa cells at an IC50 of 91,92 μg/mL. None of the extracts displayed cytotoxicity against Caco-2 cells (IC50 values > 200μg/mL). If the herbal extracts had inconclusive IC50 values in the three cell lines subsequent experiments were conducted using 100 μg/mL. The results showed that most of the combinations were antagonistic but, some combinations had synergistic or enhancement effects(1:3 for cisplatin with grape seed or green tea and tamoxifen with grapeseed or green tea, and 3:1 for cisplatin with green tea as well as for tamoxifen with fermented rooibos or green rooibos, and all the 1:1 combinations of 5- fluorouracil with all herbal extracts) with a combination index (CI) < 1. Grape seed and green tea were found to induce apoptosis in the three cell lines. Assays that were conducted to detect apoptosis induction showed positive staining for phosphatidylserine (PS), activated caspase 3, and reactive oxygen species (ROS), mitochondrial membrane depolarization. Analysis of the cell cycle showed two things; 1) that grape seed and green tea were apoptotic in HeLa and MCF7 cells only, and 2) the extracts of green tea and green rooibos, and the combinations of grape seed with all drug compounds arrested the cell in more than one phase of the cell cycle. The combinations of grapeseed and green tea potentially induced apoptosis in various manners but those with both rooibos extracts were unclear in all the cell lines. The results for combinations with grapeseed and green tea are promising and provide a basis for further research as combinations of chemotherapeutic drugs and herbal extracts may be effective therapeutic strategies. , Thesis (MPharm) -- Faculty of Health Sciences, School of Clinical Care & Medicinal Sciences, 2024
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  • Date Issued: 2024-04

Pharmaco-chemical investigation of Erythrina caffra: extracts, isolated compounds and their biological activities

  • Authors: Nogqala, Simnikiwe
  • Date: 2023-03-29
  • Subjects: Coast coral tree , Traditional medicine South Africa , Antibacterial agents , Antineoplastic agents , Organic compounds
  • Language: English
  • Type: Academic theses , Master's theses , text
  • Identifier: http://hdl.handle.net/10962/422459 , vital:71944
  • Description: In this study, secondary metabolites isolated from Erythrina caffra, a medicinal plant indigenous to South Africa, were investigated. E. caffra is well-known for its healing properties and it is traditionally used for treating bacterial infections like tuberculosis (TB), abscesses, tooth aches and ear infections. Its extracts have also been used to treat cancer. Though many studies have been done on this plant, most of them tended to focus solely on the isolated compounds. In the present study however, extracts, fractions and isolated compounds from E. caffra were evaluated for their anticancer, anti-oxidant, anti-enzymatic, antibacterial and cytotoxicity. The methanol crude extract (B1) from the stem bark of E. caffra was used to extract alkaloidic fractions (B2 and B3) using ethyl acetate and n-butanol respectively, a third fraction (B4) was also extracted using ethyl acetate this fraction was called a neutral fraction. The neutral fraction (B4) was fractionated and through a sequence of column chromatography three active secondary metabolites were isolated. The isolated compounds included Lupeol (1), stigmasterol (2) and 5,7-Dihydroxy-4'-methoxy-3',5'-diprenylflavanone (3). These isolated compounds were characterized and identified using spectroscopic techniques including IR, NMR and high-resolution Mass