Positioning of an unprecedented spiro[5.5]undeca ring system into kinase inhibitor space.

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 bin

SUBMITTER: Venkanna A 

PROVIDER: S-EPMC7719162 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature