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Synthesis and biological evaluation of a novel class of curcumin analogs as anti-inflammatory agents for prevention and treatment of sepsis in mouse model

Authors Zhao C, Zhang Y, Zou P, Wang J, He W, Shi D, Li H, Liang G, Yang S, Zhang X

Received 15 October 2014

Accepted for publication 20 November 2014

Published 18 March 2015 Volume 2015:9 Pages 1663—1678

DOI https://doi.org/10.2147/DDDT.S75862

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Shu-Feng Zhou


Chengguang Zhao,1,2,* Yali Zhang,1,2,* Peng Zou,1 Jian Wang,3 Wenfei He,2 Dengjian Shi,2 Huameng Li,2 Guang Liang,2 Shulin Yang1

1School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, 2Chemical Biology Research Center, School of Pharmaceutical Sciences, 3Department of Orthopedics, The 1st Affiliated Hospital, Wenzhou Medical University, Wenzhou, People’s Republic of China

*These authors contributed equally to this work

Abstract: A novel class of asymmetric mono-carbonyl analogs of curcumin (AMACs) were synthesized and screened for anti-inflammatory activity. These analogs are chemically stable as characterized by UV absorption spectra. In vitro, compounds 3f, 3m, 4b, and 4d markedly inhibited lipopolysaccharide (LPS)-induced expression of pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6 in a dose-dependent manner, with IC50 values in low micromolar range. In vivo, compound 3f demonstrated potent preventive and therapeutic effects on LPS-induced sepsis in mouse model. Compound 3f downregulated the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 MAPK and suppressed IκBα degradation, which suggests that the possible anti-inflammatory mechanism of compound 3f may be through downregulating nuclear factor kappa binding (NF-κB) and ERK pathways. Also, we solved the crystal structure of compound 3e to confirm the asymmetrical structure. The quantitative structure–activity relationship analysis reveals that the electron-withdrawing substituents on aromatic ring of lead structures could improve activity. These active AMACs represent a new class of anti-inflammatory agents with improved stability, bioavailability, and potency compared to curcumin. Our results suggest that 3f may be further developed as a potential agent for prevention and treatment of sepsis or other inflammation-related diseases.

Keywords: asymmetric mono-carbonyl analogs of curcumin (AMACs), stability, anti-inflammatory property, sepsis, QSAR
 

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