Spectrometry. Using the cell line HCC-70, isolated from a primary ductal carcinoma, in vitro anticancer assays were carried out on the crude extract from the bark, fractions, isolated compounds and an unseparated mixture of two compounds. These samples were also evaluated for their anti-oxidant, anti-enzymatic, antibacterial and cytotoxicity activities. The crude extract inhibited the cell viability by over 30% and had no effect on the HeLa cells at concentrations of 20μM. Abyssinone V’ 4-methyl-ether (3) and the mixture of stigmasterol (2) and an unidentified compound exhibited potent anticancer activity against the HCC-70 cell line with IC50 of 18.05μM and 9.04μM respectively. Antibacterial assays were also carried out on the crude extracts, fractions and concoctions made from the fractions with the best activity combined with the ones that performed poorly. The concoctions were prepared as two separate series (S and N series). The crude extract inhibited more than 80% of the Staphylococcus aureus cells at a concentration of 20μM with only minimal damage to the HeLa cells. In the concoctions however, the N series managed to inhibit over 96% of the S. aureus while exhibiting no cytotoxicity towards HeLa cells. The extract and its fractions also showed good anti-oxidant activities. Molecular docking of these compounds was done on the Human estrogen receptor (PDB ID:3ERT) and Abyssinone V’ 4-methyl-ether (3) showed the best docking score of -6.6 Kcal/mol, for the simulation against Epidermal growth factor receptor (PDB ID: 1M17) Stigmasterol (2) showed the best docking score of -3.8 Kcal/mol. In silico docking on 3ERT and 1M17 were done to test the binding affinity of the isolated compounds to the proteins which are well known to be overexpressed in some types of cancer. Flavonoids isolated from Erythrina species have been reported to possess good antiplasmodial activity. However, due to the minute amounts isolated in the present study in-vitro assays could not be carried out. Nevertheless, in-silico assays were conducted on the most prominent protozoal parasite which causes malaria in the majority of African countries. In-silico simulations were done against Plasmodium falciparum protein (PDB ID: 7KJH), of the tested compounds Abyssinone V’ 4-methyl-ether (3) was found possess the best docking score of -4.4 Kcal/mol. The molecular docking of 7KJH was done to assess the inhibitory potential of the isolated compounds on protozoal parasites. Pharmacokinetic properties of the isolated compounds were also assessed in silico to assist in evaluating the drug likeness of these compounds. The compounds showed a percent human oral absorption of 100% except for Abyssinone V’ 4-methyl-ether (3), which showed 93.83%, this indicates a remarkable oral bioavailability. Stigamsterol (2) exhibited a Caco-2 cell permeability (QPPCaco) greater than 500 which indicates outstanding results for good intestinal absorption. The compounds also displayed a blood-brain partition co-efficient (QPlogBB) ranging from -1.433 to 0.128 suggesting they will have less potential to cross the blood-brain barrier, thus reducing any CNS related toxicity. Molecular networking of the crude extracts and the fractions was done through GNPS which allowed the identification of known compounds including one isolated in the present study, Abyssinone V’ 4-methyl-ether (3). Possible derivatives that have not been isolated from this plant before were also putatively identified. , Thesis (MSc) -- Faculty of Science, Chemistry, 2023
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  • Date Issued: 2023-03-29

