The proposed project seeks to compile a library of potential small molecule insulin-mimics, based on a known pharmacophore, through the use of synthetic organic chemistry. This library of compounds will be tested for activation of the human insulin receptor. Broadly, the project focuses on the synthesis of kojic acid-derived compounds based on a natural product insulin mimic, demethylasterriquinone B1 (DAQ B1). DAQ B1 was found to activate the insulin receptor in cells and lower glucose in mouse models of diabetes, but the presence of the quinone ring in its structure impeded the compound's progression into clinical trials. Specifically, this project seeks to train the applicant in the techniques and practices common in synthetic organic chemistry and pharmaceutical research, such as development and optimization of multistep syntheses. Synthetic routes to DAQ B1 relatives with the problematic quinone replaced with kojic acid derivatives will be optimized for efficiency. The synthesized library of compounds will be tested by other laboratory members for activation of the insulin receptor, with the ultimate goal being the identification of small molecules that mimic the protein insulin. The process of devising synthetic routes to various targets in an insulin-mimic library not only serves as an excellent training experience for a career in pharmaceutical research and development, but is also relevant to the NIH mission. The research could have immediate application to public health, as it focuses on the discovery of drugs for the treatment of diabetes. The project is also relevant to public health in that the discovery of a small molecule that replaces insulin would be a monumental development in pharmaceutical science. Such a compound could be an orally-administered replacement for insulin injections. A small molecule insulin-mimic drug would enhance public health because production and therefore consumer costs would decrease and more patients would be able to receive a low-cost and convenient diabetes treatment.
|Pirrung, Michael C; Nalbandian, Jenifer N (2013) Catalyzed Claisen rearrangements of O-allyl kojates. Tetrahedron Lett 54:|