Expeditious synthesis of hymenialdisine and its analogs and their evaluation as adjuvants in cancer therapy

The dissertation focuses primarily on three aspects of the research carried out during the PhD. These include the efforts towards synthesis of hymenialdisine and its analogs and their evaluation for improving chemotherapy; the development of the methodology to access triazolines and triazoles from oxazol-5(4H)-ones and synthesis of imidazoline for the study of the interaction of this class of compounds with the 20s proteasome using photoaffinity labeling studies.;Previous studies have shown that Checkpoint kinase 2 (ChK2) plays an important role in cell cycle regulation in response to the various DNA damaging agents including chemotherapeutics. There is evidence that the cellular role of ChK2 can be utilized to improve the existing chemotherapeutic techniques. Hymenialdisine is a natural product known to inhibit ChK2. The first part of the dissertation presents the improved synthesis of the natural product and the synthesis of the new analogs. Two classes of analogs are presented: First the 2-phenylpyrroloazepinone based analogs, prepared via single step modification of a common intermediate; and second, the benzoazepinone analogs that utilize the ring expansion strategy to achieve the synthesis of key intermediate. This part also presents the kinase profiling of these compounds.;The second part of the dissertation describes the development of the cycloaddition reaction of oxazol-5(4H)-ones and azodicarboxylates. Previously, our group has reported the utility of oxazol-5(4H)-ones in diversity oriented synthesis enabling access to a wide range of heterocyclic scaffolds. This part presents the research work done in extending the chemistry to access triazoline and triazole compounds. The dissertation describes the initial discovery of the reaction and the exploration of the reaction substrate scope to give 1,2,4-triazoline compounds. The dissertation also describes the aromatization of these 1,2,4-triazoline compounds to respective triazole compounds.;The last part of the dissertation focuses on contributions towards the study of inhibition of 20s proteasome. The 20s proteasome is shown in the literature to decreases the efficiency of the cancer therapeutics by degrading IkappaB and thus allowing NF-kappaB to translocate into nucleus and transcribe the antiapoptotic genes in the cancer cells. Our group has prepared the imidazoline compounds as a novel class of 20s proteasome inhibitor. These compounds are non-competitive inhibitors, unlike the other clinically relevant inhibitors of the proteasome. This part of the dissertation presents the synthesis of photoaffinity labeled imidazoline to study the interaction of these compounds with the proteasome. Lastly, the evaluation of the new hymenialdisine derivatives for their ability to inhibit 20s proteasome is presented.