3-(β-D-glucopyranosyl)oleanolic acid benzyl ester | 1229037-80-2

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 3-(β-D-glucopyranosyl)oleanolic acid benzyl ester
• 英文别名: benzyl (4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10-[(2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylate
• CAS: 1229037-80-2
• 化学式: C₄₃H₆₄O₈
• 分子量: 708.976
• InChiKey: IKAHBYNVZAQFRV-BRCSGPMYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.72
• 重原子数：
  51.0
• 可旋转键数：
  6.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  125.68
• 氢给体数：
  4.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  3-(β-D-glucopyranosyl)oleanolic acid benzyl ester 在 吡啶 、 4-二甲氨基吡啶 、 三氟甲磺酸三甲基硅酯 、 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， -10.0~50.0 ℃ 、101.33 kPa 条件下， 反应 43.17h， 生成 3β-O-[2,4-di-O-(2,3,4-tri-O-acetyl-α-L-rhamnopyranosyl)-β-(3,6-di-O-acetyl)-D-glucopyranosyl]olean-12-en-28-oic acid
  参考文献：
  名称：

  3- O -β-木香油基齐墩果烷型三萜作为潜在的H5N1进入抑制剂的构效关系

  摘要：

  基于我们先前发现的小分子抑制剂皂苷1，已经设计，合成和评估了一系列3 - O -β-木糖醇齐墩果酸类似物作为H5N1进入抑制剂。对化合物1糖苷配基的详细结构-活性关系（SARs）研究表明，齐墩果酸作为糖苷配基的微妙修饰对抗病毒活性具有关键影响。这些结果表明，在OA的17-COOH处引入双取代酰胺结构或将OA的C-3构型从3β转变为3α形式均可显着提高选择性指数，同时保持其体外抗病毒活性。化合物8由于其出色的抑制活性和良好的选择指数，因此被选择用于进一步的机理研究。分子模拟研究和表面等离子体共振分析证实，化合物8通过与氨基酸残基LYS-26，ASN-53，ASN-27和ASN-50结合，稳定了血凝素（HA）的HA2亚基，因此可以防止HA进行构象重排，这是病毒进入的关键步骤。

  DOI：

  10.1016/j.ejmech.2016.04.061
• 作为产物：
  描述：

  在 sodium methylate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 3-(β-D-glucopyranosyl)oleanolic acid benzyl ester
  参考文献：
  名称：

  3- O -β-木香油基齐墩果烷型三萜作为潜在的H5N1进入抑制剂的构效关系

  摘要：

  基于我们先前发现的小分子抑制剂皂苷1，已经设计，合成和评估了一系列3 - O -β-木糖醇齐墩果酸类似物作为H5N1进入抑制剂。对化合物1糖苷配基的详细结构-活性关系（SARs）研究表明，齐墩果酸作为糖苷配基的微妙修饰对抗病毒活性具有关键影响。这些结果表明，在OA的17-COOH处引入双取代酰胺结构或将OA的C-3构型从3β转变为3α形式均可显着提高选择性指数，同时保持其体外抗病毒活性。化合物8由于其出色的抑制活性和良好的选择指数，因此被选择用于进一步的机理研究。分子模拟研究和表面等离子体共振分析证实，化合物8通过与氨基酸残基LYS-26，ASN-53，ASN-27和ASN-50结合，稳定了血凝素（HA）的HA2亚基，因此可以防止HA进行构象重排，这是病毒进入的关键步骤。

  DOI：

  10.1016/j.ejmech.2016.04.061

文献信息

• An Oleanolic Acid Derivative Inhibits Hemagglutinin-Mediated Entry of Influenza A Virus
  作者：Mengdie Ye、Yixian Liao、Li Wu、Wenbao Qi、Namrta Choudhry、Yahong Liu、Weisan Chen、Gaopeng Song、Jianxin Chen

