Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory agents.
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.
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210093, PR China.
Peng
P
Teng
Hai-Liang
HL
Liu
Lei
L
Zhang
Li-Li
LL
Feng
Yue
Y
Huai
Zhang-Shuang
ZS
Deng
Yang
Y
Sun
Qiang
Q
Xu
Jian-Xin
JX
Li
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009019:Morphinans / Q000737:chemistry*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009019:Morphinans; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C009271:sinomenine; D052247:Nitric Oxide Synthase Type II; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases