Discovery of caffeic acid phenethyl ester derivatives as novel myeloid differentiation protein 2 inhibitors for treatment of acute lung injury

• DOI: 10.1016/j.ejmech.2017.11.066
• Publication Date: 2017-12-01T19:15:37Z
• Authors: Lingfeng Chen; Yiyi Jin; Hongjin Chen; Chuchu Sun; Weitao Fu; Lulu Zheng; Min Lu; Pengqin Chen; Gaozhi Chen; Yali Zhang; Zhiguo Liu; Yi Wang; Zengqiang Song; Guang Liang
• Keywords: Inflammation; Lipopolysaccharides; 0301 basic medicine; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Macrophages; Acute Lung Injury; Anti-Inflammatory Agents, Non-Steroidal; Lymphocyte Antigen 96; Phenylethyl Alcohol; 3. Good health; Mice, Inbred C57BL; Mice; Structure-Activity Relationship; 03 medical and health sciences; Caffeic Acids; 13. Climate action; Drug Discovery; Animals; Cytokines; Humans

Myeloid differentiation protein 2 (MD2) is an essential molecule which recognizes lipopolysaccharide (LPS), leading to initiation of inflammation through the activation of Toll-like receptor 4 (TLR4) signaling. Caffeic acid phenethyl ester (CAPE) from propolis of honeybee hives could interfere interactions between LPS and the TLR4/MD2 complex, and thereby has promising anti-inflammatory properties. In this study, we designed and synthesized 48 CAPE derivatives and evaluated their anti-inflammatory activities in mouse primary peritoneal macrophages (MPMs) activated by LPS. The most active compound, 10s, was found to bind with MD2 with high affinity, which prevented formation of the LPS/MD2/TLR4 complex. The binding mode of 10s revealed that the major interactions with MD2 were established via two key hydrogen bonds and hydrophobic interactions. Furthermore, 10s showed remarkable protective effects against LPS-caused ALI (acute lung injury) in vivo. Taken together, this work provides new lead structures and candidates as MD2 inhibitors for the development of anti-inflammatory drugs.