Synthesis of Resolvin E1 and Its Conformationally Restricted Cyclopropane Congeners with Potent Anti-Inflammatory Effect

• Published in: ACS medicinal chemistry letters Vol. 12; no. 2; pp. 256 - 261
• Main Authors: Ishimura, Kohei, Fukuda, Hayato, Fujiwara, Koichi, Muromoto, Ryuta, Hirashima, Koki, Murakami, Yuto, Watanabe, Mizuki, Ishihara, Jun, Matsuda, Tadashi, Shuto, Satoshi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.02.2021; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; anti-inflammatory; proresolving lipid mediator; Resolvin E1; cyclopropane congener
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.0c00639

RvE1 (1) 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 (2a–d), 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 trans-β-CP-RvE1 (2d), which was significantly more active than RvE1, as a potential lead for anti-inflammatory drugs of a novel mechanism of action.