CN116589522A - 齐墩果酸c28葡萄糖三聚体衍生物及其应用 - Google Patents

齐墩果酸c28葡萄糖三聚体衍生物及其应用 Download PDF

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CN116589522A
CN116589522A CN202310236447.8A CN202310236447A CN116589522A CN 116589522 A CN116589522 A CN 116589522A CN 202310236447 A CN202310236447 A CN 202310236447A CN 116589522 A CN116589522 A CN 116589522A
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oleanolic acid
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trimer derivative
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glucose
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俞飞
张鸳
蔡铭
杨帆
张继虹
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Kunming University of Science and Technology
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Abstract

本发明公开了一类结构式如下式所示的齐墩果酸C28葡萄糖三聚体衍生物：将该类化合物应用于预防或治疗流感病毒疾病中，实验结果表明齐墩果酸C28葡萄糖三聚体衍生物对流感病毒具有明显的抑制作用，并且能有效阻止流感病毒进入细胞，有着很好的抗流感病毒活性。

Description

齐墩果酸C28葡萄糖三聚体衍生物及其应用
技术领域
本发明涉及一类齐墩果酸C28葡萄糖三聚体衍生物，及其在用于生产预防或/和治疗流感疾病药物中的应用。
背景技术
流感是由流感病毒(Influenza virus)引起的一种急性上呼吸道感染疾病。根据其内部核蛋白(NP)和基质蛋白(M)的抗原性不同，流感病毒可分为A型、B型、C型和D型。A型(又称甲型)流感病毒大规模流行可引起极高的发病率和死亡率，严重威胁着人类的健康(Virology Journal.2007,4,1-5)。A型流感病毒在二十世纪主要引起了三次大型流感，即1918年的H1N1，1957年的H2N2以及1968年的H3N2，共造成约5000万人死亡(EmergingInfectious Diseases.2006,12,9-14；Journal of the American Medical Association,2007,18,2025-2027)。2009年甲型流感也是由H1N1流感病毒引起(New England Journalof Medicine.2009,370,1335-1342)，其传播之迅速，引起了世界的关注。据统计，全世界平均每年有30-50万人死于流感(Southern Medical Journal.2007,57,1-60)。
迄今，FDA批准的抗流感药物主要有两类：第一类，达菲(Oseltamivir)和乐感清(zanamivir)主要抑制流感病毒的神经氨酸酶(NA)，阻断流感病毒从感染细胞中释放出来(Nature Medicine.2004,10,82-87；Journal of the American Chemical Society.1997,119,681-690)；第二类，金刚烷胺(amantadine)和金刚乙胺(rimantadine)主要破坏流感病毒M2蛋白离子通道活性，能够抑制流感病毒的脱衣壳过程(Proceedings of the NationalAcademy of Sciences of the United States of America.2008,105,10967-10972)。然而，美国疾病预防控制中心抽样调查发现，2008/2009年的H3N2毒株和2009年大流行的H1N1病毒中，100％的毒株对金刚烷类药物都具有耐药性；99.6％的季节性H1N1流感病毒对达菲具有耐药性。
三萜类化合物是自然界中广泛存在的一类天然化合物，其结构包括A、B、C、D、E五个环，30个碳原子(Journal of the American Chemical Society,1996,35,8509-8509)。三萜类化合物由于其多种多样的生物及药理活性而引起越来越广泛的关注，根据我们课题组研究发现，齐墩果酸(C28)葡萄糖缀合物有着较好的抗流感病毒活性，且具有广谱性(European Journal of Medicinal Chemistry.2019,182,111622.)。北京大学周德敏教授课题组首次发现了自然界广泛存在的五环三萜天然产物与不同的环糊精偶联具有很强的抗流感病毒进入的活性，并对其机制进行了深入的研究(European Journal of MedicinalChemistry.2017,134,133-139；Biomaterials.2016,78,74-85)。齐墩果酸C28葡萄糖三聚体衍生物对流感病毒的抑制作用则未见报道。
发明内容
本发明提供了一类齐墩果酸C28葡萄糖三聚体衍生物及其制备方法，它们能够阻止或抑制流感病毒的感染机体。
本发明齐墩果酸C28葡萄糖三聚体衍生物结构式如下式所示:
式中：R1为(-CH2-)m，m＝1-5；
A为取代或未取代的苯环、取代或未取代的碳原子、取代或未取代的环己烷、取代或未取代的哌嗪、三嗪，其中取代基包括C1-C6烷氧基、羟基、硝基或卤素；
R2为CH3COO-或-OH。
本发明齐墩果酸C28葡萄糖三聚体衍生物的具体结构如下之一：
式中：R选自
本发明齐墩果酸C28葡萄糖三聚体衍生物还包括齐墩果酸C28葡萄糖三聚体衍生物药学上可接受的盐、齐墩果酸C28葡萄糖三聚体衍生物药学上可接受的盐的水合物。
本发明另一目的是将上述齐墩果酸C28葡萄糖三聚体衍生物应用在制备预防或/和治疗流感疾病中，尤其是甲型流感。
上述齐墩果酸C28葡萄糖三聚体衍生物也可用于制备阻止或抑制流感病毒进入细胞的药物。
本发明化合物可以以纯净化合物或化合物的混合物的形式给药，或者优选在药物赋形剂，稀释剂或载体中给药。可以通过任何适当的途径来施用活性剂进行治疗。适当的施用途径可以包括口服，直肠，鼻，气雾或颗粒吸入剂，局部(包括含化和舌下)，经皮，阴道，膀胱内，伤口内和胃肠外(包括皮下，肌内，静脉内，胸骨内，膜内，硬膜外和真皮内)。
本发明也涉及组合物，包含本发明化合物，或其药学可接受的盐，与一种或多种药学可接受的添加剂和任选的其他药物一起。药学可接受的添加剂可以是载体、稀释剂、佐剂和(或)赋形剂的形式，可以包括所有常规的溶剂、分散剂、填充剂、固体载体、包衣剂、抗真菌或抗菌剂、皮渗透剂、表面活性剂等张剂和吸收剂，和缓释或控释基质。活性剂可以以适合同时，分开或连续施用活性剂的组分的试剂盒的形式；在与组合物的其他成分相容和患者生理耐受的意义上，每种载体，稀释剂，佐剂和/或赋形剂必须是“药学可接受的”。该组合物可以方便地以单元剂型的形式存在，可以通过制药领域公知的方法来制备；这些方法包括将活性成分与载体相混合的步骤，其中载体是由一种或多种助剂组成的；一般地，制备该组合物，包括将活性成分与液体载体、稀释剂、佐剂和/或赋形剂或精细分离的固体载体或两者均匀和直接地混合，然后如果必要使产物成型。
适合口服的本发明的组合物可以是以每个都包含预定量的活性成分的分离单元例如胶囊、囊剂或片剂的形式存在；作为粉末或颗粒；作为水相或非水液体中的溶液或混悬液；或者作为水包油性液体乳剂或油包水性乳剂。活性成分也可以以大丸剂、药糖剂或糊剂的形式存在。可以通过任选与一种或多种助剂压片或成模来制备片剂；可以通过在适当的机器中压制自由流动形式例如粉末或颗粒的活性成分来制备压制片，任选与粘合剂(例如惰性稀释剂、防腐剂、崩解剂、淀粉羟乙酸钠、交联聚维酮、交联羧甲基纤维素钠)，表面活性剂或分散剂混合。可以通过在适当的机器中将用惰性液体稀释剂湿润的粉末状化合物的混合物成型来制备模印片；任选可以将片剂包衣或刻痕，可以通过配制来缓释或控释活性成分，例如使用不同比例的羟丙基甲基纤维素来产生所需的释放性质；片剂任选可以具有肠溶衣，以在肠部分而不是胃中释放。
适合胃肠外施用的组合物包括水性和非水性等张无菌注射溶液，其可以包含抗氧化剂，缓冲剂，抑菌剂和使组合物与所预期的患者的血液等张的溶质；和水性和非水性无菌混悬液，其可以包括助悬剂和增稠剂。该组合物可以存在于单位剂量或多剂量的密封容器例如安瓿和管中，可以贮存在冷冻-干燥(冻干)条件下，仅需要在使用前加入无菌液体载体例如注射用水。可以由上述种类的无菌粉末，颗粒和片剂来制备无准备的注射溶液和混悬液。适合局部施用于皮肤，即经皮施用的组合物可以包含溶解或悬浮在任何适当的载体或基质中的活性剂，可以是洗剂、凝胶、乳膏、糊剂、软膏等等的形式。适当的载体可以包括液状石蜡、丙二醇、蜡、聚氧乙烯和长链醇。也可以使用经皮装置例如贴剂，可以包含适当材料例如硝酸/乙酸纤维素、丙烯和聚碳酸酯制成的微孔膜。贴剂也可以包含适当的皮肤粘附性和基底材料。
本发明的活性化合物也可以以植入物的形式存在，其可以包含药物的聚合性装置，其中聚合物是生物相容性的和无毒性的。适当的聚合物可以包括水凝胶、硅酮、聚乙烯和生物可降解的聚合物。
