Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 143, Issue -, Pages 361-375Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.11.066
Keywords
Myeloid differentiation protein 2; Toll-like receptor 4; Caffeic acid phenethyl ester; Anti-inflammatory; Acute lung injury
Categories
Funding
- National Natural Science Funding of China [81703352, 81770825, 81622043, 81670768]
- Natural Science Funding of Zhejiang Province [LR16H310001, LR18H160003, LQ18B020004]
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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. (C) 2017 Elsevier Masson SAS. All rights reserved.
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