Positioning of an unprecedented spiro[5.5]undeca ring system into kinase inhibitor space
- Authors
- Venkanna, A.; Subedi, L.; Teli, M.K.; Lama, P.D.; Nangunuri, B.G.; Lee, Sang-Yoon; Kim, Sun Yeou; Kim, Mi-hyun
- Issue Date
- Dec-2020
- Publisher
- Nature Research
- Citation
- Scientific Reports, v.10, no.1
- Journal Title
- Scientific Reports
- Volume
- 10
- Number
- 1
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/79873
- DOI
- 10.1038/s41598-020-78158-9
- ISSN
- 2045-2322
- Abstract
- In-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. © 2020, The Author(s).
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Collections - 약학대학 > 약학과 > 1. Journal Articles
- 의과대학 > 의예과 > 1. Journal Articles
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