Assessment of cytotoxic artemisinin and its derivatives as DNA damaging inducing agents in triple-negative breast cancer cells

  • Authors: Mkhwanazi, Ntando
  • Date: 2022-10-14
  • Subjects: Breast Cancer , Artemisinin , DNA damage , Antineoplastic agents , Breast Cancer Treatment
  • Language: English
  • Type: Academic theses , Master's theses , text
  • Identifier: http://hdl.handle.net/10962/362960 , vital:65378
  • Description: In developing countries, including South Africa, breast cancer is the primary cause of cancer-related deaths among women. TNBC (triple-negative breast cancer) is an aggressive breast cancer subtype that is more prevalent in women of African descent. This subtype lacks the key receptors, namely the estrogen receptor (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 (HER2-) that are the basis of successful targeted therapies for other subtypes of the disease. To date, there are no effective, standardized targeted therapies for TNBC. Artemisinin is an anti-malarial drug and numerous derivatives of the compound have been developed to improve the potency and solubility of the parent compound. Artemisinin and its derivatives have gained attention as potential anti-cancer agents; however, such studies have not yet progressed to clinical trials and the precise mechanism of action of these compounds is yet to be fully explained. In this study, artemisinin, and its known derivative artesunate, as well as a novel derivative, WHN11, were investigated as DNA damage-inducing agents in TNBC. WHN11 was found to be the most potent of the three compounds, displaying an IC50 of 3.20 μM against HCC70 cells, artemisinin displayed an IC50 of 214.70 μM and artesunate displayed an IC50 of 25.48 μM. The compounds were less toxic to the MCF12A non-cancerous cells, with IC50 values 298.30, 87.53, and 8.35 μM for artemisinin, artesunate, and WHN11, respectively, and displayed selectivity indices of 1.39, 3.44 and 2.61 μM for artemisinin, artesunate, and WHN11, respectively. In silico and in vitro studies revealed that the artemisinin compounds bind to DNA through the minor groove. While all three compounds were able to bind to DNA, a comet assay revealed that only artemisinin and artesunate, and not WHN11, were able to cause DNA damage compared to the vehicle control, DMSO. Finally, a topoisomerase I (TOPO I) enzyme assay demonstrated that while the compounds appeared to display a degree of inhibition of TOPO I, as evidenced by a downward shift in the plasmid band on the agarose gel, they were not able to fully inhibit the enzyme to return the plasmid to the supercoiled conformation. In addition, combination studies revealed that artemisinin, artesunate, and WHN11 acted synergistically in combination with camptothecin, but displayed either an additive (artemisinin) or antagonistic (artesunate and WHN11) relationship when used in combination with etoposide. In conclusion, artemisinin, its known derivative artesunate, and novel and highly toxic derivative WHN11, all bind to DNA via the minor groove, however only artemisinin and artesunate, and not WHN11, cause DNA damage, indicating a potentially different mechanism of action of the three artemisinins. All three compounds act synergistically with camptothecin, which suggests interference with topoisomerase activity, partially supported by slight inhibition of TOPO I activity, and could indicate either direct inhibition of the enzyme or interference with enzyme function by competitive binding to the DNA. Further studies could help explore alternate DNA damage assays, to validate these findings, and the effect of the compounds on TOPO II activity could also be assessed. , Thesis (MSc) -- Faculty of Science, Biochemistry and Microbiology, 2022
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  • Date Issued: 2022-10-14

