新型丹参素衍生物的合成及初步活性研究
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摘要
目的:对传统中药第一大药丹参中的有效水溶性成分丹参素进行化学结构修饰,设计合成一系列新型丹参素衍生物,研究新衍生物对缺血性心脏病的治疗作用,并在此基础上进一步系统地研究丹参素的构效关系,以期获得药效更强,选择性更高,毒副作用更低的用于治疗缺血性心脏病的新药先导化合物。方法:对丹参素结构中的羧基、酚羟基、醇羟基部位分别进行化学修饰,合成了三系列的衍生物;应用分析方法(1H-NMR、ESI-MS、1HRMS、EA等)对新合成的丹参素衍生物进行结构确证;观察丹参素衍生物对叔丁基过氧化氢(t-BHP)氧化损伤的乳鼠心肌细胞的保护作用。结果:合成了丹参素新衍生物及其中间体共17个,新型丹参素衍生物在不同程度上均能够抗t-BHP(150μM)诱导的乳鼠的心肌细胞损伤,其保护作用呈现剂量依赖关系,其中化合物7,16,20与丹参素相比具有更好的生物活性,可作为先导化合物深入研究。
Objectives: Danshensu, one of the active components of the herb Salvia miltiorrizaBunge, has a variety of biological acticvity. In our research, a series of new Danshensu derivatives were designed and synthesized, and their cardioprotective effect was evaluated. Methods: New Danshensu derivatives were synthesized by modifying at the o-diphenol hydroxyl,α-hydroxyl and carboxyl groups of Danshensu. They were identified by ESI-MS, 1H-NMR, HRMS, EA; The cardioprotective effects of these new compounds were evaluated against t-BHP-induced cell damage in neonatal rat ventricular myocytes. Results: Seventeen new compounds were obtained and all of them showed significant protective effect in vitro. Furthermore, the therapeutic efficacy of compound 7, 16, 20 were significantly higher than Danshensu and other Danshensu derivatives. The results suggest that these compounds were potential new treatment for cardiovascular diseases.
Objectives: Danshensu, one of the active components of the herb Salvia miltiorrizaBunge, has a variety of biological acticvity. In our research, a series of new Danshensu derivatives were designed and synthesized, and their cardioprotective effect was evaluated. Methods: New Danshensu derivatives were synthesized by modifying at the o-diphenol hydroxyl,α-hydroxyl and carboxyl groups of Danshensu. They were identified by ESI-MS, 1H-NMR, HRMS, EA; The cardioprotective effects of these new compounds were evaluated against t-BHP-induced cell damage in neonatal rat ventricular myocytes. Results: Seventeen new compounds were obtained and all of them showed significant protective effect in vitro. Furthermore, the therapeutic efficacy of compound 7, 16, 20 were significantly higher than Danshensu and other Danshensu derivatives. The results suggest that these compounds were potential new treatment for cardiovascular diseases.
引文
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[22]李承珠,林嘉宝,杨诗春.丹参素对血小板释放血管收缩物质的影响[J].西医结合杂志, 1984, 4(10): 565-567.
[23]姜开余,顾振纶,阮长耿.丹参素对CD11b、P-selection、ICAM-1、VCAM-1 E-selection表达的影响[J].中国药理学通报, 2000, 16(4): 682-684.
[24]顾扬洪,张彩英,黄桂秋.丹参和丹参素对牛内皮细胞抗凝和纤溶功能的影响[J].上海第二医科大学学报, 1990, 10(4): 208-210.
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