title: Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice.
abstract: Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N'-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure-activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China.
authors.forename: Meiyang
authors.initials: M
authors.lastname: Xi
authors.affiliation: Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China; Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China. Electronic address: wangxiaojian@imm.ac.cn.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China.
authors.forename: Chenbin
authors.initials: C
authors.lastname: Sun
authors.affiliation: Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China.
authors.forename: Tianqi
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China; Department of Medicinal Chemistry, Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1st Xian Nong Tan Street, Beijing 100050, PR China. Electronic address: yindali@imm.ac.cn.
authors.forename: Dali
authors.initials: D
authors.lastname: Yin
mesh_terms: D000818:Animals; D003092:Colitis / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D000099157:Sphingosine Kinase
chemical_list: D016264:Dextran Sulfate; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase
keywords: Colitis; DSS; Inflammation; SphK