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
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摘要
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,~(13)C 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 IC_(50) was0.786 mmol/L (IC_(50) 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.
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,~(13)C 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 IC_(50) was0.786 mmol/L (IC_(50) 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.
引文
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[4]李馨,α-葡萄糖苷酶抑制剂TD-01和米格列醇的药物动力学研究[D].长春:吉林大学,2006.
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[6]Chen L,Zhang Y,Kong X,et al.Design,synthesis,and antihepatocellular carcinoma activity of nitric oxide releasing derivatives of oleanolic acid[J].Journal of Medicinal Chemistry,2008,51(15):4834-4838.
[7]Piccolella S,Nocera P,Carillo P,et al.An apolar Pistacia lentiscus L.leaf extract:GC-MS metabolic profiling and evaluation of cytotoxicity and apoptosis inducing effects on SH-SY5Y and SK-N-BE(2)C cell lines[J].Food and Chemical Toxicology,2016,95:64-74.
[8]Jannet H B,Cheriaa J,Jegham S,et al.Antibacterial activities of a few prepared derivatives of oleanolic acid and of other natural triterpenic compounds[J].Comptes Rendus Chimie,2003,6(4):473-483.
[9]钱珊.具有抗糖尿病活性的齐墩果酸衍生物研究进展[J].时珍国医国药,2012,23(5):1233-1236.
[10]Vinayagam R,Xiao J B,Xu B J.An insight into anti-diabetic properties of dietary phytochemicals[J].Phytochemistry Reviews,2017,16(3):535-553.
[11]Huang J,Wang Y H,Li C,et al.Triterpenes isolated from acorns of Quercus serrata var.brevipetiolata exert antiinflammatory activity[J].Industrial Crops and Products,2016,91:302-309.
[12]赵昱,陈海永,郑汉其,等.A环和c环多氧化取代的五环三萜及其制备方法和用途:中国,101117348[P].
[13]Xu J,Nie X,Hong Y,et al.Synthesis of water soluble glycosides of pentacyclic dihydroxytriterpene carboxylic acids as inhibitors ofα-glucosidase[J].Carbohydrate Research,2016,424:42-53.
[14]唐初,陈玉,柏舜,等.齐墩果酸的结构修饰与生物活性研究进展[J].有机化学,2013,33(1):46-65.
[15]Nie W,Luo J G,Wang X B,et al.Synthesis of newα-glucosidase inhibitors based on oleanolic acid incorporating cinnamic amides[J].Cheminform,2011,59(8):1051-1056.
[16]李文良,陈剑,马丽,等.齐墩果酸衍生物的合成及其降血糖活性研究[J].中国药物化学杂志,2014(1):7-13.
[17]陈玉华,邹凤竹,龙燕,等.蚕桑中1-脱氧野尻霉素药理药效的研究进展[J].时珍国医国药,2014(10):2486-2488.
[18]Yu D,Hu F F,Zhang Y,et al.Chem Inform abstract:Synthesis and biological activity of novel deoxynojirimycin derivatives as potentα-glucosidase inhibitors[J].Cheminform,2013,44(36):383-390.
[19]Cheng K G,Su CH,Huang JY,et al.Conjugation of uridine with oleanolic acid derivatives as potential antitumor agents[J].Chemical Biology and Drug Design,2016,88(3):329-340.
[20]Liu M C,Yang SJ,Jin LH,et al.Synthesis and evaluation as potential antitumor agents of novel ursolic acid derivatives[J].Medicinal Chemistry Research,2016,25(10):2267-2279.
[21]朱娟娟,尹忠平,陈继光,等.微量α-葡萄糖苷酶抑制剂筛选模型及抑制类型的判断方法[J].现代食品科技,2016,(12):164-170.
[22]Wardrop D J,Waidyarachchi SL.Synthesis and biological activity of naturally occurringα-glucosidase inhibitors[J].Cheminform,2011,42(2):1431-1468.
[23]尹忠平.青钱柳悬浮培养细胞三萜酸积累、分离鉴定及其降糖机制研究[D].南昌:南昌大学,2011.
[24]Ding H F,Hu X,Xu X M,et al.Inhibitory mechanism of two allosteric inhibitors,oleanolic acid and ursolic acid onα-glucosidase[J].International Journal of Biological Macromolecules,2018,107:1844-1855.
[25]杨东健,贾俊强,李少辉,等.用分子对接法研究1-脱氧野尻霉素的降血糖作用机制[J].蚕业科学,2016(5):897-900.