title: Synthesis and Structure-Activity Relationships of Quaternary Coptisine Derivatives as Potential Anti-ulcerative Colitis Agents.
abstract: Thirty quaternary coptisine derivatives from a synthesized library were found to activate the in vitro transcription of x-box-binding protein 1 (XBP1). Among these, the dihydrocoptisines were demonstrated by in vitro XBP1 transcriptional activity assays and animal experiments to be much more active anti-ulcerative colitis (UC) agents than quaternary coptisines, tetrahydrocoptisines, and the positive control. Unsubstituted dihydrocoptisine exhibited more significant anti-UC efficacy than dihydrocoptisines substituted at the C-8 or C-13 position. The EC50 value of dihydrocoptisine for XBP1 transcriptional activation was 2.25 nM. Dihydrocoptisine exhibited a significant dose-effect relationship, as indicated by biomarkers in in vitro and in vivo experiments. According to this study, the starting material's reductive states and the substitution patterns of the dihydrocoptisines were determined to be the critical parameters for modulating their anti-UC efficacy, and the dihydrocoptisine skeleton was designated as the key pharmacophore. The synthesized dihydrocoptisine is a promising lead for developing anti-UC drugs.
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Zhi-Hui
authors: ZH
authors: Zhang
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Hai-Jing
authors: HJ
authors: Zhang
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: An-Jun
authors: AJ
authors: Deng
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Bo
authors: B
authors: Wang
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Zhi-Hong
authors: ZH
authors: Li
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Yang
authors: Y
authors: Liu
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Lian-Qiu
authors: LQ
authors: Wu
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Wen-Jie
authors: WJ
authors: Wang
authors: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing 100050, China.
authors: Hai-Lin
authors: HL
authors: Qin
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D003106:Colon / Q000187:drug effects / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics; D016264:Dextran Sulfate; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics; D015533:Transcriptional Activation; D000071717:X-Box Binding Protein 1
chemical_list: D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; C034384:coptisine; D001599:Berberine; D016264:Dextran Sulfate