本发明的化合物可以以持续(即控释)或缓释的形式施用。持续释放制剂是其中施用后活性成分在患者体内缓慢释放并在最小的时间里维持所需的药物浓度的制剂。持续释放制剂的制备是本领域技术人员公知的。剂型可以包括口服形式、植入物和经皮形式。对于缓释施用，活性成分可以作为例如缓释颗粒悬浮或在脂质体内。
本发明另一目的是提供了上述齐墩果酸C28葡萄糖三聚体衍生物的制备方法：
(1)将齐墩果酸2-5mmol溶于四氢呋喃中，依次加入2-7.5mmol苯并三唑四甲基四氟硼酸(TBTU)、2.5-7.5mmol N,N-二异丙基乙胺(DIEA)，反应获得齐墩果酸活泼酯中间体；
(2)将齐墩果酸活泼酯中间体溶于四氢呋喃或N,N-二甲基甲酰胺(DMF)中，再加入1-5mmol 2-炔丙胺、1.5-3mmol三乙胺(TEA)或Na2CO3，反应得产物；
(3)将步骤(2)所得产物与1-3mmol的2,3,4,6-O-四乙酰基-D-吡喃葡萄糖基叠氮化物、0.5-5mmol的五水硫酸铜、0.5-5mmol的抗坏血酸钠进行CuAAC反应，得产物；
(4)将步骤(3)获得的产物1mmol利用三光气反应与0.2-5mmol不同链长的氨基炔衍生物通过酰胺键偶联，所得产物再与0.2-2mmol的3-叠氮基-2,2-(二叠氮甲基)丙基-1-醇或1,3,5-三叠氮甲基苯、0.5-5mmol的五水硫酸铜、0.5-5mmol的抗坏血酸钠进行CuAAC反应，得到齐墩果酸C28乙酰葡萄糖三聚体衍生物，经脱乙酰保护基后，获得齐墩果酸C28葡萄糖三聚体衍生物。
本发明的优点和技术效果如下：
1、本发明将齐墩果酸C28葡萄糖缀合物聚合形成三聚体，从而模拟生物体内糖配体与蛋白之间可以通过多价效应的协同作用增强它们之间的亲和性、特异性，产生所谓的“多价效应”；
2、通过多个药效团对同病变位点的多价态结合作用，增加载药量并提高药物在血浆中的稳定性和药效；
3、本发明中的化合物以流感病毒进入细胞阶段为靶点，从源头上抑制了流感病毒感染，为抗流感病毒抑制剂的研究提供了依据。
附图说明
图1为化合物B2a加药时间点实验流程示意图(上图)及结果数据图(下图)；
图2为化合物B2a血凝抑制实验结果，其中上图为化合物B2a对A/WSN/33(H1N1)的血凝抑制图，下图为阳性对照HA抗体的血凝抑制图；
图3为流感病毒H1N1感染BALB/c小鼠实验流程图；
图4为化合物B2a对体内感染流感病毒小鼠体重变化图；
图5为化合物B2a对体内感染流感病毒小鼠存活率变化图；
图6为化合物B2a对体内感染流感病毒小鼠的肺部切片HE染色图(200x)，其中空白对照组Control(14d)，病毒模型组Virus(6d)，OSV阳性对照组(14d)，化合物B2a-1表示高浓度剂量组(14d)，化合物B2a-2表示低浓度剂量组(14d)。
具体实施方式
下面通过实施例对本发明作进一步详细说明，但本发明的保护范围不局限于所述内容，实施例中方法如无特殊说明均采用常规方法，使用试剂如无特殊说明，均为常规市售试剂或采用常规方法配置的试剂。
实施例1：齐墩果酸C28葡萄糖三聚体的制备
(1)化合物1的合成
取650mg(1mmol)2,2-双(溴甲基)-3-溴-1-丙基醇于100mL反应瓶中，加20mL N,N-二甲基甲酰胺(DMF)溶解，再加入520mg(4mmol)叠氮钠(NaN3)，80℃下反应过夜，薄层色谱(TLC)检测，展开剂体系为石油醚/乙酸乙酯(3/1，v/v)，CMC显色剂显色。
反应完成后，将反应瓶中溶剂蒸干，用水和乙酸乙酯体系萃取3次，收集有机相并用无水硫酸钠(Na2SO4)干燥，之后浓缩以及留样，柱层析纯化分离(石油醚/乙酸乙酯，6/1，v/v)得无色透明液体产物1，产率：87％。
(2)化合物2的合成
取200mg(0.56mmol)1,3,5-三(溴甲基)苯放入50mL圆底反应瓶中，于10mL N,N-二甲基甲酰胺(DMF)溶解，再加入146mg(2.24mmol)NaN3，80℃下反应17h后，TLC检测，展开剂体系为石油醚/乙酸乙酯(3/1，v/v)，CMC显色剂显色；
反应完成后，将溶剂蒸干，用水/乙酸乙酯体系萃取3次，收集有机相用无水Na2SO4干燥，之后通过硅胶柱层析分离(石油醚/乙酸乙酯，3/1v/v)分离样品，得到液体产物化合物2。
(3)齐墩果酸C28葡萄糖三聚体连接臂的合成
1)化合物3a的合成(3b、3c、3d和3e与此步骤一致)
取420mg(5mmol)炔丙醇于100mL圆底反应瓶中，加入20mL二氯甲烷溶解，加入三乙胺(2mL)，将反应瓶置于0℃冰浴中，用常压滴液漏斗滴加1412mg(7.5mmol)4-甲苯磺酰氯(TsCl)的二氯甲烷溶液，滴毕，移至室温，反应过夜；TLC检测，展开剂体系为石油醚/乙酸乙酯(3/1，v/v)，CMC显色剂显色；
反应完成后，用水和二氯甲烷体系萃取3次，收集有机相并用无水Na2SO4干燥，之后浓缩、留样、柱层析纯化分离(石油醚/乙酸乙酯，9/1，v/v)得无色透明液体产物3a，产率95％。
2)化合物4a的合成(4b、4c、4d和4e与此步骤一致)
取238mg(1mmol)化合物3a于50mL圆底反应瓶中，加入10mL N,N-二甲基甲酰胺(DMF)溶解，加入97.5mg(1.5mmol)NaN3，70℃油浴搅拌，反应过夜；TLC检测，展开剂体系为石油醚/乙酸乙酯(3/1,v/v)，CMC显色剂显色。
反应完成后，蒸干反应溶剂后，反应体系用水/乙酸乙酯体系萃取2次，饱和食盐水萃取1次，有机相用无水Na2SO4干燥，之后浓缩、留样、硅胶柱层析分离(石油醚/乙酸乙酯，4/1v/v)，得无色透明液体产物4a，产率75.6％。
3)化合物5a的合成(5b、5c、5d和5e与此步骤一致)
取218mg(2.0mmol)化合物4a于50mL圆底反应瓶中，于5mL四氢呋喃溶解，加入657mg(2.5mmol)的三苯基膦(PPh3)和5mL纯水，60℃油浴搅拌过夜；TLC检测，展开剂体系为石油醚/乙酸乙酯(3/1,v/v)，茚三酮显色剂显色。
反应完成后，蒸干混合溶剂中的四氢呋喃，再加入1mol/L HCl使其成盐，用水和二氯甲烷体系萃取3次，蒸干水相，得棕黄色油状产物5a，产率80.4％。
(4)以sp3杂化碳原子为中心的齐墩果酸C28葡萄糖三聚体合成
1)化合物A1的合成
取2mmol齐墩果酸(OA)溶解于20mL四氢呋喃，分别加入苯并三唑四甲基四氟硼酸2.5mmol和N,N-二异丙基乙胺3mmol，室温反应12h后，薄层检测(展开剂石油醚:乙酸乙酯＝3:1)；蒸干溶剂，采用水/乙酸乙酯体系(水与乙酸乙酯均为100mL)萃取3次，取有机相用Na2SO4干燥后蒸除溶剂，重结晶(乙醇:水＝3:1)；得絮状固体A1，待用；
2)化合物A2的合成
取1g(1.75mmol)上述产物A1用四氢呋喃溶解，加入121mg(2.2mmol)的炔丙胺，再加入279mg(2.6mmol)的碳酸钠，室温反应4h；薄层检测(展开剂石油醚:乙酸乙酯＝3:1)；硅胶柱分离纯化，洗脱剂为石油醚:乙酸乙酯＝3:1，收集洗脱液后干燥后，得白色粉末产物A2；
3)化合物A3的合成：
取560mg(1.14mmol)上述产物A2和460mg(1.23mmol)2,3,4,6-O-四乙酰基-D-吡喃葡萄糖基叠氮化物加入溶剂(二氯甲烷/水＝1:1)后，再分别加入抗坏血酸钠301mg(1.5mmol)和五水硫酸铜407mg(1.6mmol)，室温快速搅拌反应8h后停止反应；TLC检测(展开剂石油醚:乙酸乙酯＝1:1)；直接将反应液倾入分液漏斗补加二氯甲烷和水进行萃取，取有机相蒸干，得白色粉末A3；
4)化合物A4a的合成(化合物A4b、A4c、A4d和A4e合成步骤与之类似)
取100mg(0.12mmol)化合物A3溶解于无水四氢呋喃中，在搅拌下加入固体三光气103mg(0.35mmol)和0.46mmol的氨基炔衍生物，反应3h后，薄层色谱检测反应进程，展开剂石油醚:乙酸乙酯＝1:1，待反应完全后，蒸干溶剂，再用10mL无水四氢呋喃溶解，在50℃油浴中搅拌2-3h后，加入15mg炔丙胺，3h后，薄层色谱检测进程，展开剂石油醚:乙酸乙酯＝1:1，待反应完全后，蒸干无水四氢呋喃，采用水/二氯甲烷体系萃取3次，取有机相于Na2SO4干燥后蒸除溶剂，硅胶柱分离纯化，洗脱条件石油醚:乙酸乙酯＝2:1，得白色固体A4a；
化合物A4a：M.p.:115.6-117.5℃；1H NMR(600MHz,CDCl3)δ:0.67,0.88,0.90,1.16,1.25,1.26,1.27(7×CH3),2.04,2.05,2.07,2.10(s,4×CH3CO),0.60-2.02(m,otheraliphatic ring protons),2.55(d,J＝9.84Hz,1H),3.95-4.43(m,6H),4.63(q,J＝15.12Hz,1H),5.25(t,J＝5.46,1H),5.40-5.47(m,2H),5.84(d,J＝8.94Hz,1H),6.60(t,J＝5.34Hz,1H),7.79(s,1H).13C NMR(150MHz,CDCl3)δ:16.7,20.3,20.8,21.1,23.7,25.8,28.0,30.8,32.2(2C),33.0,34.1,35.0,36.8,38.1,39.4,42.0(2C),46.2,46.6,47.5,55.2,60.5,61.5,67.6,70.3,72.7,75.1,76.9,77.2,77.4,81.9,85.7,121.2,123.2,144.5,145.4,156.3,168.8,169.4,170.1,170.6,171.3,178.6.ESI-HRMS(m/z)[M+Na]+calcd for C51H73N5NaO12,970.5148；found,970.5152.
