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Resolvins are pro-resolving lipid mediators with highly potent anti-inflammatory effects. Because of their polyunsaturated structures, however, they are unstable to oxygen as a drug prototype. To address this issue, we designed and synthesized CP-RvE3 as oxidatively stable congeners of RvE3 by replacing the cis -olefin with a cis -cyclopropane to avoid the unstable bisallylic structure. Although the oxidative stabilities of CP-RvE3 were not improved, β-CP-RvE3 was 3.7 times more metabolically stable than RvE3. Thus, we identified β-CP-RvE3 as a metabolically stable equivalent.

We synthesized RvE3 and its deoxy derivatives, 17-deoxy-RvE3 and 18-deoxy-RvE3, by a common route via Sonogashira coupling as a key step. The evaluation of their anti-inflammatory activities revealed that 18-deoxy-RvE3 was remarkably more potent than the parent RvE3 and significantly active at a 300 fg dose in mice; additionally, 17-deoxy-RvE3 was significantly less potent than the parent RvE3. For the first time, we found that the 17-hydroxy group of RvE3 is very important for anti-inflammatory activity.