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Cited 8 time in webofscience Cited 5 time in scopus
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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-YoonKim, Sun YeouKim, 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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