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The design, synthesis and antiplasmodial activity of a series of halogenated fosmidomycin analogues and hybrid drugs

- Afolayan, Anthonia Folake

Authors: Afolayan, Anthonia Folake
Date: 2012
Subjects: Uncatalogued
Language: English
Type: text , Thesis , Doctoral , PhD
Identifier: http://hdl.handle.net/10962/64370 , vital:28538
Description: Malaria continues to be a devastating disease and a major cause of death in sub-Saharan Africa. With resistance against most of the available antimalarial drugs, there is a need for ongoing research and development of antimalarial agents. Fosmidomycin and its acetyl analogue FR900098 have been identified as potent inhibitors of Plasmodium falciparum, the causative agent of the most deadly form of malaria. Clinical trials of these agents have revealed poor absorption due to their high hydrophilicity. In the present studies the effect of halogenation of the acyl chain as well as the biological effect of extending the acyl sidechain was explored. This provided the basis on which fosmidomycin hybrids were designed to investigate the feasibility of hybrid extending into NADPH binding pocket. Synthesis of a series of halogenated FR900098 analogues was carried out in three stages. This included i) The introduction of the phosphonate group by reaction with 1,3dibromopropane in an Arbuzov reaction, ii) The introduction of a hydroxamate group by reaction of the propyl phosphonate by means of a nucleophilic substitution reaction with BocNHOBn and iii) The introduction of a halogenated acyl side chain on a protected fosmidomycin backbone. The synthesis of fosmidomycin-hybrids for which chloroquinefosmidomycin hybrids were used as the prototype, involved convergence of the two separately constructed moieties i.e. fosmidomycin and the quinoline moieties in a covalent linkage. The quinoline moiety was easily synthesized from the reaction of 4,7dichloroquinoline with 1,2-diamino ethane. The aminoquinoline so formed resulted in chloroquine-fosmidomycin hybrids 3.8 and 3.9 when reacted with halogenated FR900098 analogues. Antiplasmodial assays were conducted on the chloroquine-fosmidomycin hybrids and the halogenated fosmidomycin derivatives against the chloroquine resistant Gambian FCR-3 strain of P. falciparum. The most potent iodoacetyl fosmidomycin analogues 2.21 gave an IC50 value of 5.54 µM which is eight times more potent than the known antiplasmodial FR900098 which gave an IC50 value of 41.67 µM. All the halogenated FR900098 analogues showed better antiplasmodial activity than their non-halogenated derivatives. This indicated that the presence of halogens in the FR900098 analogues contributes to their biological Chapter 1 Literature review activity. The acetyl and propyl linked hybrids 3.8 and 3.9 showed potent antiplasmodial activity with IC50 values of 0.18 and 0.82 µM respectively. These were by far the most potent hybrids synthesized and provided leads for a new class of promising antimalarial agents. Preliminary E. coli DXR enzyme inhibition assays were carried out on the halogenated fosmidomycin analogues. The results showed good inhibition of the enzyme by the phosphonic acids of the chloroacetyl and chloropropyl analogues 2.1 and 2.2 respectively. Molecular modelling of the compounds on E. coli (PDB code: 2EGH) and P. falciparum (PDB code: 3AUA) DXR showed strong binding of the halogenated fosmidomycin analogues while the hybrids in the absence of docked NADPH showed minimum binding to the enzymes.
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Date Issued: 2012

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Self-reports on the effectiveness of psychotherapy with therapists-in-training: an 18-month follow-up study at a psychology training clinic

- Angus, Catherine Clare

Authors: Angus, Catherine Clare
Date: 1993
Subjects: Uncatalogued
Language: English
Type: Master's theses , text
Identifier: http://hdl.handle.net/10962/193069 , vital:45295
Description: The purpose of this study is to ascertain whether the clients who make use of the services of the Psychology Clinic at Rhodes University perceive the masters students being trained at the Clinic as providing adequate psychotherapy. Using a sample of 18 clients, who underwent psychotherapy at the Rhodes Psychology Clinic during 1990, a follow-up study was conducted to ascertain the perceived success of that psychotherapy. Those variables most pertinent to the outcome of psychotherapy are examined. The study uses both qualitative and quantitative methodology and shows that, overall, 89% of the clients who participated in this study perceived the psychotherapy at the Rhodes Psychology Clinic to be satisfactory. The study also highlights those factors which were perceived to be negative in the psychotherapeutic equation and it is hoped that the findings can be beneficial in planning more efficient services for the Clinic in the future. , Thesis (MA) -- Faculty of Humanities, Psychology, 1993
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Date Issued: 1993