Biochemical evaluation of Tulbaghia violacea harv.rhizomes in diet induced hypercholestrolemic rats

  • Authors: Olorunnisola, Olubukola Sinbad
  • Date: 2012
  • Subjects: Violaceae , Anticoagulants (Medicine) , Antineoplastic agents , Rats , Hypercholesteremia , Cardiovascular agents , Medicinal plants
  • Language: English
  • Type: Thesis , Doctoral , PhD (Biochemistry)
  • Identifier: vital:11273 , http://hdl.handle.net/10353/d1006900 , Violaceae , Anticoagulants (Medicine) , Antineoplastic agents , Rats , Hypercholesteremia , Cardiovascular agents , Medicinal plants
  • Description: Discovery of cheap, nontoxic and readily available antiatherosclerotic drugs is an extraordinary challenge in this modern world. Atherosclerosis and cardiovascular diseases have been predicted to be the leading cause of death by the year 2030. Hence, this thesis was designed to search for plant (s) with anti-atherogenic properties, investigate its possible side effects and extrapolate its likely mechanism(s) of action. An ethnobotanical survey was employed in identification of locally important plants used for the management and treatment of cardiovascular diseases and its predisposing factors in Nkonkobe Municipality, Eastern Cape in South Africa. Information on the names of plants, their parts used and methods of preparation was collected through a questionnaire which was administered to herbalists, traditional healers and rural dwellers. The most frequently used plant (Rhizomes of Tulbaghia violacea Harv.) was investigated for toxicity using brine shrimp lethality (in vitro) and in vivo toxicity test (acute and subchronic) on rats to determine safety dosage. The in vitro antioxidant and free radical scavenging activity of the plant was investigated using models such as 1,1-diphenyl-2- picrylhydrazyl (DPPH), superoxide anions, hydrogen peroxide (H2O2), nitric oxide (NO), 2,2’- azinobis [3-ethylbenzothiazoline-6-sulfonic acid] diammonium salt (ABTS), lipid peroxidation inhibition and the ferric reducing agent. Phytochemical content and the effect of oral administration of fresh methanolic extract rhizomes of Tulbaghia violacea (250, 500 mg/kg. bwt/day) on Lipid peroxidation (TBARS), serum and tissue antioxidant enzymes in normal, hypercholesterolemic and diet induced atherogenic rats were also assessed. More so, the potential of the extract (250 and 500 mg/kg. bwt) to protect against atherogenic diet (4 percentage cholesterol 1 pecentage cholic acid and 0.5 percentage thiouracil) induced fatty streaks formation, dyslipidemia, oxidative stress and endothelial dysfunction was also investigated. Ethnobotanical study revealed that 19 plant species are used for the treatment of heart related diseases in the Municipality. 53 percentage of the plants mentioned were used for the management of chest pain, 47 percentage for high blood pressure, 42 percent for heart disease, 16 percentage for stroke and 11 percentage for the treatment of hypercholesterolemia. Tulbaghia violacea was repeatedly mentioned as the plant species used for the treatment of high blood pressure and predisposing factors in the study area. The brine shrimp cytotoxicity test revealed that fresh, dried methanolic extracts and essential oil of the T. violacea exhibited a high degree of cytotoxic activity with IC50 values of 18.18 (fresh) and 19.24 (dried) μg/ml. An IC50 value of 12. 59 μg/ml was obtained for the essential oil of the plant. The low cytotoxicity values obtained, suggested that rhizome of T. violacea may serve as a potential source of antimicrobial and anticancer agents. In vivo acute study of single oral administration of 5g/kg dose does not produce mortality or significant behavioral changes during 14 days observation. In the sub-chronic study, the extract (250, 500 mg/kg/bwt/ day) administered for a period of 28 days showed no mortality or morbidity. The weekly body and organ weight of the rats showed no significant differences between the control and the rats treated with the extract. The extract at all doses does not show any effect on of biomarkers of liver or renal damage. However, a significant decrease in the activity of ƔGT was observed in the extract treated groups. Hematological evaluation revealed that oral administration of fresh methanolic extracts of rhizomes of T. violacea does not cause anaemia or leucocytosis in the animals. Furthermore, histopathology results of the internal organs revealed no detectable inflammation. These results demonstrated that the rhizome extract of T. violacea was potentially safe for consumption orally even in chronic concentration. In vitro antioxidant evaluation showed that the essential oil, fresh and dried methanolic extracts exhibited potent antioxidant activities in a concentration dependent manner. Phytochemical investigation reveals that the fresh and the dry extract of RTV are rich in flavonoid, flavonol, phenols, tannin and proanthocyanidin, while the essential oil contained dimethy disulfide, dimethyl trisulfide, (methyl methylthio) methyl, 2,4-dithiapentane (11.35 percent) and (methylthio) acetic acid, 2- (methylthio) ethanol, 3-(methylthio) - and propanenitrile (7.20 percent). The fresh extract had higher radicals scavenging activity than the essential oil or dried extract, with 50 percentage inhibition of DPPH, hydrogen peroxide and lipid peroxidation at a concentration of 35.0 ± 0.12, 19.3 ± 0.11 and 17.9 ± 0.15 μg/ml respectively. Oral administration of methanolic extract of RTV in 125, 250 and 500 mg/kg to female Wistar rats significantly inhibited reduction of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). The extracts also inhibited (p< 0.05) lipid peroxidation in normal, high cholesterol and diet induced atherosclerosis fed rats in a dose dependant manner. Also the extract (250 and 500 mg/kg/bwt/day) caused a significant (p<0.05) improvement in body weight of treated animals compared with untreated hypercholesterolemia control rats. The extracts also protected significantly (p<0.05) against atherogenic diet induced liver damage or fatty streaks formation in the aorta as revealed by histological examination. The anti-cholesterolemia and anti-atherosclerotic activities of the extract compared favorably well with standard drugs Gemfibrozil and Atorvastatin respectively. Conclusively, rhizomes of T. violacea possess significant anti-atherogenic activity and its mechanism of action(s) may be due to its antioxidant and anti-hypercholesterolemia properties. The results of this study also suggested that rhizome of T. violacea is relatively safe for human consumption and it may be used as an alternative to garlic.
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  • Date Issued: 2012

