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

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 Yang<sup>1

1</sup>School 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