TY - JOUR
T1 - Controllable conformation and reactivity of bicyclic α-methylene cyclopentanones and their NF-κB pathway inhibitory activity
AU - Kohyama, Aki
AU - Shiuchi, Aya
AU - Zhou, Yue
AU - Tanioka, Masaru
AU - Sugimoto, Kenji
AU - Sakurai, Hiroaki
AU - Matsuya, Yuji
N1 - Publisher Copyright:
© 2023 The Royal Society of Chemistry
PY - 2023/5/10
Y1 - 2023/5/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85160402603&partnerID=8YFLogxK
U2 - 10.1039/d3ob00357d
DO - 10.1039/d3ob00357d
M3 - 学術論文
C2 - 37212260
AN - SCOPUS:85160402603
SN - 1477-0520
VL - 21
SP - 4656
EP - 4660
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 22
ER -