A bioinorganic investigation of some metal complexes of the Schiff base, N,N'-bis(3-methoxysalicylaldimine)propan-2-ol

  • Authors: Mopp, Estelle
  • Date: 2010 , 2012-04-13
  • Subjects: Schiff bases , Bioinorganic chemistry , Metal complexes , Transition metal complexes , Transition metals , Cancer -- Chemotherapy , Ligands -- Toxicity , Antineoplastic agents
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:4413 , http://hdl.handle.net/10962/d1006768 , Schiff bases , Bioinorganic chemistry , Metal complexes , Transition metal complexes , Transition metals , Cancer -- Chemotherapy , Ligands -- Toxicity , Antineoplastic agents
  • Description: This thesis includes the synthesis, characterisation, antioxidant and antimicrobial activities of Cu(II)-, Co(II)- and Co(III) complexes with N,N'-bis(3- methoxysalicylaldimine)propan-2-ol, 2-OH-oVANPN. The Schiff base ligand, 2-OHoVANPN, is derived from o-vanillin and 1,3-diaminopropan-2-ol. The o-vanillin condensed with 1,3-diaminopropan-2-ol in a 2:1 molar ratio yields this potential tetraor pentadentate ligand. The complexes synthesized are tetra (or penta or hexa) coordinated. Formation of the complexes is symbolized as follows:- MX₂ + 2-OH-oVANPN (2:1) -> [M(2-OH-oVANPN)Xn] + HnX MX₂ + 2-OH-oVANPN (2:1) -> [Mn(2-OH-oVANPN)OH] + H₂X₂ MX₂ + (o-vanillin : diaminopropanol) (1:1) -> [M(1:1)X₂] MX₂ + (o-vanillin : diaminopropanol) (1:1) -> [M₃(1:1)X₄] M = Cu(II), Co(II) or Co(III); X = Cl; n = 1, 2. Their structural features have been deduced from their elemental analytical data, IR spectral data, and electronic spectral data. With the exception of {Cu₃(C₁₁H₁₄N₂O₃)(Cl)₄(H₂O)₆}(A4), the Cu(II) complexes were monomeric with 2-OH-oVANPN acting as a tetradentate ligand. A binuclear Co(II) complex, [Co₂(C₁₉H₁₉N₂O₅)(OH)] (B1), was synthesised and the rest of the Co(II) and Co(III) complexes were monomeric with chloride ions coordinating to the metal centre in some cases. Electronic data suggest that the cobalt(II) complexes have octahedral geometries and the copper(II) complexes have square planar structures – Co(III) is likely to be octahedral. Thermal analyses, which included the copper-block-method for determining sublimation temperatures, revealed that some copper(II) and cobalt(II) complexes are hygroscopic and sublime at 200 °C and below. DSC analyses of the Cu(II) complexes gave exotherms around 300 °C for complexes K[Cu(C₁₉H₂₀N₂O₅)(OH)]·2H₂O (A1) and [Cu(C₁₁H15N₂O₃)(Cl)₂]·2H₂O (A2) and above 400 °C for [Cu(C₁₁H₁₆N₂O₃)(Cl)₂] (A3) and {Cu₃(C₁₁H₁₄N₂O₃)(Cl)₄(H₂O)₆} (A4). Antioxidant studies were carried out against the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·). The cobalt(II) complex, [Co₂(C₁₉H₁₉N₂O₅)(OH)] (B1), which was synthesized in the presence of KOH, had no antioxidant activity, whilst the other cobalt(II) complexes, [Co(C₁₇H₁₇N₂O₅(Cl))]·1½H₂O (B2), [Co(C₁₉H₂₂N₂O₅) (Cl)₂]·5½H₂O (B3) and [Co(C₁₉H₂₂N₂O₅)(Cl)₂]·5½H₂O (B4), which were synthesised in the absence of KOH, demonstrated antioxidant activity. The latter complexes are candidates for cancer cell line testing, while [Cu(C₁₁H₁₆N₂O₃)(Cl)₂] (A3), {Cu₃(C₁₁H₁₄N₂O₃)(Cl)₄(H₂O)₆} (A4), [Co(C₁₉H₂₁N₂O₅)(Cl)₂ ]·5H₂O (C2) and [Co(C₁₉H₂₀N₂O₅)(Cl)]·3H₂O (C3) may show anticancer activity through possible hydrolysis products. Most of the complexes synthesized displayed antimicrobial activity against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, Aspergillus niger and Candida albicans. The results indicated that complexes [Cu(C₁₁H₁₆N₂O₃)(Cl)₂](A3), [Co(C₁₉H₂₂N₂O₅)(Cl)₂]·5½H₂O (B3) and [Co(C₁₉H₂₁N₂O₅)(Cl)₂ ]·5H₂O (C2) are active against the Gram-negative Ps. aeruginosa and that the ligand, 2-OH-oVANPN, did not have any activity. The same trend was observed with 2-OH-oVANPN, {Cu₃(C₁₁H₁₄N₂O₃)(Cl)4(H₂O)₆} (A4) and [Co(C₁₉H₂₀N₂O₅)(Cl)]·3H₂O (C3) against the Gram-positive S. aureus. As for activity against E. coli and C. albicans, some complexes showed more activity than the ligand. There is an observed trend here that the metal complexes are more active (toxic) than the corresponding ligand, which is in agreement with Tweedy’s chelation theory.
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  • Date Issued: 2010

A combination of platinum anticancer drugs and mangiferin causes increased efficacy in cancer cell lines

