【作者】 彭圣明；

【导师】 林原斌；

【作者基本信息】 湘潭大学 ， 有机化学， 2009， 博士

【摘要】 NO作为一种重要的信使物质和生物活性物质,参与调节机体的一系列生理活动以及新生血管生成等病理生理过程,调节血管内皮生长,触发血管活性物质,促进血管生长与再生。而NO供体则是在体内经酶或非酶作用能释放NO。近来人们为了增加药物的活性,已经开始趋向于把NO供体结构引入到已知药物分子中去。白杨素,化学名为5,7-二羟基黄酮,是以C6-C3-C6结构为基本母核的天然有机化合物。具有一些重要的特性,如:高度的化学反应性,易进行结构修饰;很多重要的药理作用,具有抗氧化、抗焦虑、抗菌、抗癌﹑抗高血压﹑抗病毒等作用。近年来,为获得疗效更好的新型药物,开始了对白杨素进行结构修饰和化学合成。但对白杨素衍生物抗糖尿病及其并发症药物的设计开发处于起步阶段。因此,在本文中我们将设计合成几类白杨素偶联不同一氧化氮供体衍生物新型化合物,期望能同时具有α-葡萄糖苷酶抑制活性和促血管生成作用,为开发糖尿病及其血管并发症药物提供候选化合物。合成路线是以白杨素为母核,将不同类型的NO供体通过不同结构的中间链与白杨素7位活性羟基偶联,或同时在把5位羟基乙酰化。最后得到3种不同类型5个系列共16个未见文献报道的新化合物,其中包括有机硝酸酯类2个系列共9个,呋咱氮氧化物类2个系列共6个、N-羟基胍类1个系列共1个,所有目标化合物均由核磁共振氢谱、质谱等表征确认其结构。对所合成的硝酸酯偶联白杨素衍生物9个和呋咱氮氧化物偶联白杨素衍生物6个共15个,分别进行了体外α-葡萄糖苷酶抑制活性实验, MTT细胞毒性和CAM血管生成实验。发现所有15个化合物都具有α-葡萄糖酶抑制活性,其中6个化合物(7b、17、18、15b、15a、16b)的IC50值都在20μmol/L以下,酶抑制活性大大超过阳性对照药阿卡波糖;在MTT体外实验中,10μmol/L浓度下,所有目标化合物均未表现出细胞毒性,其中7a、7b、7c、5a、5b、5c、17目标化合物对HUVECs-12具有一定的促细胞增殖作用;在CAM体内实验中,目标化合物7a、7b、7c、5a、5b、5c、17、15b、15a、16b、16a促血管生成活性作用明显。根据药理实验,所合成的目标化合物中有5个(7b、17、15b、15a、16b)既有较好的α-葡萄糖苷酶抑制活性,又有较强促血管生成能力,这5个目标化合物在开发糖尿病及其血管并发症药物方面具有很好的潜力,值得深入研究。更多还原

【Abstract】 As an important messenger and biotic activator, mononitrogen monoxide (NO) was believed involved the physiology activity, promotion angiogenesis, accommodation blood vessel- endothelium growth. NO donor in the body by the enzyme or non-enzymatic can be released NO. Recently, people in order to increase the activity of drugs, have begun to tend to the NO donor into the structure of drug molecules.With C6-C3-C6 as the fundamental structure, chrysin (5,7-dihydroxyflavone) is a naturally wide distributed flavonoid, which has been reported to have many different biological activities such as anti-viral, anti-cancer, anti-bactericidal, anti-flammatory, anti-allergic, DNA cleavage, vasodilator, anti-mutagenic, anti-anxiolytic and anti-oxidant effects. To get better therapeutic effect, much effort has been devoted to the modification and chemical synthesis of chrysin in recent years. However, the research on the role of chyrin and its derivatives in anti-diabetes and anti-diabetic vascular complications is still in its infant stage.Different chrysin derivatives were successfully coupled to NO donors and we hope this kind of compounds could act asα-Glucosidase Inhibition reagents and promotion angiogenesis reagents as well as anti-diabetes and anti-diabetic vascular complications. Using chrysin as the starting material, different NO donors were coupled to the active hydroxy group at the 7-position of chrysin and acetylation of hydroxy group at the 5-position could be occurred at the same time. Thus 16 new compounds (including 9 nitro ester compounds, 6 furazan derivatives and 1 N-hydroxy carbamidine compound) were prepared by similar method and all of them were characterized by means of 1H NMR and MS (EI).In vivoα-glucosidase inhibition, MTT cell proliferation and CAM angiogenesis experiments were performed to evaluate these compounds’activity. It was found that all of the 9 nitro ester compounds and 6 furazan compounds showedα-glucosidase inhibition activity, among them, 6 compounds’(7b, 17, 18, 15b, 15a, 16b) IC50 value are less than 20μmol/L, which is much better than the reference compound acarbose. All target compounds did not show any cytotoxicity in the MTT in vivo experiments under 10μmol/L concentration, however, 7a, 7b, 7c, 5a, 5b, 5c and 17 exhibited cell proliferation activity on HUVECs-12. In the meantime, among those 15 compounds investigated by CAM assay, 7a, 7b, 7c, 5a, 5b, 5c, 17, 15b, 15a, 16b and 16a showed strong angiogenic activities.These results indicated that these compounds we prepared have excellent angiogenic activity in vivo andα-glucosidase inhibition activity, among them compounds 7b, 17, 15b, 15a and 16b are the best and worth for further investigation for anti-diabetes and anti-diabetic vascular complications applications.更多还原