7 research outputs found
Rationale and study protocol for the supporting childrenâs outcomes using rewards, exercise and skills (SCORES) group randomized controlled trial: A physical activity and fundamental movement skills intervention for primary schools in low-income communities
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Stereoselective Synthesis of Tri-Substituted Benzodihydrofurans and Dihydrobenzoxanthone Natural Products By CâH Insertion of Donor/Donor Carbenes into Stereogenic Centers
This dissertation describes two projects in the organic chemistry field centering around the stereoselective synthesis of trisubstituted benzodihydrofurans and related natural products through CâH insertion of donor/donor carbenes into stereogenic centers. The first chapter reports the development of a stereoselective methodology to make 2,2,3-trisubstituted benzodihydrofurans. The method expands intramolecular CâH insertion reactions with donor/donor carbenes to stereogenic insertion centers, thereby enabling benzodihydrofuran formation in high diastereoselectivity and enantioselectivity. Computational studies on the system illuminate the origins of divergent stereochemical outcomes for different substrate classes. The second chapter applies this methodology to the asymmetric synthesis of two dihydrobenzoxanthone natural products, cycloartobiloxanthone and artoindonesianin Z-2. First, an introduction to the natural product subclass outlines structural variations and biosynthetic pathways for the isolated natural products found in the family and their reported biological activities. Progress towards the synthesis of these two natural products is split into three main stages. The first stage reports a first-generation route and its related benzylic oxidation roadblock. The second stage details numerous route-scouting endeavors. The third stage outlines a second-generation route and future work toward completing the asymmetric synthesis of cycloartobiloxanthone and artoindonesianin Z-2
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Systematic Variation of Both the Aromatic Cage and Dialkyllysine via GCE-SAR Reveal Mechanistic Insights in CBX5 Reader Protein Binding
Development of inhibitors for histone methyllysine reader proteins is an active area of research due to the importance of reader protein-methyllysine interactions in transcriptional regulation and disease. Optimized peptide-based chemical probes targeting methyllysine readers favor larger alkyllysine residues in place of methyllysine. However, the mechanism by which these larger substituents drive tighter binding is not well understood. This study describes the development of a two-pronged approach combining genetic code expansion (GCE) and structure-activity relationships (SAR) through systematic variation of both the aromatic binding pocket in the protein and the alkyllysine residues in the peptide to probe inhibitor recognition in the CBX5 chromodomain. We demonstrate a novel change in driving force for larger alkyllysines, which weaken cation-Ï interactions but increases dispersion forces, resulting in tighter binding. This GCE-SAR approach establishes discrete energetic contributions to binding from both ligand and protein, providing a powerful tool to gain mechanistic understanding of SAR trends