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The novobiocin-induced turnover of fibronectin via low density lipoprotein receptor-related protein 1 alters matrix morphology with physiological consequences on cell growth and migration

- Boёl, Natasha Marie-Eraine

Authors: Boёl, Natasha Marie-Eraine
Date: 2020
Subjects: Uncatalogued
Language: English
Type: Master's theses , text
Identifier: http://hdl.handle.net/10962/114778 , vital:34034 , 10.21504/10962/114778
Description: Fibronectin (FN), an extracellular matrix protein, is secreted as a soluble dimer which is assembled into an insoluble extracellular matrix. The dynamics of FN matrix assembly and degradation play a large role in cell migration and invasion thereby contributing to the metastatic potential of cancer cells. Previous studies have shown the direct binding of Heat Shock Protein 90 kDa (Hsp90) and FN in vitro, and that inhibition of Hsp90 with novobiocin (NOV) caused internalisation of the FN matrix. Low density lipoprotein receptor-related protein 1 (LRP1) is a ubiquitous receptor known to bind both Hsp90 and FN. Using an LRP1 expressing Hs578T breast cancer cell line and an isogenic mouse embryonic fibroblast (MEF) model system of differential LRP1 expression we demonstrate that LRP1 is involved in turnover of FN in response to C-terminal Hsp90 inhibition. The first objective of this study was to identify the mechanism of NOV-induced LRP1-mediated FN turnover. Our data show that NOV-mediated FN turnover via LRP1 did not require the activity of matrix metalloproteinases (MMPs), which play an important role in processing and degradation of the extracellular matrix and FN. In addition, the levels of the main FN receptor responsible for its extracellular assembly, β1-integrin, did not change in response to NOV. LRP1 is known to undergo regulated intramembrane proteolysis (RIP) which generates smaller fragments that may translocate to the nucleus and modulate gene transcription. Using inhibitors of LRP1 cleavage and nuclear fractionation we determined that LRP1 processing was not required for the NOV-induced FN response suggesting that a mechanism unrelated to LRP1 RIP is involved. A possible mechanism may be in altered Hsp90-LRP1 cell signalling as we observed disruption of the FN-Hsp90-LRP1 complex at the cell surface in NOV treated cells. How this affects downstream eHsp90-LRP1 signalling is still to be determined but may be related to a significant increase in phospho-AKT and loss of phospho-ERK upon NOV-treatment; two key signalling proteins involved in FN matrix regulation and which are downstream of LRP1 signalling. The second objective of this study was to determine the physiological consequences associated with FN turnover in response to NOV treatment. Using migration assays we demonstrated that levels of insoluble matrix-associated FN and FN concentration are not solely responsible for migratory capacity of cells on decellularized extracellular matrices, but rather that structural composition and integrity of the matrix plays a bigger role. Using confocal and scanning electron microscopy, we identified NOV treated matrices to be flatter, less mature and contain thicker, rope-like FN fibrils to which cells adhered better but were generally less proliferative. Comparatively, cells adhered less to the more mature and 3-dimensional untreated matrices but exhibited increased spreading and cell growth, which may in part be due to the thinner fibrils and web-like matrix. In summary, this study substantiates the role of LRP1 in NOV-mediated FN turnover, and provides new insights into the possible mechanisms of the Hsp90-LRP1 mediated loss of FN matrix. This is the first study to demonstrate some of the functional consequences related to FN turnover by NOV at the ECM level. , Thesis (PhD) -- Faculty of Science, Biochemistry and Microbiology, 2020
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Date Issued: 2020

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Construction Unions Negotiators Conference

- Building & Wood Workers International (BWI)

Authors: Building & Wood Workers International (BWI)
Date: 2009-05
Subjects: Uncatalogued
Language: English
Type: text
Identifier: http://hdl.handle.net/10962/105819 , vital:32572
Description: This publication aims to familiarise negotiators with inflation statistics, which are not as straight forward as they might seem at first glance. It provides negotiators with the latest inflation figures (at the time of publication), and puts forward a few guidelines for dealing with inflation in the context of collective bargaining. After ail, if you know what the rules of the game are you can break them property , here put any information that you think is important but there is no field for it, if there isnt remove the field
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Date Issued: 2009-05

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