天然活性产物异色满-4-酮肟醚类衍生物的合成及其β-肾上腺素受体阻断活性(英文)  

Synthesis and β-adrenergic blocking activity of oxime ether hybrids derived from a natural isochroman-4-one

作　　者：白仁仁[1,2,3] 徐盛涛[1,2] 刘洁[1,2] 洪文[4] 汤依群[4] 吴晓明[1,2] 谢唯佳[1,2] 姚和权[1,2] 徐进宜[1,2] 

机构地区：[1]中国药科大学药物化学教研室,南京210009 [2]中国药科大学天然药物活性物质与功能国家重点实验室,南京210009 [3]江苏弘惠医药有限公司,南京210008 [4]中国药科大学药理研究室,南京210009

出　　处：《中国天然药物》2013年第5期538-545,共8页

基　　金：supported by a grant from"Eleventh Five-Year"Major Innovation Projects for New Drug Candidates(No.2009ZX09103-128);a grant from National Natural Science Foundation of China(No.81302635);the Project for Research and Innovation of Graduates in Colleges and Universities of Jiangsu Province(No.CXZZ11-0798);Project Program of State Key Laboratory of Natural Medicines,China Pharmaceutical University(No.JKGQ201115)~~

摘　　要：目的:为探索寻找新型心血管药物候选化合物,设计合成了一系列全新结构的异色满-4-酮肟醚类衍生物。方法:首先设计合成了天然降压活性产物3-甲基-7,8-二羟基异色满-4-酮(XJP)的类似物3和6,然后通过醚键在肟羟基上引入经典β-受体阻断剂侧链异丙醇胺基团,合成了一系列异色满-4-酮肟醚类新化合物;采用离体大鼠左心房测试了目标化合物对β1-肾上腺素受体的阻断作用。结果:获得了20个具有肟醚异丙醇胺结构的目标化合物;其β1-受体的阻断活性测试结果表明,化合物Ic活性最强,在10-7mol·L 1浓度下对β1-受体的抑制率为52.2%,优于阳性药普萘洛尔(49.7%);初步获得了构效关系信息。结论:对活性天然产物XJP结构修饰的结果可为新型心血管药物分子设计提供研究思路。AIM： In a search for new cardiovascular drug candidates, a series of novel oxime ethers derived from a natural isochroman-4-one were synthesized. METHOD： Compounds 3 and 6, derived from the natural antihypertensive compound 7, 8-dihydroxy-3-methyl-isochroman-4-one （XJP）, were designed and synthesized. Subsequently, a series of novel isochroman-4-one oxime ether hybrids were prepared by hybridizing various N-substituted isopropanolamine functionalities to isochroman-4-one oxime. Furthermore, βt-adrenergic blocking activities of the synthesized compounds were assayed using the isolated rat left atria. RESULTS： Twenty target compounds were obtained, and the preliminary structure-activity relationships were deduced. The most promising com- pound Ic exhibited β1-adrenoceptor blocking activity （inhibition： 52.2%） at 10^-7 mol.L^-1, which was superior to that of propranolol （inhibition： 49.7%）. CONCLUSION： The results suggested that natural product XJP/isopropanolamine moiety hybrids may provide a promising approach for the discovery of novel cardiovascular drug candidates.

关 键 词：异色满-4-酮衍生物 肟醚 杂合体 β-受体阻断活性 抗高血压活性 

分 类 号：R284.3[医药卫生—中药学]