艾里莫芬烷倍半萜抗白血病构效关系探究.docVIP

艾里莫芬烷倍半萜抗白血病构效关系探究 　【摘要】 目的研究艾里莫芬烷倍半萜抗白血病作用构效关系，为该类倍半萜结构修饰和开发利用提供参考依据。方法对呋喃艾里莫芬烷倍半萜-橐吾酮（ligularone，9）进行结构修饰，采用MTT法对从橐吾属植物中分离得到的艾里莫芬烷倍半萜以及橐吾酮结构修饰物进行体外抑制人早幼粒白血病细胞（HL-60）生长活性评价。结果以橐吾酮为原料通过光敏氧化得内酯倍半萜（10），鉴定为6-oxo-8β-methoxyeremophilenolide，通过还原和乙酰化反应获得了2个呋喃倍半萜修饰产物，分别为epiligularol(11)，epiligularol acetate(12)。活性评价实验结果表明所有内酯艾里莫芬烷倍半萜对HL-60细胞生长有明显的抑制作用，化合物1～6的IC50＜10μg/ml，化合物7，8，10的IC50在10～20μg/ml之间，具有C9和C10位不饱和结构的内酯倍半萜（1～6）活性较强；所有呋喃艾里莫芬烷倍半萜没有抑制活性，而橐吾酮通过光敏氧化转化为内酯倍半萜后有抑制活性。结论首次研究了橐吾酮的光敏氧化反应，橐吾酮的呋喃环光敏氧化后可转化为内酯环；首次探讨了艾里莫芬烷倍半萜抗白血病作用构效关系。该类倍半萜的12（8）内酯环可能是抗白血病（HL-60）的关键活性基团，具有C9和C10位不饱和结构的内酯倍半萜活性较强。 【关键词】 艾里莫芬烷倍半萜； 抗肿瘤； 构效关系； 白血病 　　Abstract：ObjectiveTo study the structure-activity relationship of eremophilane sesquiterpenes against leukemia. MethodsThree derivatives(10-12) were prepared from ligularone. The in vitro cytotoxicities of nine eremophilane sesquiterpenes(1-9) which were isolated from Ligularia species and three derivatives(10-12) against cancer cell line HL-60 were evaluated.ResultsThree derivatives were prepared from ligularone and they were identified as 6-oxo-8β-methoxyeremophilenolide (10), epiligularol(11) and epiligularol acetate(12), respectively. Eremophilanolides 1-6 showed cytotoxic activities on HL-60 cancer cells with IC50＜10μg/ml and eremophilanolides 7, 8 and 10 exhibited cytotoxic activities on HL-60 cancer cells with IC50 in the range of 10 to 20μg/ml, whereas furanoeremophilanes 9, 11 and 12 showed no cytotoxic activities on HL-60 cancer cells. ConclusionLigularone, a furanoeremophilane can be converted into an eremophilanolide through photosensitized oxygenation. The lactone group of eremophilane sesquiterpenes is a key active group against leukemia and eremophilanolides with unsaturated C-9 and C-10 showed more activities. 　　Key words：Eremophilane sesquiterpene; Antitumor; Structure-activity relationship; Leukemia 　　艾里莫芬烷倍半萜(eremophilane sesquiterpenes)是菊科千里光族植物中存在的一类特征性化学成分，如千里光族的橐吾属［1］和千里光属［2］等属植物中含有许多该类成分，主要有两种类型：7（8）并呋喃型(furanoeremophilane)和1