化合物A4b：M.p.:125.6-127.1℃；1H NMR(600MHz,CDCl3)δ:0.63,0.75,0.84,0.86,0.98,1.00,1.12(7×CH3),1.84,2.00,2.04,2.06(s,4×CH3CO),0.60-2.10(m,otheraliphatic ring protons),2.52(d,1H,J＝12.06Hz),2.74-2.86(m,2H),2.89-2.96(m,2H),3.43-3.50(m,1H),3.97(q,J＝9.66,1H),4.07-4.12(m,1H),4.21-4.32(m,3H),4.40(t,J＝6.66Hz,1H),4.46(t,J＝6.60Hz,1H),4.59(q,J＝15.12Hz,1H),5.22(t,J＝9.60Hz,1H),5.37-5.43(m,3H),5.81(d,J＝8.94Hz,1H),6.58(s,1H),7.48(s,1H),7.76(s,1H).13CNMR(150MHz,CDCl3)δ:15.37,16.54,18.06,20.15,20.43,20.51,20.59,20.67,23.41,23.53,23.83,25.69,27.14,27.90,30.65,32.12,32.21,32.92,33.99,34.88,36.71,37.78,38.00,39.26,41.85,41.89,45.88,46.13,46.52,47.35,48.57,55.08,61.40,67.46,70.20,72.58,75.02,76.79,77.00,77.21,85.63,121.08,123.09,132.26,144.37,145.29,168.66,169.28,169.98,170.50,178.44.ESI-HRMS(m/z)[M+H]+calcd forC52H75N5O12,962.5490；found,962.5493.
化合物A4c：M.p.:117.6-118.9℃；1H NMR(600MHz,CDCl3)δ:0.61,0.75,0.83,0.84,0.84,0.86,1.10(7×CH3),1.82,1.98,2.02,2.04(s,4×CH3CO),0.59-2.09(m,otheraliphatic ring protons),2.16-2.19(m,2H),2.51(d,J＝10.08Hz,1H),2.71(t,J＝7.44Hz,1H),3.18(t,J＝6.42Hz,2H),3.95-3.97(m,1H),4.11(d,J＝1.92Hz,1H),4.19-4.27(m,3H),4.42(t,J＝6.90Hz,1H),4.57(q,J＝15.18Hz,1H),4.92(t,J＝5.88Hz,1H),5.20(t,J＝9.9Hz,1H),5.35-5.41(m,3H),5.80(d,J＝8.94Hz,1H),6.56(t,J＝5.52Hz,1H),7.36(s,1H),7.74(s,1H).13C NMR(150MHz,CDCl3)δ:14.05,15.41,16.44,17.97,20.05,20.41,20.57,20.93,22.47,23.31,23.44,23.71,25.59,27.05,27.82,28.54,29.50,30.55,32.04,32.14,32.83,33.90,34.79,36.62,37.72,37.94,39.16,39.82,41.75,46.01,46.41,47.26,48.36,55.01,60.26,61.32,67.38,70.13,72.50,74.85,77.00,80.83,81.96,85.47,121.05,121.32,122.99,131.75,144.23,145.18,146.95,156.78,168.54,169.18,169.87,170.38,178.29.ESI-HRMS(m/z)[M+H]+calcd forC53H77N5O12,976.5647；found,976.5652.
化合物A4e：M.p.:120.1-122.1℃；1H NMR(600MHz,CDCl3)δ:0.63,0.77,0.84,0.85,0.86,0.87,1.12(7×CH3),1.84,2.00,2.03,2.06(s,4×CH3CO),0.60-1.98(m,otheraliphatic ring protons),2.14-2.18(m,2H),2.51(d,J＝10.14Hz,1H),3.15(t,J＝11.7Hz,2H),3.95-3.98(m,1H),4.07-4.12(m,1H),4.20-4.33(m,3H),4.59(q,J＝15.18Hz,1H),4.66(t,J＝11.51Hz,1H),5.21(t,J＝19.2Hz,1H),5.36-5.44(m,3H),5.81(d,J＝8.94Hz,1H),6.57(t,J＝10.68Hz,1H),7.75(s,1H).13C NMR(150MHz,CDCl3)δ:14.08,15.31,16.57,18.17,20.08,20.44,20.60,23.34,23.47,23.75,25.62,25.67,27.08,27.84,27.89,29.41,30.57,32.07,32.16,32.86,33.93,34.81,36.64,37.74,37.97,39.19,40.62,41.78,41.80,46.05,46.44,47.28,55.02,60.30,61.34,67.40,68.34,70.15,72.52,74.91,76.79,77.00,77.21,80.79,85.52,121.07,123.03,144.26,145.23,156.66,168.58,169.21,169.90,170.42,178.36.ESI-HRMS(m/z)[M+Na]+calcd for C55 H81N5 Na O12,1026.5774；found,1026.5782.
5)化合物A5a的合成(化合物A5b、A5c、A5d和A5e合成步骤与之类似)
取200mg(0.21mmol)化合物A4a和11mg 3-叠氮基-2,2-(二叠氮甲基)丙基-1-醇用二氯甲烷:水＝1:1混合溶剂20mL溶解，再加入63mg抗坏血酸钠和79mg五水硫酸铜，室温下快速搅拌反应，12h后薄层色谱检测(展开剂二氯甲烷:甲醇＝10:1)，反应完全，分离出有机相，干燥后硅胶柱分离，得白色固体目标产物A5a。
化合物A5a：M.p.:212.4-215.5℃；1H NMR(600MHz,CDCl3)δ:0.65,0.78,0.85,0.86,0.88,0.89,1.14(21×CH3),0.64-2.10(m,other aliphatic ring protons),1.86,2.02,2.05,2.08(s,12×CH3CO),2.53(d,J＝10.08Hz,3H),3.21(d,J＝35.64Hz,6H),3.97-4.00(m,3H),4.12-4.14(m,3H),4.22-4.35(m,15H),4.46(d,J＝4.14Hz,3H),4.61(q,J＝15.18Hz,3H),5.23(t,J＝9.84Hz,3H),5.39-5.44(m,9H),5.82(d,J＝8.94Hz,3H),6.58(t,J＝5.28Hz,3H),7.77(s,3H),7.82(s,3H).13C NMR(150MHz,CDCl3)δ:15.6(3C),15.6(3C),16.7(3C),18.2(3C),20.3(3C),20.7(3C),20.9(3C),21.2(3C),23.6(3C),23.7(3C),24.0,25.9(3C),27.3(3C),28.1(3C),29.8(3C),30.8(3C),32.3(3C),32.4(3C),33.1(3C),34.2(3C),35.0(3C),36.9(3C),38.0(3C),38.2(3C),39.4(3C),42.0(3C),46.3(3C),46.7(3C),47.5(3C),55.3(3C),60.6(3C),61.6,70.4(3C),72.8(3C),75.2(3C),85.8(3C),121.3(3C),144.6(3C),145.5(3C),168.9(3C),169.5(3C),170.2(3C),170.7(3C),171.4(3C),178.6(3C).ESI-HRMS(m/z)[M+H]+calcd for C158H228N24O37,3054.677；found,3054.6753.Purity:100％(by HPLC).
