Abstract
AbstractIn-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach. Herein, we studied how to best position the spiro[5.5]undeca ring system in kinase inhibitor space. Notably, late-stage modification of the scaffold 1 into compounds 2a-r enhanced kinase-likeness of the scaffold 1. The improvement could be depicted with (1) selectivity with target shift (from JNK-1 into GSK-3) and (2) potency (> 20-fold). In addition, ATP independent IC50 of compound 2j suggested a unique binding mode of this scaffold between ATP site and substrate site, which was explained by docking based optimal site selection and molecular dynamic simulations of the optimal binding site. Despite the shift of kinase profiling, the anti-inflammatory activity of compounds 2a-r could be retained in hyperactivated microglial cells.
Funder
National Research Foundation of Korea
Korea Health Industry Development Institute
Publisher
Springer Science and Business Media LLC
Reference60 articles.
1. Dobson, C. M. Chemical space and biology. Nature 432, 824–828 (2004).
2. Lipinski, C. & Hopkins, A. Navigating chemical space for biology and medicine. Nature 432, 855–861 (2004).
3. Taylor, R. D., MacCoss, M. & Lawson, A. D. Rings in drugs: miniperspective. J. Med. Chem. 57, 5845–5859 (2014).
4. Kumar, S., Jang, C., Subedi, L., Kim, S. Y. & Kim, M.-h. Repurposing of Ring Framework through TR screening. arXiv preprint arXiv: 1904.09243 (2019).
5. Afzal, S., Venkanna, A., Park, Hg. & Kim, Mh. Metal-free α-C (sp3)−H functionalized oxidative cyclization of tertiary N, N-diarylamino alcohols: construction of N, N-diarylaminotetrahydropyran scaffolds. Asian J. Organ. Chem. 5, 232–239 (2016).
Cited by
9 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献