Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice

Meiyang Xi; Jun Ge; Xiaojian Wang; Chenbin Sun; Tianqi Liu; Liang Fang; Qiong Xiao; Dali Yin

doi:10.1016/j.bmc.2016.05.047

Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice

Bioorg Med Chem. 2016 Jul 15;24(14):3218-30. doi: 10.1016/j.bmc.2016.05.047. Epub 2016 May 24.

Authors

Meiyang Xi¹, Jun Ge², Xiaojian Wang³, Chenbin Sun¹, Tianqi Liu², Liang Fang², Qiong Xiao¹, Dali Yin⁴

Affiliations

¹ 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.
² 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.
³ 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.
⁴ 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.

PMID: 27255176
DOI: 10.1016/j.bmc.2016.05.047

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.

Keywords: Colitis; DSS; Inflammation; SphK.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Colitis / drug therapy*
Colitis / pathology
Dextran Sulfate / toxicity*
Enzyme Inhibitors / pharmacology*
HCT116 Cells
Humans
Mice
Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Dextran Sulfate
Phosphotransferases (Alcohol Group Acceptor)
sphingosine kinase