化合物A5b：M.p.:199.3-202.6℃；1H NMR(600MHz CDCl3)δ:0.64,0.75,0.76,0.84.0.86,0.88,1.13(21×CH3),0.62-2.10(m,other aliphatic ring protons),1.85,2.02,2.05,2.08(s,12×CH3CO),2.53(d,J＝11.16Hz,3H),2.84(s,6H),3.19-3.43(m,12H),3.98(q,J＝3.9Hz,3H),4.09-4.14(m,3H),4.20-4.31(m,3H),4.61(q,J＝15.12Hz,3H),4.69(d,J＝4.50Hz,3H),5.23(t,J＝9.72Hz,3H),5.38-5.44(m,9H),5.82(d,J＝8.88Hz,3H),6.58(s,3H),7.77(s,3H).13C NMR(150MHz,CDCl3)δ:15.38(3C),16.54(3C),16.64(3C),18.07(3C),20.16(3C),20.52(3C),20.69(3C),23.42(3C),23.54(3C),23.83,25.71(3C),27.15(3C),27.93(3C),30.66(3C),32.11(3C),32.22(3C),32.93(3C),34.00(3C),34.88(3C),36.72(3C),37.84(3C),38.02(3C),39.26(3C),41.86(3C),46.13(3C),46.52(3C),47.35(3C),55.08(3C),61.42,67.48(3C),70.21(3C),72.59(3C),75.02(3C),77.00(3C),85.63(3C),121.11(3C),123.08(3C),144.38(3C),145.31(3C),168.68(3C),169.30(3C),169.99(3C),170.52(3C),178.45(3C).ESI-HRMS(m/z)[M+2H]+/2calcd forC161H234N24O37,1549.3677；found,1549.3660.Purity:90.52％(by HPLC).
化合物A5c：M.p.:160.6-163.3℃；1H NMR(600MHz,CDCl3)δ:0.62,0.76,0.79,0.84,0.85,0.99,1.11(21×CH3),0.62-2.10(m,other aliphatic ring protons),1.83,1.99,2.03,2.05(s,12×CH3CO),2.30(s,6H),2.51(d,J＝11.28Hz,3H),2.72(s,6H),3.18(t,J＝33.48Hz,6H),3.97(d,J＝6.48Hz,3H),4.09(dd,J＝6.90Hz,20.04Hz,3H),4.20-4.37(m,15H),4.59(t,J＝5.40Hz,3H),5.21(t,J＝9.36Hz,3H),5.36-5.42(m,9H),5.81(d,J＝8.82Hz,3H),6.58(s,3H),7.43(s,3H),7.76(s,3H),7.97(s,3H).13C NMR(150MHz,CDCl3)δ:14.06(3C),15.29(3C),16.45(3C),16.55(3C),17.98(3C),20.06(3C),20.42(3C),20.59(3C),20.95(3C),22.08(3C),22.49(3C),23.32(3C),23.45(3C),23.71(3C),23.77,25.61(3C),27.05(3C),27.85(3C),29.31(3C),29.48(3C),29.54(3C),30.56(3C),32.03(3C),32.14(3C),32.84(3C),33.90(3C),34.79(3C),36.62(3C),37.74(3C),37.92(3C),39.16(3C),39.84(3C),41.75(3C),46.02(3C),46.41(3C),47.26(3C),48.96(3C),54.99(3C),60.28(3C),61.33,67.39(3C),70.13(3C),72.50(3C),74.87(3C),77.00(3C),80.88(3C),85.49(3C),121.10(3C),122.99(3C),144.25(3C),145.21(3C),156.85(3C),156.89(3C),168.57(3C),169.21(3C),169.89(3C),170.41(3C),171.09(3C),178.33(3C).ESI-HRMS(m/z)[M+2H]+/2calcd for C164H240N24O37,1570.3912；found,1570.3910.Purity:94.72％(by HPLC).
化合物A5e：M.p.:169.7-173.5℃；1H NMR(600MHz,CDCl3)δ:0.65,0.78,0.86,0.88,0.89,1.14,(21×CH3),0.62-2.10(m,other aliphatic ring protons),1.86,2.02,2.05,2.08(s,12×CH3CO),2.53(d,J＝10.5Hz,3H),2.75(t,J＝7.5Hz,6H),2.93(d,J＝6.36Hz,2H),3.16(t,J＝6.18Hz,6H),3.96-3.99(m,3H),4.14(s,3H),4.23-4.34(m,15H),4.62(q,J＝15.12Hz,3H)，4.68(s,3H),5.23(t,J＝9.78Hz,3H),5.39-5.45(m,9H),5.82(d,J＝8.88Hz,3H),6.57(s,3H),7.76(s,3H),8.01(s,3H).13C NMR(150MHz,CDCl3)δ:14.15(3C),15.39(3C),16.55(3C),16.65(3C),18.08(3C),20.16(3C),20.52(3C),20.69(3C),21.04(3C),23.43(3C),23.55(3C),23.85,25.36(3C),25.71(3C),26.28(3C),27.16(3C),27.92(3C),28.87(3C),29.75(3C),30.66(3C),32.13(3C),32.22(3C),32.93(3C),34.00(3C),34.89(3C),36.72(3C),37.83(3C),38.04(3C),39.27(3C),40.76(3C),41.87(3C),41.90(3C),46.13(3C),46.53(3C),47.36(3C),48.21(3C),55.10(3C),60.38(3C),61.40,67.48(3C),70.21(3C),72.60(3C),75.03(3C),76.79(3C),77.00(3C),77.21(3C),80.91(3C),85.64(3C),121.09(3C),123.11(3C),124.31(3C),144.39(3C),145.33(3C),148.00(3C),168.66(3C),169.28(3C),169.99(3C),170.51(3C),171.18(3C),178.44(3C).ESI-HRMS(m/z)[M+H]+calcd for C170H252N24O37,1612.4377；found,1612.4349.Purity:100％(byHPLC).
6)化合物A6a的合成(化合物A6b、A6c、A6d和A6e合成步骤与之类似)
将81mg(0.03mmol)化合物A5a溶解于10mL无水甲醇中，并加入35mg甲醇钠，室温下搅拌2h至薄层色谱检测原料反应完全，蒸除溶剂后，加入3mL 1mol/L的稀盐酸混悬，过滤，滤饼用蒸馏水洗涤后干燥，得到61mg白色固体产物A6a。
化合物A6a：M.p.:243.1-246.9℃；1H NMR(600MHz,CD3OD)δ:0.63,0.85,0.87,0.91,0.93,1.02,1.17(21×CH3)0.62-2.00(m,other aliphatic ring protons),2.06(s,3H),2.78(d,J＝8.04Hz,3H),3.51-3.58(m,9H),3.72(q,J＝12Hz,3H),3.87(d,J＝11.06Hz,6H),4.38(t,J＝35.16Hz,20H),5.36(s,3H),5.57(s,3H),8.10(d,J＝13.62Hz,6H),13C NMR(150MHz,CD3OD)δ:16.05(3C),17.27(3C),17.52(3C),19.22(3C),24.06,24.46(3C),24.90(3C),26.62(3C),28.33(3C),28.65(3C),30.35(3C),30.63(3C),31.55(3C),33.50(3C),33.62(3C),33.89(3C),34.94(3C),35.82(3C),37.00(3C),37.91(3C),38.92(3C),39.21(3C),40.45(3C),42.38(3C),42.73(3C),47.48(3C),50.96(3C),56.57(3C),61.24,62.22(3C),70.64(3C),73.80(3C),78.22(3C),80.87(3C),82.74(3C),89.39(3C),123.98(3C),144.92(3C),147.02(3C),159.01(3C),180.34(3C).ESI-HRMS(m/z)[M+Cl]-calcd for C134H204N24O25,2584.5112；found,2584.5022.Purity:99.93％(by HPLC).
