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Updated: Jul 29, 2025

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Controllable conformation and reactivity of bicyclic α-methylene cyclopentanones and their NF-κB pathway inhibitory
Aki Kohyama1, Aya Shiuchi1, Yue Zhou1
1Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. aki.kohyama.d5@tohoku.ac.jp.
Abstract:
Tuning the electrophilicities of Michael acceptors is important for the development of targeted covalent drugs. To this end, the electronic effects of electrophilic structures have been well investigated, but not the steric effects. In this work, we synthesized ten α-methylene cyclopentanones (MCPs), screened them for NF-κB inhibitory activity, and analyzed their conformations. We found that MCP-4b, MCP-5b, and MCP-6b are novel NF-κB inhibitors, whereas the corresponding diastereomers MCP-4a, MCP-5a, and MCP-6a are inactive. Conformational analysis suggested that the stereochemistry of the side chain (R) on MCPs dictates the stable conformation of the core bicyclic 5/6 ring system. The conformational preference seemed to influence their reactivity toward nucleophiles. Consequently, a thiol reactivity assay showed that MCP-5b has higher reactivity than MCP-5a. The results indicate that the conformational switching of MCPs may control reactivity and bioactivity in the presence of steric effects.
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