Xi Meiyang, Ge Jun, Wang Xiaojian, Sun Chenbin, Liu Tianqi, Fang Liang, Xiao Qiong, Yin Dali
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.
Bioorg Med Chem. 2016 Jul 15;24(14):3218-30. doi: 10.1016/j.bmc.2016.05.047. Epub 2016 May 24.
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.
鞘氨醇激酶（SphK）催化生成的1-磷酸鞘氨醇（S1P）可调节动物细胞的生长、存活、增殖以及炎症状态。在最近的研究中，我们报道了N'-（3-（苄氧基）亚苄基）-3,4,5-三羟基苯甲酰肼支架作为一种有效的SphK抑制剂。作为这些研究工作的延续，我们合成了51种衍生物，并通过SphK1/2抑制活性对其进行评估，以开展构效关系（SAR）研究。其中，化合物33被确定为最有效的SphK抑制剂。还观察到化合物33的效力可有效降低人结肠癌细胞（HCT116）中SphK1/2的表达，并显著抑制葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎以及白细胞介素（IL）-6和环氧合酶-2（COX-2）表达的降低。总体而言，化合物33被验证为一种有效的SphK抑制剂，有望作为抗炎剂用于治疗人类的炎症性肠病。