化合物A6b：M.p.:224.1.3-227.3℃；1H NMR(600MHz,CD3OD)δ:0.60,0.83,0.85,0.90,0.92,0.93,1.15(21×CH3),0.62-2.00(m,other aliphatic ring protons),2.06(s,3H),2.78(d,J＝10.08Hz,3H),3.00(s,3H),3.14(s,2H),3.50-3.60(m,12H),3.73(q,J＝9.12Hz,3H),3.86(dd,J＝8.88,23.34Hz,6H),4.22(d,J＝6.06Hz,3H),4.44(s,9H),5.35(s,3H),5.62(d,J＝7.68Hz,3H),8.12(s,3H),8.41(s,3H).13C NMR(150MHz,CD3OD)δ:13.40(3C),14.91(3C),16.13(3C),16.34(3C),18.01(3C),22.46(3C),22.93(3C),23.26(3C),23.76,24.71(3C),25.46(3C),25.79(3C),26.32(3C),26.87(3C),27.11(3C),27.53(3C),28.89(3C),29.05(3C),29.18(3C),29.26(3C),29.38(3C),29.45(3C),29.64(3C),30.38(3C),30.76(3C),31.76(3C),32.26(3C),32.47(3C),32.67(3C),33.67(3C),33.77(3C),34.60(3C),36.71(3C),37.68(3C),37.73(3C),37.99(3C),39.24(3C),39.97(3C),41.21(3C),41.57(3C),46.13(3C),46.25(3C),47.47(3C),47.54(3C),47.68(3C),47.83(3C),47.97(3C),48.11(3C),48.25(3C),48.40(3C),48.54(3C),49.44(3C),49.55(3C),55.32(3C),61.04,69.40(3C),70.14(3C),72.60(3C),76.97(3C),77.53(3C),77.75(3C),77.96(3C),79.62(3C),81.20(3C),81.38(3C),8.11(3C),122.29(3C),122.46(3C),122.84(3C),125.47(3C),143.07(3C),143.73(3C),144.63(3C),145.16(3C),157.74(3C).ESI-HRMS(m/z)[M+2H]+/2calcd for C137H210N24O25,1297.3043；found,1297.3051.Purity:95.03％(byHPLC).
化合物A6c：M.p.:219.4-222.7℃；1H NMR(600MHz,CD3OD)δ:0.61,0.85,0.89,0.91,0.93,1,15,1.27(21×CH3),0.62-2.00(m,other aliphatic ring protons),2.06(t,J＝13.56Hz,20H),2.45(s,6H),2.79(d,J＝10.92Hz,3H),2.91(s,12H),3.21(d,J＝11.46Hz,6H),3.35(s,2H),3.52(t,J＝9.36Hz,3H),3.59(t,J＝9.00Hz,6H),3.73(q,J＝12.18Hz,3H),3.86(q,J＝24.36Hz,6H),4.28(s,3H),4.39(d,J＝15.12Hz,3H),4.46(d,J＝15.12Hz,3H),4.67(d,J＝45.42Hz,9H),5.35(s,3H),5.62(d,J＝9.18Hz,3H),8.13(s,3H),8.28(s,3H),8.59(s,3H).13C NMR(150MHz,CD3OD)δ:14.48(3C),16.00(3C),17.24(3C),17.50(3C),19.19(3C),21.30(3C),21.63(3C),22.44(3C),22.60(3C),23.62(3C),23.93(3C),24.05,24.42(3C),24.91(3C),26.55(3C),28.31(3C),28.47(3C),28.64(3C),29.41(3C),29.55(3C),30.35(3C),30.62(3C),30.71(3C),31.52(3C),31.82(3C),32.9(3C),33.48(3C),33.57(3C),33.93(3C),34.91(3C),35.42(3C),37.91(3C),38.90(3C),39.19(3C),40.36(3C),40.43(3C),42.30(3C),42.70(3C),46.57(3C),47.32(3C),47.40(3C),49.85(3C),50.45(3C),51.83(3C),53.18(3C),56.60(3C),62.15,70.59(3C),73.83(3C),78.10(3C),80.96(3C),82.48(3C),89.70(3C),123.92(3C),124.23(3C),127.45(3C),127.89(3C),144.88(3C),145.29(3C),159.23(3C),180.43(3C).ESI-HRMS(m/z)[M+2H]+/2calcd for C140H216N24O25,1318.3278；found,1318.3276.Purity:92.63％(by HPLC).
化合物A6e：M.p.:222.0-224.5℃；1H NMR(600MHz,CD3OD)δ:0.62,0.85,0.88,0.91,0,93,0.94,1.17(21×CH3),0.62-2.00(m,other aliphatic ring protons),2.06(t,J＝14.40Hz,3H),2.77(dd,J＝7.62,16.14Hz,6H),3.09(t,J＝6.42Hz,3H),3.25(s,2H),3.50(t,J＝9.36Hz,3H),3.57(t,J＝9.12Hz,6H),3.72(q,J＝12.12Hz,3H),3.84-3.89(m,6H),4.26(q,J＝9.12Hz,3H),4.35(d,J＝15.12Hz,3H),4.44(d,J＝15.18Hz,3H),4.54(s,3H),5.35(s,3H),5.57(d,J＝9.18Hz,3H),7.99(s,3H),8.08(s,3H).13C NMR(150MHz,CD3OD)δ:16.03(3C),17.25(3C),17.54(3C),19.25(3C),23.99(3C),24.05,24.99(3C),25.73(3C),26.56(3C),27.17(3C),28.37(3C),28.64(3C),29.77(3C),30.54(3C),31.56(3C),33.54(3C),33.59(3C),33.98(3C),34.97(3C),35.75(3C),37.96(3C),38.96(3C),39.25(3C),40.49(3C),41.42(3C),42.38(3C),42.76(3C),46.73(3C),47.36(3C),47.49(3C),49.00(3C),51.54(3C),56.66(3C),61.35,62.27(3C),70.70(3C),73.85(3C),78.27(3C),80.95(3C),82.24(3C),89.42(3C),123.66(3C),124.00(3C),126.59(3C),144.97(3C),145.94(3C),148.27(3C),159.19(3C),180.38(3C).ESI-HRMS(m/z)[M+H]+calcd forC146H228N24O25,1360.3741；found,1360.3743.Purity:100％(by HPLC).
(5)通过CuAAC反应合成的以苯环为中心的齐墩果酸C28葡萄糖三聚体衍生物
1)化合物B1a的合成(化合物B1b、B1c、B1d、B1e合成步骤与之类似)
将648mg(0.67mmol)化合物A4a与33mg的1,3,5-三叠氮甲基苯溶解于20mL混合溶剂(二氯甲烷:水＝1:1)中，再加入167mg抗坏血酸钠和210mg五水硫酸铜，室温下快速搅拌反应，12h后TLC检测，反应完全，分离出有机相，干燥后硅胶柱分离，得白色固体产物B1a。
化合物B1a：M.p.:208.3-212.2℃；1H NMR(600MHz CDCl3)δ:0.64,0.77,0.80,0.86,0.87,0.88,1.13,(21×CH3),0.60-2.10(m,other aliphatic ring protons),1.85,2.01,2.05,2.07(s,12×
CH3CO),2.53(d,J＝10.08Hz,3H),3.97-3.99(m,3H),4.13(q,J＝12.36Hz,3H),4.21-4.29(m,10H),4.42(t,J＝5.94Hz,5H),4.60(q,J＝15.18Hz,3H),5.23(t,J＝9.78Hz,3H),5.38-5.43(m,9H),5.82(d,J＝8.94Hz,3H),6.58(t,J＝5.1Hz,3H),7.00(s,3H),7.46(s,3H),7.77(s,3H).13CNMR(150MHz,CDCl3)δ:16.6(3C),18.1(3C),20.1(3C),20.5(3C),20.7(3C),23.4(3C),23.5(3C),23.8(3C),25.7(3C),27.1(3C),27.9(3C),30.6(3C),32.9(3C),34.0(3C),34.9(3C),36.7(3C),37.8(3C),38.0(3C),39.2(3C),41.8(3C),46.1(3C),46.5(3C),47.4(3C),53.2(3C),55.1(3C),61.4(3C),67.5(3C),70.2(3C),72.6(3C),75.0(3C),76.8(3C),77.0(3C),77.2(3C),81.6(3C),85.6(3C),121.1(3C),122.2(3C),123.1(3C),127.1(3C),136.9(3C),144.4(3C),145.3(3C),146.0(3C),156.8(3C),168.7(3C),169.3(3C),170.0(3C),170.5(3C),178.4(3C).ESI-HRMS(m/z)[M+Cl]-calcd forC162H228N24O36,3120.6431；found,3120.6311.Purity:89.73％(by HPLC).