  • Authors: Du Plessis-Stoman, Debbie
  • Date: 2010
  • Subjects: Cancer -- Chemotherapy , Antineoplastic agents , Platinum compounds -- Therapeutic use , Cancer cells
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:10338 , http://hdl.handle.net/10948/d1016160
  • Description: This thesis mainly deals with some biochemical aspects regarding the efficacy of novel platinum anticancer compounds alone and in combination with mangiferin, as part of a broader study in which both chemistry and biochemistry are involved. Various novel diamine and N-S donor chelate compounds of platinum II and IV have been developed in which factors such as stereochemistry, ligand exchange rate and biocompatibility were considered as additional parameters. In the first order testing, each of these compounds was tested with reference to their “killing” potential by comparing their rate of killing, over a period of 48 hours with those of cisplatin and oxaliplatin. Numerous novel compounds were tested in this way, using the MTT cell viability assay and the three cancer cell lines MCF7, HT29 and HeLa. Although only a few could be regarded as equal to or even better than cisplatin, CPA7 and oxaliplatin, the testing of these compounds on cancer cells provided useful knowledge for the further development of novel compounds. Three of the better compounds, namely Yol 25, Yol 29.1 and Mar 4.1.4 were selected for further studies, together with oxaliplatin and CPA7 as positive controls, to obtain more detailed knowledge of their anticancer action, both alone and when applied in combination with mangiferin. In addition to the above, resistant cells were produced for each of the three different cell lines tested and all the selected compounds, both in the presence and absence of mangiferin. The effects of these treatments on the activation of NFĸB when applied to normal and resistant cell lines were also investigated. All the compounds induced apoptosis in the cell lines tested as well as alter the DNA cycle at one or more phase. Additionally, combination of these compounds with mangiferin enhanced the above-mentioned effects. Mangiferin decreases the IC50 values of the platinum drugs by up to 3.4 times and, although mangiferin alone did not induce cell cycle arrest, the presence of mangiferin in combination with oxaliplatin and Yol 25 shows an earlier and greatly enhanced delay in the S-phase, while cells treated with CPA7, Yol 29.1 and Mar 4.1.4 in combination with mangiferin showed a later, but greatly enhanced delay in the S-phase. It was also found that mangiferin acts as an NFĸB inhibitor when applied in combination with these drugs, which, in turn, reduces the occurrence of resistance in the cell lines. Resistance to oxaliplatin was counteracted by the combination with mangiferin in HeLa and HT29, but not in MCF7 cells, while resistance to CPA7 was only counteracted in the MCF7 cell line. Yol 25 and Mar 4.1.4 did not seem to induce resistance in HeLa and MCF7 cells, but did in HT29 cells, whereas Yol 29.1 caused resistance in HeLa and HT29 cells, but not in MCF7 cells. Finally, an effort was made to evaluate the different compounds by comparing them with respect to their properties relating to anticancer action with and without the addition of mangiferin.
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  • Date Issued: 2010

New platinum coordination compounds : their synthesis, characterization and anticancer application

  • Authors: Oosthuizen, Lukas Marthinus
  • Date: 2009
  • Subjects: Platinum compounds , Antineoplastic agents
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:10430 , http://hdl.handle.net/10948/d1018795
  • Description: The aim of this thesis was to investigate the properties of novel platinum compounds with possible potential as anticancer agents, and to determine how their behaviour could lead to a better understanding of the chemistry involved. The final criteria were improvement of their anticancer behaviour. Since many questions are still unanswered as to the role of sulfur in anticancer action, studies were undertaken to synthesize novel platinum(II) complexes having non-leaving groups consisting of a combination of an aromatic nitrogen and thioetherial sulfur capable of forming a five membered ring upon coordination. The structural unit was 1-methyl-2-methylthioalkyl/aryl. Numerous complexes formed by these ligands each having chloro, bromo, iodo and oxalato leaving groups were then fully characterized. The results obtained by the various synthetic methods were compared and explained in terms of the chemistry involved. The role of the sulfur donor was indicated in both the halo- and oxalato-complexes and proved to be strongly influenced by the nature of the leaving groups. Their differences are reflected in their anticancer behaviour. The study was extended to mononitroplatinum(IV) complexes, in view of the kinetically stable platinum(IV) compounds and advantages related to this. A specific mononitroplatinum(IV) complex which proved to have good anticancer and STAT 3 properties could according to the literature not be synthesized successfully in a good yield and a high degree of purity. The results of extensive studies showed that the main problem centred around the simultaneous reactions in equilibrium during the synthesis. A number of these species formed as a result of side reactions could be identified and their close separation factors indicated chromatographically. The mechanism of these reactions and the unstable intermediate species involved could be rationalized and compared to analogues in the literature. All the complexes studied were characterized by spectral and thermal methods both in solution as well as the solid state. Their anticancer behaviour towards three anticancer cell lines (Hela, MCF 7, Ht 29) were determined and acted as a guide towards possible structural modifications for their improved capability. Three crystal structures of platinum(II) complexes were determined. The extent of the ionization of the platinum(II) complexes as well the redox potentials (Pt(II) / Pt(IV)) of the platinum(IV) complexes were particularly important factors pertaining to their anticancer action.
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  • Date Issued: 2009

Synthesis and characterization of novel platinum complexes : their anticancer behaviour

