Murakami Yuto, Fukuda Hayato, Muromoto Ryuta, Hirashima Koki, Ishimura Kohei, Fujiwara Koichi, Ishihara Jun, Matsuda Tadashi, Watanabe Mizuki, Shuto Satoshi
Faculty of Pharmaceutical Sciences and Center for Research and Education on Drug Discovery, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Graduate School of Biomedical Sciences, Nagasaki University, Bunkyo-machi, Nagasaki 852-8521, Japan.
ACS Med Chem Lett. 2020 Mar 25;11(4):479-484. doi: 10.1021/acsmedchemlett.9b00596. eCollection 2020 Apr 9.
Resolvins (Rvs) are highly potent anti-inflammatory lipid mediators that are chemically and biologically unstable because of their polyunsaturated structures. To address this issue, we designed benzene congeners of RvE2, i.e., -, -, and -BZ-RvE2s, as stable equivalents of RvE2 by replacing the unstable skipped diene moiety with a benzene ring on the basis of computational conformation studies and synthesized these congeners via a short common route through two Stille couplings. -BZ-RvE2 exhibited more potent anti-inflammatory activity and much higher metabolic stability than RvE2. Thus, -BZ-RvE2 was identified as a stable equivalent of RvE2, which is useful as a lead for anti-inflammatory drugs with a new mechanism of action as well as a biotool for investigating RvE2-mediated inflammation resolving pathways.
消退素（Rvs）是一类具有高效抗炎作用的脂质介质，由于其多不饱和结构，在化学和生物学上不稳定。为了解决这个问题，我们基于计算构象研究，通过用苯环取代不稳定的跳跃二烯部分，设计了RvE2的苯类似物，即 -、 - 和 -BZ-RvE2s，作为RvE2的稳定等效物，并通过两个Stille偶联反应的短通用路线合成了这些类似物。-BZ-RvE2比RvE2表现出更强的抗炎活性和更高的代谢稳定性。因此，-BZ-RvE2被确定为RvE2的稳定等效物，它可用作具有新作用机制的抗炎药物的先导物，以及研究RvE2介导的炎症消退途径的生物工具。
