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

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.