化合物B1b：M.p.:195.1-198.3℃；1H NMR(600MHz,CDCl3)δ:0.64,0.74,0.76,0.84,0.86,0.87,1.13(21×CH3),0.62-2.10(m,other aliphatic ring protons),1.85,2.02,2.05,2.07(s,12×CH3CO),2.53(d,J＝10.5Hz,3H),2.81(s,6H),3.35(d,J＝45.36Hz,6H),3.97-3.99(m,3H),4.13(q,J＝12.18Hz,3H),4.21-4.31(m,10H),4.61(q,J＝15.06Hz,3H),4.67(s,3H),5.23(t,J＝9.72Hz,3H),5.38-5.44(m,9H),6.58(s,3H),6.93(s,3H),7.36(s,3H),7.77(s,3H),13C NMR(150MHz,CDCl3)δ:14.15(3C),15.38(3C),16.54(3C),18.07(3C),20.16(3C),20.52(3C),20.68(3C),23.54(3C),25.71(3C),27.15(3C),27.92(3C),30.65(3C),32.12(3C),32.22(3C),32.93(3C),33.99(3C),34.88(3C),36.72(3C),37.83(3C),38.04(3C),39.26(3C),41.86(3C),46.13(3C),46.52(3C),47.36(3C),53.03(3C),55.10(3C),60.38(3C),61.41(3C),67.48(3C),70.21(3C),72.59(3C),75.01(3C),81.11(3C),85.63(3C),121.12(3C),123.10(3C),136.97(3C),144.37(3C),145.31(3C),168.68(3C),169.30(3C),170.00(3C),170.52(3C),171.20(3C),178.46(3C).ESI-HRMS(m/z)[M+2H]+/2calcd for C165H234N24O36,1565.3702；found,1565.3693.Purity:100％(by HPLC).
化合物B1c：M.p.:150.1-153.5℃；1H NMR(600MHz,CDCl3)δ:0.65,0.77,0.78,0.82,0.86,0.88,1.14(21×CH3),0.62-2.00(m,other aliphatic ring protons),1.86,2.02,2.05,2.08(s,12×CH3CO),2.24-2.27(m,6H),2.53(d,J＝10.98Hz,3H),2.65-2.73(m,12H),3.19-3.24(m,6H),3.98(q,J＝9.84Hz,3H),4.13(q,J＝12.60Hz,3H),4.22-4.35(m,15H),4.61(q,J＝15.18Hz,3H),5.23(t,J＝9.84Hz,3H),5.38-5.46(m,9H),5.82(d,J＝9.00Hz,3H),6.59(s,3H),7.09(t,J＝4.74Hz,3H),7.38(t,J＝33.42Hz,3H),7.77(s,3H),13C NMR(150MHz,CDCl3)δ:14.11(3C),15.39(3C),16.55(3C),16.65(3C),18.08(3C),20.16(3C),20.52(3C),20.69(3C),22.09(3C),22.20(3C),22.57(3C),22.65(3C),23.43(3C),23.55(3C),23.83(3C),23.88(3C),25.72(3C),27.16(3C),27.95(3C),28.46(3C),29.28(3C),29.33(3C),29.47(3C),29.66(3C),30.66(3C),31.88(3C),32.13(3C),32.22(3C),32.93(3C),33.59(3C),34.00(3C),34.88(3C),35.12(3C),36.73(3C),37.85(3C),38.04(3C),39.27(3C),39.92(3C),40.05(3C),41.87(3C),46.14(3C),46.53(3C),47.37(3C),48.91(3C),53.14(3C),55.10(3C),61.42(3C),67.48(3C),70.22(3C),72.60(3C),75.02(3C),81.02(3C),85.64(3C),121.16(3C),121.30(3C),121.87(3C),123.12(3C),136.97(3C),144.37(3C),145.31(3C),146.55(3C),147.21(3C),156.94(3C),168.71(3C),169.32(3C),170.01(3C),170.54(3C),178.50(3C).ESI-HRMS(m/z)[M+2H]+/2calcd forC168H240N24O36,1586.8953；found,1586.8944.Purity:100％(by HPLC).Purity:100％(byHPLC).
化合物B1e：M.p.:178.9-183.9℃；1H NMR(600MHz,CDCl3)δ:0.64,0.77,0.80,0.85,0.87,1.12(21×CH3),0.62-2.10(m,other aliphatic ring protons),1.84,2.00,2.04,2.06(s,12×CH3CO),2.52(d,J＝10.14Hz,3H),2.67(t,J＝7.56Hz,6H),3.13(t,J＝6.54Hz,6H),3.96-3.99(m,3H),4.09-4.13(m,5H),4.21-4.32(m,10H),4.60(q,J＝15.12Hz,3H),4.80(s,3H),5.22(t,J＝9.96Hz,3H),5.37-5.43(m,9H),5.81(d,J＝8.94Hz,3H),6.58(s,3H),7.06(s,3H),7.22(s,3H),7.76(s,3H).13C NMR(150MHz,CDCl3)δ:14.12(3C),15.36(3C),16.52(3C),18.04(3C),20.13(3C),20.49(3C),20.65(3C),21.01(3C),23.39(3C),23.51(3C),23.80(3C),25.42(3C),25.68(3C),26.22(3C),27.12(3C),27.89(3C),28.85(3C),29.67(3C),30.62(3C),32.10(3C),32.19(3C),32.90(3C),33.97(3C),34.85(3C),36.69(3C),37.79(3C),38.01(3C),39.23(3C),40.67(3C),41.83(3C),41.86(3C),46.10(3C),46.49(3C),47.32(3C),53.09(3C),55.07(3C),60.35(3C),61.38(3C),67.44(3C),70.18(3C),72.57(3C),74.98(3C),76.79(3C),77.00(3C),77.21(3C),80.85(3C),85.59(3C),120.85(3C),121.09(3C),123.07(3C),127.07(3C),137.00(3C),144.33(3C),145.29(3C),156.77(3C),168.64(3C),169.27(3C),169.96(3C),170.48(3C),171.16(3C),178.42(3C).ESI-HRMS(m/z)[M+H]+calcd for C174H252N24O36,1628.4402；found,1628.4403.Purity:88.66％(by HPLC).
2)化合物B2a的合成(化合物B2b、B2c、B2d、B2e合成步骤与之类似)
将109mg(0.03mmol)B1a溶于10mL无水甲醇中与48.5mg的甲醇钠反应，室温下搅拌2h后，TLC检测，反应完全，加入3mL 1mol/L的稀盐酸混悬，过滤；滤饼用蒸馏水洗涤后干燥，得白色固体目标产物B2a。采用类似的方法制备获得B2b，B2c，B2d，B2e。
化合物B2a：M.p.:233.0-237.6℃；1H NMR(600MHz CD3OD)δ:0.61,0.80,0.83,0.86,0.89,0.91,1.15(21×CH3),0.62-2.00(m,other aliphatic ring protons),2.02(s,3H),2.70(t,J＝10.26Hz,3H),3.52-3.58(m,10H),3.72(d,J＝12.18Hz,3H),3.85(dd,J＝9.00,22.38Hz,6H),4.27-4.45(m,18H),5.36(s,3H),5.52(t,J＝9.18Hz,3H),7.18(d,J＝12.18Hz,3H),7.54(s,3H),7.70(t,J＝16.32Hz,3H),7.91(s,3H).13C NMR(150MHz,CD3OD)δ:14.40(3C),15.94(3C),15.94(3C),15.94(3C),15.94(3C),17.15(3C),17.35(3C),19.01(3C),23.46(3C),23.95(3C),24.74(3C),26.49(3C),28.11(3C),28.56(3C),30.66(3C),31.39(3C),33.50(3C),34.79(3C),35.61(3C),36.82(3C),37.71(3C),38.73(3C),39.02(3C),40.24(3C),42.25(3C),42.58(3C),47.15(3C),47.25(3C),49.00(3C),53.97(3C),54.39(3C),56.33(3C),61.38(3C),62.04(3C),70.38(3C),73.58(3C),77.95(3C),78.72(3C),80.60(3C),82.59(3C),89.10(3C),123.26(3C),123.85(3C),138.02(3C),144.74(3C),145.62(3C),147.16(3C),158.71(3C),180.28(3C).ESI-HRMS(m/z)[M+H]+calcd for C138H205N24O24,2583.5631；found,2583.5610.Purity:99.89％(by HPLC).
