Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory agents

Peng Teng; Hai-Liang Liu; Lei Zhang; Li-Li Feng; Yue Huai; Zhang-Shuang Deng; Yang Sun; Qiang Xu; Jian-Xin Li

doi:10.1016/j.ejmech.2012.01.036

Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory agents

Eur J Med Chem. 2012 Apr:50:63-74. doi: 10.1016/j.ejmech.2012.01.036. Epub 2012 Jan 28.

Authors

Peng Teng¹, Hai-Liang Liu, Lei Zhang, Li-Li Feng, Yue Huai, Zhang-Shuang Deng, Yang Sun, Qiang Xu, Jian-Xin Li

Affiliation

¹ State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, PR China.

PMID: 22325804
DOI: 10.1016/j.ejmech.2012.01.036

Abstract

Sinomenine (1) is clinically available for the treatment of rheumatoid arthritis (RA), however, its efficacy is quite weak. In the present study, a library of novel sinomenine-based homodimers and monomers through variable-length linkers were designed and synthesized, and their bioactivities were evaluated using RAW264.7 cells and mice. Among the compounds, 2f and 3b possessed much more potent inhibitory effects on the production of nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) than 1. Preliminary mechanism investigation revealed that 3b inhibited nuclear factor-κB (NF-κB) signaling pathway specifically, 2f suppressed both NF-κB and mitogen-activated protein kinase (MAPK) cascades. Moreover, 3b and 2f significantly alleviated the lipopolysaccharide (LPS)-induced mortality. These two compounds might serve as valuable candidates for anti-inflammatory drug discovery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis*
Anti-Inflammatory Agents / pharmacology*
Blotting, Western
Cell Proliferation / drug effects
Cells, Cultured
Enzyme-Linked Immunosorbent Assay
Interleukin-6 / metabolism
JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
JNK Mitogen-Activated Protein Kinases / metabolism
Lipopolysaccharides / pharmacology
Macrophages / cytology
Macrophages / drug effects*
Macrophages / metabolism
Mice
Mice, Inbred BALB C
Mitogen-Activated Protein Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinases / metabolism
Morphinans / chemistry*
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism
Nitric Oxide / metabolism
Nitric Oxide Synthase Type II / metabolism
Shock, Septic / drug therapy*
Shock, Septic / metabolism
Shock, Septic / pathology
Signal Transduction / drug effects*
Tumor Necrosis Factor-alpha / metabolism

Substances

Anti-Inflammatory Agents
Interleukin-6
Lipopolysaccharides
Morphinans
NF-kappa B
Tumor Necrosis Factor-alpha
Nitric Oxide
sinomenine
Nitric Oxide Synthase Type II
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases