title: Synthesis and biological evaluations of chalcones, flavones and chromenes as farnesoid x receptor (FXR) antagonists.
abstract: Farnesoid X receptor (FXR), a nuclear receptor mainly distributed in liver and intestine, has been regarded as a potential target for the treatment of various metabolic diseases, cancer and infectious diseases related to liver. Starting from two previously identified chalcone-based FXR antagonists, we tried to increase the activity through the design and synthesis of a library containing chalcones, flavones and chromenes, based on substitution manipulation and conformation (ring closure) restriction strategy. Many chalcones and four chromenes were identified as microM potent FXR antagonists, among which chromene 11c significantly decreased the plasma and hepatic triglyceride level in KKay mice.
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, 2A Nan Wei Road, Beijing 100050, China.
authors.forename: Guoning
authors.initials: G
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, 2A Nan Wei Road, Beijing 100050, China.
authors.forename: Shuainan
authors.initials: S
authors.lastname: Liu
authors.affiliation: NeuMed Pharmaceuticals limited, No. 9 Science Park West Avenue, Shatin, N.T., Hong Kong, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 02881, United States.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 02881, United States.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
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, 2A Nan Wei Road, Beijing 100050, China.
authors.forename: Deyang
authors.initials: D
authors.lastname: Sun
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, 2A Nan Wei Road, Beijing 100050, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huan
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, 2A Nan Wei Road, Beijing 100050, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
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, 2A Nan Wei Road, Beijing 100050, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei 230026, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: NeuMed Pharmaceuticals limited, No. 9 Science Park West Avenue, Shatin, N.T., Hong Kong, China.
authors.forename: Chiwai
authors.initials: C
authors.lastname: Wong
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, 2A Nan Wei Road, Beijing 100050, China.
authors.forename: Zhufang
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 02881, United States.
authors.forename: Ruitang
authors.initials: R
authors.lastname: Deng
authors.affiliation: School of Life Sciences, University of Science and Technology of China, Hefei 230026, China; State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Yanqiao
authors.initials: Y
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, 2A Nan Wei Road, Beijing 100050, China. Electronic address: wfang@imm.ac.cn.
authors.forename: Weishuo
authors.initials: W
authors.lastname: Fang
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000494:pharmacology*; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D047309:Flavones / Q000138:chemical synthesis / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000032:analysis; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001578:Benzopyrans; D047188:Chalcones; D047309:Flavones; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated
keywords: Antagonist; Chalcones; Chromenes; Farnesoid X receptor