化合物B2b：M.p.:223.6-227.2℃；1H NMR(600MHz,CD3OD)δ:0.61,0.82,0.85,0.90,0.92,0.93,1.16(21×CH3),0.50-2.00(m,other aliphatic ring protons),2.03-2.08(m,3H),2.75-2.81(m,6H),3.50(t,J＝9.12Hz,3H),3.56(t,J＝9.18Hz,6H),3.72(q,J＝12.12Hz,3H),3.84-3.88(m,6H),4.24(q,J＝10.92Hz,3H),4.34(d,J＝15.12Hz,3H),4.44(d,J＝15.12Hz,3H),4.62-4.67(m,6H),5.35(s,3H),5.56(d,J＝9.36Hz,3H),7.08(t,J＝10.32Hz,3H),7.64(d,J＝11.10Hz,3H),7.67(s,3H),7.96(s,3H).13C NMR(150MHz,CD3OD)δ:16.02(3C),17.24(3C),17.52(3C),19.21(3C),24.03(3C),24.45(3C),24.92(3C),26.55(3C),27.00(3C),27.48(3C),28.33(3C),28.64(3C),31.54(3C),31.82(3C),33.49(3C),33.57(3C),33.93(3C),34.95(3C),35.78(3C),37.91(3C),38.86(3C),38.91(3C),39.20(3C),40.46(3C),41.29(3C),42.37(3C),42.74(3C),47.34(3C),47.46(3C),50.58(3C),54.02(3C),56.58(3C),62.25(3C),70.68(3C),73.82(3C),78.24(3C),80.90(3C),82.37(3C),89.34(3C),123.52(3C),123.69(3C),123.99(3C),124.44(3C),138.49(3C),144.94(3C),145.95(3C),146.27(3C),158.97(3C),180.36(3C).ESI-HRMS(m/z)[M+2H]+/2calcd for C141H210N24O24,1313.3069；found,1313.3070.Purity:95.65％(by HPLC).
化合物B2c：M.p.:150.1-153.5℃；1H NMR(600MHz,CD3OD)δ:0.61,0.83,0.85,0.88,0.90,0.93,1.16(21×CH3),0.50-2.00(m,other aliphatic ring protons),2.06(dd,J＝10.38,14.46Hz,3H),2.23(t,J＝6.90Hz,6H),2.65-2.78(m,12H),3.14(dd,J＝6.48Hz,13.98Hz,6H),3.51(t,J＝9.18Hz,3H),3.56(t,J＝9.00Hz,6H),3.72(q,J＝12.18Hz,3H),3.86(dd,J＝9.18,18.30Hz,6H),4.26-4.45(m,15H),5.35(s,3H),5.55(t,J＝9.36Hz,9H),7.21(d,J＝9.42Hz,3H),7.76(d,J＝33.96Hz,6H),7.96(s,3H).13C NMR(150MHz,CD3OD)δ:15.97(3C),17.19(3C),17.43(3C),19.11(3C),23.00(3C),23.33(3C),23.99(3C),24.36(3C),24.86(3C),26.51(3C),28.21(3C),28.60(3C),29.15(3C),30.50(3C),31.46(3C),33.37(3C),33.53(3C),33.79(3C),34.86(3C),35.70(3C),37.81(3C),38.83(3C),39.11(3C),40.34(3C),40.73(3C),42.29(3C),42.65(3C),47.23(3C),47.34(3C),50.21(3C),54.01(3C),56.48(3C),62.15(3C),70.54(3C),73.70(3C),78.10(3C),80.76(3C),82.21(3C),89.22(3C),123.39(3C),123.91(3C),128.42(3C),128.50(3C),138.29(3C),144.83(3C),145.78(3C),147.59(3C),148.25(3C),159.05(3C),180.27(3C).ESI-HRMS(m/z)[M+2H]+/2calcd for C144H216N24O24,1334.3303；found,1334.3300.Purity:95.43％(by HPLC).
化合物B2e：M.p.:209.1-212.6℃；1H NMR(600MHz,CD3OD)δ:0.63,0.87,0.89,0.91,0.94,0.95,1.17(21×CH3),0.62-2.00(m,other aliphatic ring protons),2.08(t,J＝13.2Hz,3H),2.81(d,J＝7.56Hz,6H),3.09(s,3H),3.51(t,J＝9.36Hz,3H),3.58(t,J＝8.94Hz,6H),3.72(q,J＝12.24Hz,3H),3.86(dd,J＝9.12,18.6Hz,6H),4.27(d,J＝5.46Hz,3H),4.42(dd,J＝14.94,44.34Hz,6H),5.36(s,3H),5.61(d,J＝9.18Hz,3H),5.80(s,3H),7.58(s,3H),8.10(s,3H),8.41(s,3H),13CNMR(150MHz,CD3OD)δ:16.07(3C),17.31(3C),17.63(3C),19.35(3C),24.01(3C),24.10(3C),24.56(3C),24.77(3C),25.07(3C),26.60(3C),27.17(3C),28.48(3C),28.70(3C),29.18(3C),30.52(3C),31.64(3C),33.63(3C),34.11(3C),35.03(3C),35.66(3C),38.06(3C),39.05(3C),40.60(3C),41.39(3C),42.44(3C),42.83(3C),47.48(3C),47.58(3C),49.00(3C),56.01(3C),56.81(3C),62.32(3C),70.80(3C),73.98(3C),7 8.35(3C),81.14(3C),89.75(3C),124.05(3C),126.96(3C),130.89(3C),137.08(3C),145.08(3C),147.08(3C),159.31(3C),180.52(3C).ESI-HRMS(m/z)[M+H]+calcd for C150H228N24O24,1376.3768；found,1376.3769.Purity:97.55％(by HPLC).
实施例2：齐墩果酸C28葡萄糖三聚体衍生物抑制流感病毒的生物活性评价实验
1、细胞病变(CPE)抑制试验
流感病毒感染细胞后会导致细胞病变，使得细胞活力降低。如果药物能够抑制流感病毒复制，则会降低细胞病变数量，提高细胞活力，具体来说：
(1)将犬肾上皮细胞(MDCK)以1:3的比例传代到白色的96孔板中，在37℃细胞培养箱中用含10％FBS的DMEM培养基培养24h；
(2)将流感病毒[A/WSN/33(H1N1)，感染复数(MOI)＝0.001]与100μmol/L的待检化合物加入到100μL含有2μg/mL TPCK处理的胰酶、1％FBS的DMEM中，充分混匀；化合物的阴性对照为1％DMSO(稀释化合物所用的溶剂)；同时设立一组只加各化合物不加病毒实验组，用来检测化合物对细胞活力的影响；
(3)将96孔板中的MDCK细胞的培养基吸出，将混合有病毒和化合物的培养基加入到MDCK细胞中，37℃细胞培养箱中培养48h；每个样品三个复孔；
(4)用CellTiter-Glo荧光细胞活性检测试剂盒(Cat.G7571，Promega)检测细胞活力，首先将细胞和CellTiter-Glo检测试剂放于室温环境，待其温度平衡至室温，将100μL/孔的CellTiter-Glo检测试剂加入到细胞的培养上清中，震动2min后，避光静置10min，用仪器TecanInfinite M2000PROTM检测细胞活力；
(5)IC50的计算方法：首先对化合物进行浓度系列稀释，然后利用上述方法测定出细胞活力；化合物对细胞病变的保护率＝100×(1-(Test compound–Median Virus1)/(Median Cells-Median Virus2))，其中Test compound表示只加待检化合物不加病毒组的细胞活力；
Median Virus1表示加了待检化合物和病毒组的细胞活力；Median Cells表示只加入1％DMSO组的细胞活力；Median Virus2表示加入1％DMSO和病毒组的细胞活力；将化合物浓度和相应的保护率输入到软件Prism，即可计算IC50；此方法已被广泛应用于抗病毒药物筛选领域；
