10.1002/anie.201610816
The study reports the discovery of L-45, also known as L-Moses, which is the first potent, selective, and cell-active chemical probe for the PCAF bromodomain (Brd). The research involved iterative cycles of rational inhibitor design, biophysical characterization, and synthesis to develop L-45 from readily available (1R,2S)-(+)-norephedrine in enantiopure form. The chemical probe serves to disrupt the PCAF-Brd interaction with histone H3.3 in cells, as demonstrated using a nanoBRET assay. The study also presents a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum, which rationalizes the high selectivity for PCAF and GCN5 bromodomains. The chemicals used in the study include triazolopthalazine-based compounds, various amine nucleophiles, and other synthetic intermediates, all of which were employed in the development and testing of L-45 for its potential as a therapeutic target in diseases such as cancer, HIV infection, and neuroinflammation. The purpose of these chemicals was to create a compound that could selectively target and modulate the PCAF Brd, providing a tool for investigating the role of PCAF in disease states and potentially leading to new treatments.
10.1016/j.tetasy.2009.01.018
The research aims to develop a large-scale synthesis procedure for enantiopure b3-neopentylglycine and its Cbz-protected derivative. L-(-)-norephedrine is used as a resolving agent to separate the enantiomers of Cbz-b3-neopentylglycine. The study found that L-(-)-norephedrine, compared to other chiral amines tested, provided the best results in terms of yield and enantiopurity. Specifically, it formed diastereomerically pure salts with the Cbz-protected b3-neopentylglycine, allowing for the efficient resolution of the racemic mixture. The use of L-(-)-norephedrine resulted in a diastereomeric ratio of approximately 2.5:97.5 (R:S) and an S-factor of around 0.70–0.74, indicating high enantioselectivity. The study concludes that this resolution method is efficient and represents a unique example of resolving an aliphatic b-amino acid, providing a valuable route for synthesizing enantiomerically pure b3-neopentylglycine for potential applications in pharmaceuticals.
