title: Synthesis and Structure-Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1.
abstract: In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose-effect relationships with EC50 values of 0.0708-0.0132 μM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs.
authors.affiliation: 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, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Xie
authors.affiliation: 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, People's Republic of China.
authors.forename: Hai-Jing
authors.initials: HJ
authors.lastname: Zhang
authors.affiliation: 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, People's Republic of China.
authors.forename: An-Jun
authors.initials: AJ
authors.lastname: Deng
authors.affiliation: 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, People's Republic of China.
authors.forename: Lian-Qiu
authors.initials: LQ
authors.lastname: Wu
authors.affiliation: 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, People's Republic of China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: 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, People's Republic of China.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Li
authors.affiliation: 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, People's Republic of China.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Wang
authors.affiliation: 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, People's Republic of China.
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Qin
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D004268:DNA-Binding Proteins / Q000187:drug effects*; D008297:Male; D015394:Molecular Structure; D000071701:Regulatory Factor X Transcription Factors; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000187:drug effects*
chemical_list: D000577:Amides; D000588:Amines; D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; C034384:coptisine; D001599:Berberine