(6)CC50的计算方法：CellTiter-Glo也可以用来检测化合物对细胞的毒性；首先对化合物进行浓度系列稀释，然后将其加入到细胞中，方法同步骤(2)-(4)，但不加入病毒，培养48h后，测定细胞活力；然后将对照组细胞活力(1％DMSO)定义为100％，将其他各化合物组细胞活力标准化，除以对照组1％DMSO的细胞活力，再乘以100％；将化合物的浓度和相应的标准化的细胞活力输入到软件Prism，即可计算出CC50；
实验结果见表1，结果显示该系列化合物均有明显的抑制活性，其中化合物B2a的IC50值最小，即它对A/WSN/33的抑制活性较其他化合物更高。因此，化合物B2a作为代表化合物进行后续抗流感病毒机制探究及动物水平体内抗流感活性评价。
表1OA-C28位葡萄糖三聚体衍生物抗A/WSN/33(H1N1)的IC50测定
结果表明本发明化合物可以有效抑制A/WSN/33引起的细胞病变(CPE)，B1a、B2a对流感病毒有着明显的抑制作用。
2、加药时间点实验，用以分析化合物作用于病毒感染细胞的哪一阶段，具体步骤如下：
(1)将MDCK细胞传代到六孔板中，在37℃细胞培养箱中用含10％FBS的DMEM培养基培养24h；
(2)将A/WSN/33(H1N1)病毒(MOI＝1)稀释到不含血清的DMEM中，感染MDCK细胞；
(3)流感病毒从吸附到子代病毒粒子释放，其复制周期约为6-8h；故在以下时间段将药物加入到细胞培养基中：0-10h，0-2h，2-5h，5-8h或8-10h；
(4)感染10h后，用冰预冷的PBS清洗细胞一次，用200μL/孔的PIPA裂解液裂解细胞；用细胞刮将细胞刮下，吸入1.5mL EP管中，置于冰上15min；以12000rpm 4℃离心10min，将上清液转移到另一个1.5mL EP管中；
(5)吸取30μL样品与等体积的2×蛋白上样缓冲液混合，100℃煮样10min；
(6)将煮好的样品各20μL加入到12％的蛋白质凝胶加样孔中，进行SDS-PAGE电泳；
(7)用免疫印迹法(Western blotting)检测流感病毒的NP蛋白的表达水平(以此来检测病毒在细胞内的复制情况)；同时以细胞蛋白GAPDH作为细胞内参(也可用于验证药物对细胞的毒性)；
实验结果见图1，结果显示化合物B2a在全程给药(0-10h)以及0-2h加药均能够有效地抑制流感病毒的复制，图中显示病毒感染MDCK细胞后0-2h内几乎无NP蛋白和M2蛋白的表达，表明化合物B2a发挥了抑制作用，而在感染2h之后的各时间段加药处理与DMSO对照组相比，NP蛋白与M2蛋白的表达量与DMSO组蛋白表达量稍弱或相当。结论表明化合物B2a主要作用于流感病毒进入细胞过程中，且干扰了病毒与细胞受体之间的结合，这一过程中达到抗流感病毒目的。
3、血凝抑制试验，此方法用来检测药物是否影响病毒与细胞受体之间的结合，具体方法如下：
(1)制备1％(v/v)的鸡红细胞悬液
选1-2只健康鸡，将血液采集到等量抗凝液中混匀，置4℃冰箱保存，以800-1000rpm离心5分钟，用吸管吸去上清液和红细胞上层的白细胞薄膜，将沉淀的红细胞加生理盐水，慢慢混合均匀，再在离心机中800rpm离心5分钟，弃去上清液，再加生理盐水混匀，如此反复离心4-5次，最后一次离心后的红细胞，弃去上清液。放入4℃冰箱中可保存2-3天；使用时用1mL吸管吸取0.1mL红细胞，然后加入9.9mL的生理盐水，此即1％红细胞悬液；
(2)确定病毒的血凝效价，将WSN流感病毒以2倍梯度做倍比稀释，稀释液为PBS；
(3)将病毒液与1％红细胞悬液等体积(各50μL)混合加入到V底的96孔板中，置于微量振荡器上振荡1min，室温静置孵育30min；
(4)将反应板倾斜成45°，沉于孔底的红细胞沿着倾斜面向下呈线状流动者为沉淀，表明红细胞未被或不完全被病毒凝集；如果孔底的红细胞铺平孔底，凝成均匀薄层，表明红细胞被病毒所凝集。在确定流感病毒的血凝效价后，确定合适的病毒使用量；
(5)将药物、DMSO(阴性对照)或抗HA的特异性单克隆抗体(阳性对照)与病毒液混合后加入到细胞混悬液中，观察化合物对红细胞凝集有没有抑制效果。
通过将化合物B2a的储备液进行2倍梯度稀释，同时，用HA抗体作为血凝抑制实验的阳性对照，实验结果见图2，血凝结果显示当化合物B2a浓度达到0.06μM时，显示出血凝现象，表明当化合物浓度小于或等于0.06μM浓度时，不能有效抑制HA与SA的结合；当浓度处于1.94μM-0.12μM时，结果显示化合物B2a产生抑制血凝现象，有效抑制HA与SA的结合。结论表示化合物B2a在一定浓度下可能作用于HA，抑制了HA与宿主细胞上唾液酸受体的识别，从而阻断了流感病毒和靶细胞之间的相互作用，达到了抑制流感病毒感染的效果。
4、体内抗流感病毒实验，此方法用来检测药物在小鼠体内抗流感病毒效果，具体步骤如下：
为了评估化合物B2a在体内抗流感病毒的效果，如图3所示，将BALB/c小鼠分为5组，每组各5只，分别为空白对照组、病毒模型组、化合物高、低剂量组、磷酸奥司他韦组，小鼠滴鼻接种流感病毒40μL(含5个LD50)，空白对照组滴鼻生理盐水；小鼠于感染前24小时开始给药至感染后第7天，每天同一时间观察小鼠体重变化和健康状态，记录体重，持续14天；体重变化结果见图4所示，空白对照组小鼠体重始终平稳上升；用H1N1流感病毒感染小鼠后，病毒模型组小鼠在感染后第1、2天体重无明显变化，从第3天开始，体重开始有明显下降趋势。经阳性对照奥司他韦组(10mg/kg/d)治疗的小鼠的体重先降后升，表明OSV对感染后的小鼠有明显的治疗效果；高剂量药物B2a组(12.5mg/kg/d)和低剂量药物B2a组(6.25mg/kg/d)处理后的小鼠体重，小鼠体重呈先降后升的趋势，与OSV处理组趋势相当；存活率结果见图5。
为明确化合物B2a对小鼠肺组织病理变化的影响，于14天后对各组小鼠进行解剖并取其肺部，用4％多聚甲醛固定并置于4℃冰箱保存，之制作组织的石蜡切片，进行HE染色，最后将封好的组织切片放置在正置荧光显微镜下观察，并使用CellSens Standard软件拍照记录结果。
结果见图6所示，与病毒模型组比较，化合物B2a高浓度剂量组有轻微的肺泡壁增厚，肺间质渗出减少，肺组织水肿减轻，有少量炎性细胞浸润，肺泡炎症程度明显减轻，疗效与OSV阳性对照组相当，化合物B2a低浓度剂量组缓解症状不明显。
通过建立BALB/c小鼠流感病毒感染模型，观察到小鼠感染病毒后出现厌食、窘迫、行动迟缓、精神状态不佳等症状。化合物B2a高剂量治疗组与阴性对照组相比体重下降减少，小鼠存活时间有所延长，肺部炎症明显改善，具有一定的体内抗流感病毒作用。
采用以上相同的实验方法，对本申请的其他化合物进行了相同或相关的实验测定，结果均表明它们均具有与上述化合物相同或类似的实验结果。由此表明申请的化合物具备较好的抗流感的治疗效果。

Claims (5)

1.结构式如下式所示的齐墩果酸C28葡萄糖三聚体衍生物：
式中：R1为(-CH2-)m，m＝1-5；
A为取代或未取代的苯环、取代或未取代的碳原子、取代或未取代的环己烷、取代或未取代的哌嗪、三嗪，其中取代基包括C1-C6烷氧基、羟基、硝基或卤素；
R2为CH3COO-或-OH。
2.根据权利要求1所述的齐墩果酸C28葡萄糖三聚体衍生物，其特征在于，化合物为如下任一结构：
式中：R选自
3.根据权利要求1所述的齐墩果酸C28葡萄糖三聚体衍生物，其特征在于：还包括齐墩果酸C28葡萄糖三聚体衍生物药学上可接受的盐、齐墩果酸C28葡萄糖三聚体衍生物药学上可接受的盐的水合物。
4.权利要求1或2所述的齐墩果酸C28葡萄糖三聚体衍生物的制备方法，其特征在于，步骤如下：
(1)将2-5mmol的齐墩果酸溶于四氢呋喃中，依次加入2-7.5mmol的苯并三唑四甲基四氟硼酸和2.5-7.5mmol的N,N-二异丙基乙胺，反应获得齐墩果酸活泼酯中间体；
(2)将步骤(1)中获得的齐墩果酸活泼酯中间体溶于四氢呋喃或N,N-二甲基甲酰胺中，再加入1-5mmol的2-炔丙胺、1.5-3mmol的TEA或Na2CO3，反应得产物；
(3)将步骤(2)所得产物与1-3mmol的2,3,4,6-O-四乙酰基-D-吡喃葡萄糖基叠氮化物、0.5-5mmol的五水硫酸铜、0.5-5mmol的抗坏血酸钠进行CuAAC反应，得产物；
(4)将1mmol步骤(3)获得的产物利用三光气反应与0.2-5mmol不同链长的氨基炔衍生物偶联，所得产物再与0.2-2mmol的3-叠氮基-2,2-(二叠氮甲基)丙基-1-醇或1,3,5-三叠氮甲基苯、0.5-5mmol的五水硫酸铜、0.5-5mmol的抗坏血酸钠进行CuAAC反应，得到齐墩果酸C28乙酰葡萄糖三聚体衍生物，经脱乙酰保护基后，获得齐墩果酸C28葡萄糖三聚体衍生物。
5.权利要求1-3任一项所述的齐墩果酸C28葡萄糖三聚体衍生物在制备预防或/和治疗流感的药物及阻止流感病毒进入细胞的药物中的应用。
CN202310236447.8A 2023-03-13 2023-03-13 齐墩果酸c28葡萄糖三聚体衍生物及其应用 Pending CN116589522A (zh)

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