酸性神经鞘磷脂酶直接抑制剂的设计、合成及生物活性  

Design,Synthesis and Biological Activity of Acid Sphingomyelinase Inhibitors

作　　者：杨侃[1] 张阔军[1] 胡松源[1] 顾勤兰[2] 董继斌[3] 王进欣[1] 

机构地区：[1]中国药科大学药物分子设计与优化江苏省重点实验室,南京210009 [2]中国药科大学高等职业技术学院,南京211198 [3]复旦大学药学院生物化学教研室,上海201203

出　　处：《高等学校化学学报》2015年第2期279-286,共8页Chemical Journal of Chinese Universities

基　　金：南京市领军型创业人才计划(批准号:2013B14007);华海药业研究生培养创新基金(批准号:CX13S-001HH)资助~~

摘　　要：构建了基于配体的酸性神经鞘磷脂酶抑制剂药效团模型.根据此模型,以α-倒捻子素(α-Mangostin)为先导化合物进行结构优化,完成了11个新型酸性神经鞘磷脂酶直接抑制剂的设计与合成,其结构经过核磁共振波谱和质谱鉴定正确.初步体外酶抑制活性筛选结果显示,化合物Ⅰb,Ⅰd,Ⅰe和Ⅰf具有较好的酶抑制活性,其中化合物Ⅰf的酶抑制率为88.9%.Acid sphingomyelinase（ ASM） plays an important role in sphingolipid catabolism, which catalyzes the hydrolysis of sphingomyelin to ceramide and phosphorylcholine. Ceramide serves as one of the most impor-tant second messengers, and there is growing evidence shows that ASM activation and ceramide accumulation are involved in the development of various common human diseases. Nevertheless, only few inhibitors directly and selectively interacted with ASM. According to the reported inhibitors and their suppressive activity of ASM, 3D-pharmacophore model of ASM inhibitors based on ligands was built for the first time. Due to potent inhibitory ASM activity ofα-Mangostin, a phytochemical content derived from garcinia mangostana linn, it was chosen as the lead compound for structure optimization. Then 11 new ASM direct inhibitors were designed and synthesized successfully. Their structures were confirmed by 1 H NMR, 13 C NMR and mass spectrometry. Pre-liminary activity screening results in vitro showed that the compounds Ⅰb,Ⅰd,Ⅰe and Ⅰf had potent ASM inhibitory activity. The ASM inhibition rate of compoundⅠf was 88.9%. The structure-activity relationship indicated that the introduction of chain amino would influence the ASM activity obviously and removal of alke-nyl had little impact on the ASM activity. This result will play a guiding role for designing better ASM inhibi-tors and proceeding basic research of ASM.

关 键 词：酸性鞘磷脂酶 直接抑制剂 药效团模型 α-倒捻子素 

分 类 号：O626[理学—有机化学]