title: Synthesis, Anti-inflammatory Activities and Mechanisms of 3,5- dihydroxycinnamic Acid Derivatives.
abstract: BACKGROUND
  3,4-dihydroxycinnamic acid and its derivatives exhibit numerous biologic activities. Such activities have not previously been reported for 3,5-dihydroxycinnamic acid derivatives. In this study, ten derivatives of 3,5- dihydroxycinnamic acid were synthesized and their anti-inflammatory activities were tested in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema. Molecular biological studies have shed lights on their anti-inflammatory mechanism.
  
  
  METHODS
  Anti-inflammatory activities of ten new synthesized derivatives of 3,5-dihydroxycinnamic acid were tested in 12-O-tetradecanoylphorbol 13-acetate-induced mouse ear edema, and their anti-inflammatory mechanism was studied by ELISA, real-time RT-PCR, MPO assay and AA-induced mouse ear edema.
  
  
  RESULTS
  Compound 7 showed a pronounced anti-inflammatory effect and the inhibition rate was 65.6% at a dose of 1.6mg/ear. This compound acted by reducing mRNA and protein synthesis of tumor necrosis factor-α, interleukins 1β and 6, and also by decreasing the levels of activated neutrophil infiltrates. Furthermore, compound 7 significantly suppressed arachidonic acid-induced edema as well. Cell-based assays showed that compound 7 inhibited the production of cyclooxygenase- 2-catalyzed prostaglandin E2 from lipopolysaccharide-treated RAW 264.7 cells, and also inhibited 5-lipoxygenase production from A23187-treated RBL-1 cells, and consequently reduced leukotriene B4 production.
  
  
  CONCLUSIONS
  This investigation revealed that some of the derivatives of 3,5-dihydroxycinnamic acid exhibit a more pronounced anti-inflammatory effect than 3,4-dihydroxycinnamic acid. Therefore, 3,5-dihydroxycinnamic acid derivatives, especially compound 7, represent potential value for antiinflammatory drug development.
authors.forename: Meng-Jun
authors.initials: MJ
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Zhou
authors.forename: Wen
authors.initials: W
authors.lastname: Cao
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Feng
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Guo
authors.forename: Qing-Juan
authors.initials: QJ
authors.lastname: Han
authors.forename: Wen-Xuan
authors.initials: WX
authors.lastname: Cao
authors.forename: Xiao
authors.initials: X
authors.lastname: Guan
authors.forename: Yun-Yun
authors.initials: YY
authors.lastname: Li
authors.forename: Jianbo
authors.initials: J
authors.lastname: Qin
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Analysis and Analytical Chemistry, College of Pharmacy, Third Military Medical University, Chongqing 400038, China. 1667354954@qq.com.
authors.forename: Hui-Jing
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: Chongqing Academy of Science & Technology, Chongqing 400038, China. li98bin@126.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D015232:Dinoprostone / Q000378:metabolism; D004423:Ear / Q000473:pathology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D005260:Female; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013755:Tetradecanoylphorbol Acetate
chemical_list: D000893:Anti-Inflammatory Agents; D002934:Cinnamates; D016207:Cytokines; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D016718:Arachidonic Acid; C045631:3,5-dihydroxycinnamic acid; D000001:Calcimycin; D009195:Peroxidase; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate