Browsing by Author "Van der Westhuyzen, Aletta Elizabeth"
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- ItemSynthesis of novel staurosporine analogues as potential kinase inhibitors(2015-03) Van der Westhuyzen, Aletta Elizabeth; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: Protein kinases are enzymes that promote phosphorylation – transferring a phosphate group from ATP to a substrate protein. Due to the central involvement of kinases in growth factor signaling, cell cycle control, apoptosis and angiogenesis, they have been linked to cancer development and are attractive drug targets for cancer therapeutics. Staurosporine is a natural, potent kinase inhibitor, initially isolated from the bacterium Streptomyces staurosporeus. It does not serve as a viable therapeutic drug since it exhibits poor selectivity. However, this natural product has been widely used in research and serves as a “structural muse” for the design of protein kinase inhibitors with improved specificity and selectivity. This project involved the synthesis of potential reversible and irreversible kinase inhibitors inspired by the natural product staurosporine. A primary objective was to develop compounds with improved selectivity, while maintaining the potency of staurosporine. The design strategy incorporated a driving portion, resembling the structural features of staurosporine, carrying a specific warhead to form a reversible or irreversible interaction within the kinase domain. This project comprises of two main parts – the design of pyrrolocarbazole structures and the generation of structures based on the “open” form of the indolocarbazoles. The development of the pyrrolocarbazole compounds was motivated by the encouraging results exhibited by 6-(3-hydroxypropyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (29), previously synthesized in our group. The major steps involved in the synthesis were the reduction, oxidation, Wittig, Diels-Alder and aromatization reactions. Introducing different warheads, allowed for the generation of unaromatized and aromatized pyrrolocarbazole target compounds having an N-tether hydroxyl, propargyl and nitrile functionality. The synthesis of the “open” form structures utilized click chemistry. The synthetic methodology towards the bisaryl maleimide structures involved a “double click” approach, which presented various challenges. In addition, the synthesis of indolyl maleimide click products also proved to be difficult. Finally, a promising route towards bisamino maleimide compounds led to the development of two target compounds containing the acryloyl and propargyl warhead functionality respectively. Biochemical screening by German collaborators against the wild type, and two mutant forms of the EGFR kinase, was undertaken with the target compounds, utilizing the HTRF KinEASE-TK assay. Overall, only the aromatized pyrrolocarbazole N-two carbon linker hydroxyl target compound exhibited inhibitory activity in the μM range. Finally, a number of optimization measures are described to potentially improve the inhibitory activity of both the pyrrolocarbazole compounds and bisamino maleimides.