Browsing by Author "Van Otterlo, Willem"

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    Aberrant apoptotic response of colorectal cancer cells to novel nucleoside analogues
    (Public Library of Science, 2015) Harmse, Leonie; Dahan-Farkas, Nurit; Panayides, Jenny-Lee; Van Otterlo, Willem; Penny, Clement
    Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues.
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    From synthetic methodology to making molecules with a mission – a research summary of the first 10 years
    (Stellenbosch : Stellenbosch University, 2011-06) Van Otterlo, Willem
    Willem van Otterlo was born in Amsterdam, The Netherlands. As a child he moved to Southern Africa and received his primary and secondary schooling in Windhoek, Namibia, and Johannesburg, South Africa. In 1989 he started his BSc and in 1999 he graduated with a PhD that involved the synthesis of analogues of the michellamines. The PhD was performed under the mentorship of Profs CB de Koning and JP Michael at the School of Chemistry, University of the Witwatersrand (WITS), Johannesburg. He then spent two years in the research group of Prof. Stephen Hanessian (University of Montreal, Quebec, Canada) as a postdoctoral fellow, involved in projects focused on medicinal chemistry and synthesis utilising peptide-based building blocks. In 2001 he returned to his alma mater to take up a lecturing position and initiated a research programme involving the application of organometallic reagents to the synthesis of small benzo-fused molecules, eventually attaining the rank of Associate Professor. In July 2008 he joined Prof. Dr Herbert Waldmann’s Chemical Biology group at the Max Planck Institute, Dortmund, as a von Humboldt (Georg-Forster) Research Fellow for a sabbatical year to learn more about the interaction between chemistry and biology. He then took up the Chair of Organic Chemistry at Stellenbosch University, Western Cape. Since June 2010 he has been striving to nurture a team environment at the Department of Chemistry and Polymer Sciences so that organic and medicinal chemistry research can be performed in collaboration with talented colleagues. His current research interests are focused on the synthesis of small molecules with potential bioactivity, particularly molecules based on natural templates such as pancratistatin, podophyllotoxin, colchicine and purpurogallin, as well as research focused on the design of better ligands for enzymes (kinases and phosphatases) and nuclear receptors (estrogen receptor).