Controllable conformation and reactivity of bicyclic α-methylene cyclopentanones and their NF-κB pathway inhibitory activity

Aki Kohyama*, Aya Shiuchi, Yue Zhou, Masaru Tanioka, Kenji Sugimoto, Hiroaki Sakurai, Yuji Matsuya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)4656-4660
Number of pages5
JournalOrganic and Biomolecular Chemistry
Volume21
Issue number22
DOIs
StatePublished - 2023/05/10

ASJC Scopus subject areas

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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