[Challenging the Elucidation of Anti-inflammatory Mechanisms Using Chemical Probes of Resolvins]

Resolvins are endogenous polyunsaturated fatty acids that show strong anti-inflammatory activity and are therefore expected to be promising new anti-inflammatory drug candidates. However, resolvins have many problems, including instability. This article reviews efforts to improve the stability of resolvin E2 (RvE2) and develop chemical probes to elucidate its anti-inflammatory mechanism. First, to improve the oxidative stability of RvE2, α- and β-CP-RvE2 were designed and synthesized by introducing cyclopropanes (CP) to C11-C12 of RvE2, and the oxidative stability of RvE2 was significantly improved. Next, 5-, 18-, and 20-AP-β-CP-RvE2 were designed and synthesized by introducing azidopropyl (AP) groups to C5, C18, and C20 of β-CP-RvE2 so as to determine the position of introduction of functional groups. The anti-inflammatory activity and phagocytosis of macrophages were evaluated, and it was revealed that 5-AP-β-CP-RvE2 has the same activity as RvE2 and β-CP-RvE2. In addition, to simplify the structure of RvE2, o-, m-, and p-BZ-RvE2 were designed and synthesized by introducing a benzene (BZ) ring into C9-C14 of RvE2. It was found that the metabolic stability of o-BZ-RvE2 was improved compared with RvE2, and the anti-inflammatory activity of o-BZ-RvE2 was equal to or greater than that of RvE2.