  • Authors: Myburgh, Jolanda
  • Date: 2009
  • Subjects: Complex compounds -- Synthesis , Platinum compounds , Antineoplastic agents
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:10429 , http://hdl.handle.net/10948/d1018621
  • Description: In this dissertation novel non-leaving groups were employed to synthesize platinum complexes which can contribute to the understanding or improvement of anticancer action. These complexes basically consist of (NS)-chelate and amineplatinum complexes. Bidentate (NS)-donor ligands were used as non-leaving ligands in the syntheses of platinum(II) complexes with iodide, chloride, bromide and oxalate anions as leaving groups. These complexes were synthesized and studied since many questions regarding the interaction of sulfur donors and platinum still exists. These relate to thermodynamic and kinetic factors and their influence on anticancer action. In this dissertation the properties of novel platinum(II) complexes of a bidentate ligand having an aromatic nitrogen-donor atom in combination with a thioethereal sulfur atom capable of forming a five membered ring with platinum(II) were studied. The general structure of the (NS) -ligands used were N-alkyl-2-methylthioalkyl imidazole. Alkyl groups used were methyl, ethyl and propyl. Although amine complexes of platinum have been extensively studied there are some new aspects of these that are worthwhile investigating. In this dissertation amines having planar attachments which will be at an angle with the coordination plane viz. benzylamine and amines having cyclic aliphatic groups namely cyclopropyl and cyclohexyl were investigated. Some of the (NS) - and amineplatinum(II) complexes were oxidised to their mononitroplatinum(IV) analogues . The motivation for the synthesis of these complexes was the greater kinetic stability of platinum(IV) and recent research has shown that a specific type of platinum(IV) compound shows suitable properties as an anticancer agent. These complexes were characterised by a variety of spectral means (IR, NMR, mass spectroscopy) as well as elemental analysis, solubility determinations, thermal analysis (TGA), ionization studies and finally their anticancer behaviour towards three different cell lines(Hela, MCF 7, Ht29) and in this process they were compared to the behaviour of cisplatin as a reference. A few have shown promising anticancer behaviour.
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  • Date Issued: 2009

Novel aspects of platinum-amine coordination compounds: their chemistry and anticancer application

  • Authors: Bouwer, Yolanda
  • Date: 2008
  • Subjects: Coordination compounds , Platinum compounds , Antineoplastic agents
  • Language: English
  • Type: Thesis , Doctoral , PhD
  • Identifier: vital:10444 , http://hdl.handle.net/10948/d1021052
  • Description: The aim in this thesis, was to synthesize novel platinum coordination compounds, in order to develop compounds with improved anticancer action which could lead to an improved understanding of the mechanism by which they operate and at the same time, improve synthetic methods for their products. The initial work included the development of a novel synthetic method for 1R,2R-diaminocyclohexaneoxalato-platinum(II) (oxaliplatin), by using an essentially non-aqueous solvent medium and direct ligand exchange at elevated temperatures. This was done by a study of the kinetics of the reaction in a variety of conditions; such as relative reagent concentrations and ratios as well as solvent mixtures. An effective method was developed which could be applied industrially. An international patent was taken out on this method. Various amine complexes of platinum(II) were synthesized using chloro, bromo and oxalato groups as leaving groups. The non-leaving groups were selected having certain specific characteristics in mind. Novel mononitroplatinum(IV) complexes were synthesized, mostly with oxalato leaving groups. One of these in particular, had excellent anticancer behaviour. Another trichloromononitro complex was also synthesized with very good anticancer properties. Two international patents were filed for the latter two compounds. As far as possible, all compounds were studied by spectrometric, chromatographic and thermal methods. They were also tested against 3 cancer cell lines namely cervical (Hela), Colon (HT29) and Breast (MCF7) cancer cells.
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  • Date Issued: 2008

Synthesis of triprenylated toluquinone and toluhydroquinone metabolites from a marine-derived Penicillium fungus