  DOI：10.3390/v12020225

  日期：——

  Influenza A viruses (IAV) have been a major public health threat worldwide, and options for antiviral therapy become increasingly limited with the emergence of drug-resisting virus strains. New and effective anti-IAV drugs, especially for highly pathogenic influenza, with different modes of action, are urgently needed. The influenza virus glycoprotein hemagglutinin (HA) plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a potential target for the development of anti-influenza drugs. In this study, we show that OA-10, a newly synthesized triterpene out of 11 oleanane-type derivatives, exhibited significant antiviral activity against four different subtypes of IAV (H1N1, H5N1, H9N2 and H3N2) replications in A549 cell cultures with EC50 ranging from 6.7 to 19.6 μM and a negligible cytotoxicity (CC50 > 640 μM). It inhibited acid-induced hemolysis in a dose-dependent manner, with an IC50 of 26 µM, and had a weak inhibition on the adsorption of H5 HA to chicken erythrocytes at higher concentrations (≥40 µM). Surface plasmon resonance (SPR) analysis showed that OA-10 interacted with HA in a dose-dependent manner with the equilibrium dissociation constants (KD) of the interaction of 2.98 × 10−12 M. Computer-aided molecular docking analysis suggested that OA-10 might bind to the cavity in HA stem region which is known to undergo significant rearrangement during membrane fusion. Our results demonstrate that OA-10 inhibits H5N1 IAV replication mainly by blocking the conformational changes of HA2 subunit required for virus fusion with endosomal membrane. These findings suggest that OA-10 could serve as a lead for further development of novel virus entry inhibitors to prevent and treat IAV infections.

  流感病毒A型（IAV）一直是全球主要的公共卫生威胁，随着出现抗药病毒株，抗病毒治疗的选择越来越有限。需要紧急开发新型、有效的抗IAV药物，特别是高致病性流感的不同作用模式。流感病毒的糖蛋白血凝素（HA）在病毒感染的早期阶段发挥关键作用，包括受体结合和膜融合，因此成为开发抗流感药物的潜在靶点。本研究表明，OA-10是11个齐墩果型衍生物中新合成的三萜类化合物，对A549细胞培养中4种不同亚型的IAV（H1N1、H5N1、H9N2和H3N2）复制具有显著的抗病毒活性，EC50范围为6.7至19.6μM，细胞毒性极低（CC50 > 640μM）。它以剂量依赖性方式抑制酸诱导的溶血，IC50为26μM，并且在较高浓度（≥40μM）下对H5 HA吸附到鸡红细胞的抑制作用较弱。表面等离子体共振（SPR）分析表明，OA-10以剂量依赖性方式与HA相互作用，平衡解离常数（KD）为2.98×10-12 M。计算机辅助分子对接分析表明，OA-10可能结合到HA茎区的空腔中，这个区域在膜融合过程中会发生重大重组。我们的结果表明，OA-10主要通过阻止HA2亚单位所需的构象变化来抑制H5N1 IAV复制。这些发现表明，OA-10可以作为进一步开发新型病毒进入抑制剂的引领，以预防和治疗IAV感染。
• Synthesis and α-glucosidase inhibitory activity of oleanolic acid derivatives
  作者：Shan Qian、Jiao Hai Li、Yu Wei Zhang、Xin Chen、Yong Wu

  DOI：10.1080/10286020903405456

  日期：2010.1.1

  Glucosidations of oleanolic acid (1) and its dihydroxy-olide derivatives (2) were carried out to provide eight glycosides. All synthesized compounds were evaluated by in vitro -glucosidase inhibitory activity assay. 3-Acetyl dihydroxy-olide oleanolic derivative 15 showed the most potent inhibitory effect. Structure-activity relationships within these compounds are discussed.
• Structure-activity relationships of 3-O-β-chacotriosyl oleanic acid derivatives as entry inhibitors for highly pathogenic H5N1 influenza virus
  作者：Sumei Li、Xiuhua Jia、Xintian Shen、Zhuwen Wei、Zhiyan Jiang、Yixian Liao、Yiming Guo、Xiaojun Zheng、Guohua Zhong、Gaopeng Song

  DOI：10.1016/j.bmc.2017.06.025

  日期：2017.8

  Highly pathogenic H5N1 virus (H5N1) entry is a key target for the development of novel anti-influenza agents with new mechanisms of action. In our continuing efforts to identify novel potential anti-H5N1 entry inhibitors, a series of 3-O-beta-chacotriosyl oleanolic acid analogs have been designed, synthesized and evaluated as H5N1 entry inhibitors based on two small molecule inhibitors 1 and 2 previously discovered by us. The anti-H5N1 entry activities were determined based on HA/HIV and VSVG/HIV entry assays. Compound 15 displayed the most promising anti-H5N1 entry activities with average IC50 values of 4.05 mu M and good selective index (22.9). Detailed structure-activity relationships (SARs) studies suggested that either the introduction of an additional oxo group to position 11 at OA or alteration of the C-3 configuration of OA from 3 beta- to 3 alpha-forms can significantly enhance the selective index while maintaining their antiviral activities in vitro. Molecular simulation analysis confirmed that the compounds exert their inhibitory activity through binding tightly to hemagglutinin (HA2) protein near the fusion peptide and prevent virus entry. (C) 2017 Elsevier Ltd. All rights reserved.