title: A novel compound C12 inhibits inflammatory cytokine production and protects from inflammatory injury in vivo.
abstract: Inflammation is a hallmark of many diseases. Although steroids and cyclooxygenase inhibitors are main anti-inflammatory therapeutical agents, they may cause serious side effects. Therefore, developing non-steroid anti-inflammatory agents is urgently needed. A novel hydrosoluble compound, C12 (2,6-bis(4-(3-(dimethylamino)-propoxy)benzylidene)cyclohexanone), has been designed and synthesized as an anti-inflammatory agent in our previous study. In the present study, we investigated whether C12 can affect inflammatory processes in vitro and in vivo. In mouse primary peritoneal macrophages, C12 potently inhibited the production of the proinflammatory gene expression including TNF-α, IL-1β, IL-6, iNOS, COX-2 and PGE synthase. The activity of C12 was partly dependent on inhibition of ERK/JNK (but p38) phosphorylation and NF-κB activation. In vivo, C12 suppressed proinflammatory cytokine production in plasma and liver, attenuated lung histopathology, and significantly reduced mortality in endotoxemic mice. In addition, the pre-treatment with C12 reduced the inflammatory pain in the acetic acid and formalin models and reduced the carrageenan-induced paw oedema and acetic acid-increased vascular permeability. Taken together, C12 has multiple anti-inflammatory effects. These findings, coupled with the low toxicity and hydrosolubility of C12, suggests that this agent may be useful in the treatment of inflammatory diseases.
authors.affiliation: Bioorganic and Medicinal Chemistry Research Center, School of Pharmaceutical Science, Wenzhou Medical College, Wenzhou, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Congcong
authors.initials: C
authors.lastname: Yu
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.forename: Jianling
authors.initials: J
authors.lastname: Li
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.forename: Faqing
authors.initials: F
authors.lastname: Ye
authors.forename: Shulin
authors.initials: S
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Li
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D000208:Acute Disease; D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D003512:Cyclohexanones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood; D004195:Disease Models, Animal; D004487:Edema / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000097:blood; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis
chemical_list: C569561:2,6-bis(4-(3-(dimethylamino)propoxy)benzylidene)cyclohexanone; C526289:2,6-bis(benzylidene)cyclohexanone; D001597:Benzylidene Compounds; D003512:Cyclohexanones; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases