In this application we propose to synthesize libraries based on the following scaffolds, tropinones, hydroxyprolines, 2(1H)-pyridone ring systems and 1,5-dioxaoctahydroindenes. These scaffolds were chosen for a variety of reasons, including their inherent activity, stability, availability and common methods that can be used in the synthesis of analogs. The general approach that will be taken in the synthesis of each of the libraries proposed is to start with a scaffold that can be synthesized in sufficient quantities to ensure that access to the starting core will not limit the ability to synthesize libraries. (The synthesis of the dysiherbaine core is more complicated and consequently smaller libraries will be synthesized around this scaffold.) So that we are assured to being able to provide the libraries we propose, each core has functional groups with orthogonal reactivity that allows for the attachment of pharmacophores by reliable chemistry. To help ensure that the libraries have the desired physical properties such as solubility and stability the scaffolds that have been chosen have all been found to be biologically active. Additionally, we have entered in to a collaboration with Dr. Shuxing Zhang from M.D. Anderson Cancer Center to provide computational support in the design of diverse libraries.
The compounds synthesized during the project period will be used to support the National Institutes of Health Molecular Libraries initiative and the National Small Molecule Repertory. The proposed work will create valuable research tools to study biology and support the biomedical research community in the United States.
|Do, Ha; Kang, Chang Won; Cho, Joon Hyung et al. (2015) Enantioselective Synthesis of (-)-Dysiherbaine. Org Lett 17:3972-4|
|De, Subhasis; Chen, Lu; Zhang, Shuxing et al. (2013) Synthesis of a 2(1H)-pyridone library via rhodium-catalyzed formation of isomunchones. ACS Comb Sci 15:340-3|
|Khalaf, Juhienah; Estrella-Jimenez, Maria E; Shashack, Matthew J et al. (2011) Design, synthesis, and diversification of 3,5-substituted enone library. ACS Comb Sci 13:351-6|
|Tanifum, Eric A; Gilbertson, Scott R (2010) Design, synthesis, and diversification of 5,5-dimethyl cyclohexen-1,4-dione library. J Comb Chem 12:318-20|