Biochemical studies of targeted and bimodal analogues of the natural anticancer compounds combretastatin A-4 and illudin M
This thesis presents a study on novel chemotherapeutics based on naturally designed scaffolds. The cytotoxicity of promising pharmaceutical compounds was tested on various cells of neural and/or cancerous origin, monitoring their specificity, re-growth retardation and mechanism of apoptosis induction. The proposed drug uptake was analysed using specific inhibitors to disable certain transporters/carriers. Changes in the shapes of cellular and sub-cellular components resulting from drug treatment were observed by light microscopy, immune-fluorescence microscopy, time-lapse recording microscopy and transmission electron microscopy. The apoptotic signals, increased cellular activity of caspase-3 or redundant calcium level, were monitored during drug incubation. Because DNA-degradation plays an important role in apoptosis, DNA-drug interactions affecting chromosomal or plasmid DNA were investigated from various perspectives. Since resistance is a constricting factor for drug efficiency, the interaction of the drugs with glutathione and various efflux transporters were analysed.
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