  • Authors: Scheepers, Brent Ashley
  • Date: 2007
  • Subjects: Penicillium , Antineoplastic agents , Marine fungi , Quinone
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:4373 , http://hdl.handle.net/10962/d1005038 , Penicillium , Antineoplastic agents , Marine fungi , Quinone
  • Description: This project forms part of a collaborative effort between the marine natural products chemists at Rhodes University and the medical biochemists at the University of Cape Town’s School of Medicine. Our UCT collaborators tested the cytotoxicity of a group of toluhydroquinones and toluquinones (9-15) against the oesophageal cancer cell line WHCO1 and revealed that the triprenylated toluhydroquinone 11 and it’s oxidised analogue 12 were the most active. This thesis presents an investigation into the role of the polyprenyl side-chain in the cytotoxicity of compound 11 and it’s oxidised analogue 12 by synthesizing and testing the cytotoxicity of simplified analogues of this compound. The synthesis of the two ortho-prenylated toluhydroquinone analogues 5-methyl-2-[(2'E,6'E)-3',7' -dimethyl-2',6'-octadienyl]-1,4-benzenediol (19) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-1,4-benzenediol (21) and their two ortho-prenylated toluquinone analogues, 5-methyl-2-[(2'E,6'E)-3',7'-dimethyl-2',6'-octadienyl]-2,5-cyclohexadiene-1,4-dione (20) and 5-methyl-2-[(2'E,6'E)-3',7',11'-trimethyl-2',6',10'-dodecatrienyl]-2,5-cyclohexadiene-1,4-dione (22) is described. Our initial attempts to couple geranyl bromide, farnesyl bromide and farnesal to the aromatic precursors m-cresol and 1,4-dimethoxy-2-methylbenzene using directed ortho-prenylation and phenoxide carbon-alkylation were unsuccessful. The four target analogues were eventually synthesized via the initial metal halogen exchange reaction between 1-bromo-2,5-dimethoxy-4-methylbenzene and geranyl bromide/farnesyl bromide using n-BuLi and TMEDA in ditheyl ether at 0 °C to yield 92 and 104 respectively in moderate yield. The demethylation of both compounds preceded smoothly using AgO giving the target analogues 20 and 22 in good yield (approx. 90 %). The reduction of quinones 20 and 22 with sodium dithionite gave 19 and 21 in quantitative yield. The synthesis reported here is the first regioselective synthesis of these compounds. The anti-oesophageal cancer activity of 19-22 and two commercially available non-prenylated analogues 17 and 18 were tested against WHCO1. The conclusion drawn from the anti-oesophageal cancer study was that the polyprenyl side-chain plays a negligable role in the cytotoxicity of compounds such as 11 and 9 against the oesophageal cancer cell line WHCO1.
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  • Date Issued: 2007

An investigation of the in vitro anticancer properties of selected platinum compounds

  • Authors: Du Plessis-Stoman, Debbie
  • Date: 2006
  • Subjects: Antineoplastic agents , Platinum compounds , Cancer -- Immunological aspects , Cancer -- Chemotherapy
  • Language: English
  • Type: Thesis , Masters , MSc
  • Identifier: vital:10334 , http://hdl.handle.net/10948/498 , http://hdl.handle.net/10948/d1012002 , Antineoplastic agents , Platinum compounds , Cancer -- Immunological aspects , Cancer -- Chemotherapy
  • Description: This dissertation mainly deals with some biochemical aspects regarding the efficacy of novel platinum anticancer compounds, as part of a broader study in which both chemistry and biochemistry are involved. Various novel diamine and N-S donor chelate compounds of platinum II and IV have been developed in which factors such as stereochemistry, ligand exchange rate and biocompatibility were considered as additional parameters. In the first order testing, each of these compounds was tested with reference to their “killing” potential by comparing their rate of killing, over a period of 48 hours with those of cisplatin and oxaliplatin. Some 80 compounds were tested in this way. Although only a few could be regarded as equal to or even better than cisplatin and oxaliplatin, the testing of these compounds on cancer cells provided useful knowledge for the further development of novel compounds. Four of the better compounds, namely Y9, Y14, Y16 and Lt16.2 were selected for further studies to obtain more detailed knowledge of their anticancer action, including some flow cytometric studies. In addition to the above, cisplatin resistant cells were produced for each of the three different cell lines tested, namely, HeLa, HT29 and MCF7 cancer cell lines, by intermittent and incremental exposure to cisplatin (all the cell lines tested became resistant to cisplatin). Each of the selected compounds were exposed to the cells in the same manner, in order to attempt the induction of resistance against these compounds in the three cell lines tested (i.e. whether these cells will become resistant to the various compounds). Each of these selected platinum containing compounds were subsequently tested against the “cisplatin resistant” cell lines in order to determine their efficacy against such cells. One such compound could be singled out, since cervical cancer cells (HeLa cells) do not become resistant to it. This behaviour is similar to that of oxaliplatin against cervical cancer and colon cancer (HT29) cells (oxaliplatin is the number one treatment for colon cancer at present). This compound also proved to be more active against cisplatin resistant cell lines. It was found that all the compounds induced apoptosis in the cell lines tested as well as inhibit the DNA cycle at one or more phase. Finally, an effort was made to evaluate the different compounds by comparing them with respect to their properties relating to anticancer action.
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  • Date Issued: 2006
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