Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
Org Biomol Chem. 2023 Jun 7;21(22):4656-4660. doi: 10.1039/d3ob00357d.
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.
调节迈克尔受体的亲电性对于靶向共价药物的发展非常重要。为此，人们已经很好地研究了亲电结构的电子效应，但没有研究其空间效应。在这项工作中，我们合成了十个α-亚甲基环戊酮（MCPs），筛选了它们对 NF-κB 抑制活性，并分析了它们的构象。我们发现 MCP-4b、MCP-5b 和 MCP-6b 是新型 NF-κB 抑制剂，而相应的非对映异构体 MCP-4a、MCP-5a 和 MCP-6a 则没有活性。构象分析表明，MCPs 侧链（R）的立体化学决定了核心双环 5/6 环系统的稳定构象。构象的偏好似乎影响了它们对亲核试剂的反应性。因此，硫醇反应性测定表明 MCP-5b 的反应性高于 MCP-5a。结果表明，在存在空间效应的情况下，MCPs 的构象转换可能控制其反应性和生物活性。
