Chemistry to Biology and Back Again: Small Molecule Regulation of HIF Transcription Factors and the Development of a Platform for the Discovery of New Biocatalyzed Organic Transformations
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This work is divided into two parts. The first is the description of the regulation of the hypoxic response pathway via small molecule inhibitors. The hypoxia response pathway is a way in which cells sense and regulate oxygen levels in cells. Specifically, when oxygen levels in the cells are low, a family of transcription factors known as hypoxia inducible factors (HIFs) is up regulated. Importantly, the hypoxic response pathway is often mis–regulated in cancer. As a result, the regulation of this pathway offers a promising target for cancer treatment. Previous work on HIF identified a large internal cavity, which provided an opportunity for allosteric binding and regulation of HIF. After identification of a small molecule inhibitor of HIF through a high–throughput screening campaign, an SAR analysis was performed on the lead molecule. This led to a greater understanding of the structural requirements to strong binding with HIF. In addition, a sterol natural product was identified through the screen that also inhibits HIF. This molecule led to the search for the endogenous ligand of the HIF transcription factor and has developed a better understanding of the natural regulation of the hypoxic response pathway. The second part of this work describes the development of a new discovery platform for the identification of new, biocatalyzed organic transformations. Biocatalyzed organic transformations have been used by organic chemists for decades as these reactions offer many benefits to the synthetic chemist. For example, reactions catalyzed by biological enzymes tend to be very stereo- and regiospecific. In addition, biocatalyzed transformation can occur on unfunctionalized organic substrates. However, research into new biocatalyzed reactions has been limited due to the challenges in searching for these new reactions. We have developed a discovery platform designed to screen a vast library of bacteria for new reactivity by introducing 13C labeled substrates to cultures. This platform is illustrated with the discovery of a tunable indole oxidation reaction.