ABSTRACTSYNTHESIS AND EVALUATION OF NOVEL INHIBITORS OF THE CHK2 AND NF-κB PATHWAYSByMicah LudererThe first chapter of this thesis describes synthetic efforts towards novel checkpoint kinase II inhibitors (Chk2). Inhibitors of Chk2 have the potential to protect healthy cells during ionizing radiation treatments by preventing the activation of p53, a cellular apoptotic pathway. Previously our group reported the synthesis of indoloazepine, a hymenialdisine derived natural product. Indoloazepine was found to be a more potent inhibitor of Chk2 compared to the natural product hymenialdisine. The main goal within this thesis was developing a synthesis for the constitutional isomer, iso-indoloazepine. Compared to indoloazepine, the inverted indole ring of iso-indoloazepine was believed to be capable of making an additional hydrogen bond to Glu-308 in the binding pocket of Chk2. Iso-indoloazepine and other analogs have been found to be selective inhibitors of Chk2. The second chapter of this thesis describes synthetic work to further our understanding of how imidazolines inhibit the proteasome. Primarily, synthetic efforts were directed to resolve several racemic imidazolines into their individual enantiomers. This synthetic work was aimed to elucidate enantioselectivity of the proteasome.
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