Although anti-tumor properties have been observed for several organosilicon compounds, the potential for a diverse silyl-functionalized library has not yet been realized. The goal of the proposed research is to develop and synthesize a library of diverse small molecules exploiting a novel allylsilane annulation strategy on solid support. Branching Sakurai, [3+2] annulation and intramolecular cyclization pathways of allylsilanes will be employed with various building blocks to generate diverse natural product-like scaffolds. This strategy will provide rapid access to biologically active heterocycles and carbocycles such as tetrahydrofurans, pyrrolidines, pyrrolidinones, isoxazolidines, quinone derivatives, tetrahydroquinolines, lactams, and cyclopentane rings, as well as homoallylic alcohols and peptidomimetics. There will be four diversity-generating steps for this library: 1) loading the aldehyde substrate, 2) formation of the allylsilane functionality, 3) branching pathways of allylsilanes to afford structurally diverse heterocycles and homoallylic substrates, and 4) cleavage of the small molecule product from the solid phase to either retain the silyl group in the product or provide a hydroxy substituted heterocycle. This strategy will afford a structurally distinct library with a minimum of 200,000 silyl- and hydroxy-functionalized compounds. These diverse small molecule ligands will be utilized in a chemical genetics approach to explore biological function and disease pathways. Both phenotypic and protein-binding assays will be performed to generate direct leads for drug development and cancer treatment. Examples of cancer-relevant phenotypic screens include inhibition of cell division, motor protein inhibition, cell cycle progression, and inhibition of apoptosis.
| McLachlan, Stela; Page, Kathryn E; Lee, Seung-Min et al. (2017) Hamp1 mRNA and plasma hepcidin levels are influenced by sex and strain but do not predict tissue iron levels in inbred mice. Am J Physiol Gastrointest Liver Physiol 313:G511-G523 |
