齐墩果酸-1-脱氧野尻霉素衍生物的合成及其对α-葡萄糖苷酶活性的抑制

Synthesis of Oleanolic Acid-1-deoxynojirimycin Derivatives and Its Inhibition on α-glucosidase Activity

根据拼合原理,以齐墩果酸(OA)为先导物,对C-28号位的羧基进行修饰,通过溴代、氮代,引入1-脱氧野尻霉素(1-DNJ)设计合成了不同碳链长度的齐墩果酸-1-DNJ衍生物(OADs),其中5个目标化合物其结构均以高分辨质谱、核磁共振谱进行结构表征。利用微量α-葡萄糖苷酶-PNPG检测模型对这一系列化合物的活性进行了筛选,并通过分子对接初步分析了其构效关系。结果表明:所合成的系列化合物的抑制活性较齐墩果酸有较大提高,且当碳链长度为3时(化合物2b)抑制活性最好,其IC_(50)=0.786 mmol/L(OA的IC_(50)=2.387 mmol/L);酶抑制动力学分析表明其为α-葡萄糖甘酶混合型抑制剂;分子对接和热力学参数结果显示,化合物与酶的结合主要是通过氢键和范德华力,形成的氢键个数越多,抑制活性越强; 2b与酶之间形成了7个氢键,结合自由能为-17.19 kJ/mol,接近于阳性对照阿卡波糖。因此,所合成的齐墩果酸-1-DNJ衍生物(2b)对α-葡萄糖苷酶具有较好的抑制活性。

OA was linked with 1-Deoxynojirimycin (1-DNJ) at its C-28 through acarbon chain by bromine substitution and nitrogen substitution,five novel oleanolic acid derivatives (OADs) of that were designed and synthesized by the active group combination,which were confirmed by 1H NMR,13C NMR and HRMS determination.The inhibittion activity of these five OADs on α-glucosidase activity was further evaluated using amicro determination model based on the reaction of α-glucosidase and PNPG,the structure-activity relationship of these OADs was investigated by molecular docking as well.The results showed that all of the five OADs had higher inhibition activity on α-glucosidase than OA,and the OADs with a bridge link which consisted of three methylenes between OA and 1-DNJ group (compound 2 b) showed the highest inhibition activity,of which the IC50 was0.786 mmol/L (IC50 of OA was 2.387 mmol/L).Enzyme inhibition kinetic analysis suggested that these compounds were mixed-type inhibitor of α-glucosidase. The results of molecular docking indicated that hydrogen bond and van der Waals force played critical roles in the combination between the inhibitor and α-glucosidase,the inhibition activities enhanced with the increasing of the number of the hydrogen bonds.Seven hydregon bonds were found in the molecular docking model between the compound 2b and α-glucosidase. The free energy of the binding between compound 2b and α-glucosidase was only-17.19 k J/mol,which was slightly higher than acarbose.Therefore,the synthesized oleanolic acid-1-DNJ derivative (2b) had a good inhibitory activity against α-glucosidase.