具有强效抗炎作用的消退素E1及其构象受限环丙烷类似物的合成。
Synthesis of Resolvin E1 and Its Conformationally Restricted Cyclopropane Congeners with Potent Anti-Inflammatory Effect.
作者信息
Ishimura Kohei, Fukuda Hayato, Fujiwara Koichi, Muromoto Ryuta, Hirashima Koki, Murakami Yuto, Watanabe Mizuki, Ishihara Jun, Matsuda Tadashi, Shuto Satoshi
机构信息
Faculty of Pharmaceutical Science and Center for Drug Discovery and Education, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-Machi, Nagasaki 852-8521, Japan.
出版信息
ACS Med Chem Lett. 2021 Jan 21;12(2):256-261. doi: 10.1021/acsmedchemlett.0c00639. eCollection 2021 Feb 11.
RvE1 () is an endogenous lipid mediator with very potent anti-inflammatory activity, which is due to the inhibition of neutrophil chemotaxis and inflammatory cytokine production and the promotion of macrophage phagocytosis. On the basis of the conformational analysis of RvE1, we designed its four cyclopropane congeners (-), in which the conformationally flexible terminal C1-C4 moiety of RvE1 was rigidified by introducing stereoisomeric cyclopropanes. The four congeners and also RvE1 were efficiently synthesized via a common synthetic route. The evaluation of the anti-inflammatory effects of the compounds in mice resulted in the identification of -β-CP-RvE1 (), which was significantly more active than RvE1, as a potential lead for anti-inflammatory drugs of a novel mechanism of action.
RvE1（）是一种具有非常强抗炎活性的内源性脂质介质，这归因于其对中性粒细胞趋化性和炎性细胞因子产生的抑制以及对巨噬细胞吞噬作用的促进。基于RvE1的构象分析，我们设计了其四种环丙烷类似物（-），其中通过引入立体异构环丙烷使RvE1构象灵活的末端C1-C4部分刚性化。这四种类似物以及RvE1通过一条共同的合成路线高效合成。对这些化合物在小鼠体内抗炎作用的评估导致鉴定出-β-CP-RvE1（），其活性显著高于RvE1，作为一种具有新型作用机制的抗炎药物的潜在先导化合物。
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