CN103570780B - 鬼臼毒素糖苷物和酰化糖苷物及其药物组合物和其制备方法与应用 - Google Patents
鬼臼毒素糖苷物和酰化糖苷物及其药物组合物和其制备方法与应用 Download PDFInfo
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- CN103570780B CN103570780B CN201310495291.1A CN201310495291A CN103570780B CN 103570780 B CN103570780 B CN 103570780B CN 201310495291 A CN201310495291 A CN 201310495291A CN 103570780 B CN103570780 B CN 103570780B
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- podophyllotoxin
- glucosides
- butyrylation
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Abstract
下述通式（I）所示的鬼臼毒素糖苷物和酰化糖苷物，利用鬼臼毒素为先导化合物，通过对其4位羟基、4ˊ位甲氧基进行结构改造，合成一系列该类化合物，活性筛选表明其具有较好的抗肿瘤活性。同时提供以该类化合物为活性成分的药物组合物，该类化合物的制备方法及其在制备抗肿瘤药物和抑制剂中的应用。
Description
技术领域
本发明属于药物技术领域，具体地说，主要涉及鬼臼毒素糖苷物和酰化糖苷物，以其为活性成分的药物组合物，其制备方法及其在制备抗肿瘤药物和抑制剂中的应用。
背景技术
鬼臼毒素属于木脂素类化合物中的环木脂内酯类化合物，具有显著的抗肿瘤活性。由于鬼臼毒素及其衍生物的毒性及不良反应，促使了以鬼臼毒素为先导化合物的结构修饰研究。以鬼臼毒素为母核经过结构改造多的衍生物依托泊苷(VP-16)及其磷酸盐(Etopophos)和替尼泊苷(VM-26)已成为应用于临床的抗癌药物，他们对小细胞肺癌、睾丸癌、急性白血病以及恶性淋巴肿瘤等多种癌症均有良好的疗效(高蓉，田暄等，农药学学报，2002,2,1,1-6.石建功等，木脂素化学，(刊名)2009,138-140)。然而，在临床应用中发现VP-16和VM-26仍存在抗癌谱较窄、耐药性、水溶性差以及较严重的骨髓抑制与胃肠道反应等缺点。为进一步寻找高效低毒的抗肿瘤新药，近年来本申请人对鬼臼毒素进行了一系列的结构改造工作。
目前，现有技术中未见有通式（I）所示的鬼臼毒素酰化糖苷物及其药物组合物和其制备方法及应用的报道，未见有通式（I）所示的鬼臼毒素糖苷物及其药物组合物应用的报道。
发明内容
本发明的目的是提供一类4β-取代的鬼臼毒素衍生物，主要指4β鬼臼毒素糖苷物和酰化糖苷物衍生物，意图利用鬼臼毒素为先导化合物，通过结构改造，合成一系列具有抗肿瘤活性的化合物，研发出抗肿瘤活性较高、毒性较低的抗肿瘤药物，以其为活性成分的药物组合物，其制备方法及其在制备抗肿瘤药物和抑制剂中的应用。
本发明的下述技术方案是用来实现上述的发明目的的：
下述通式(I)所示的鬼臼毒素糖苷物和酰化糖苷物衍生物：
其中
R为CH3或H；
X为无取代基；或者结构片段或者结构片段其中m为0–6，r为0或1，Y为O或NH；n为0–10；
R1为乙酰化、丙酰化、丁酰化、戊酰化、己酰化、或游离的葡萄糖、半乳糖、甘露糖、N-乙酰基-D-葡萄糖、N-乙酰基-D-半乳糖糖、N-乙酰基-D-甘露糖糖、果糖、木糖、核糖、阿拉伯糖、氨基糖、山梨糖、鼠李糖、岩藻糖、海藻糖、水酥糖、麦芽糖、乳糖、棉子糖。
药物组合物，其中含有治疗有效量的所述的鬼臼毒素糖苷物和酰化糖苷物衍生物和药学上可接受的载体。
所述的鬼臼毒素糖苷物和酰化糖苷物衍生物在制备药物中的应用。
所述的鬼臼毒素糖苷物和酰化糖苷物衍生物在制备抗肿瘤抑制剂中的应用。
所述的鬼臼毒素糖苷物和酰化糖苷物衍生物在制备抗肿瘤药物中的应用。
上述的鬼臼毒素酰化糖苷物衍生物，为丁酰化糖苷物衍生物。
上述的鬼臼毒素酰化糖苷物衍生物，为丁酰化葡萄糖苷物衍生物。
按照所述的鬼臼毒素酰化糖苷物衍生物，为丁酰化葡萄糖苷物衍生物，其中X为结构片段
按照所述的鬼臼毒素糖苷物和酰化糖苷物衍生物，其中X为无取代基。
上述的鬼臼毒素酰化糖苷物衍生物，为丁酰化糖苷物衍生物。
上述的鬼臼毒素酰化糖苷物衍生物，为丁酰化葡萄糖苷物衍生物。
按照上述的鬼臼毒素糖苷物和酰化糖苷物衍生物,其中X为结构片段其中m为0–6，r为0或1，Y为O或NH。
上述的鬼臼毒素酰化糖苷物衍生物，为丁酰化糖苷物衍生物。
上述的鬼臼毒素酰化糖苷物衍生物，为丁酰化葡萄糖苷物衍生物。
本发明还提供了制备通式I的鬼臼毒素糖苷物和酰化糖苷物衍生物的方法，由三甘醇、六甘醇等得到不同链长度的端炔醇与不同的糖及酰化糖醚化后得到端炔糖苷及端炔酰化糖苷；然后由鬼臼毒素及由鬼臼毒素制备成4'-O-去甲基鬼臼毒素和不同的端炔糖苷及端炔酰化糖苷溶于无水二氯甲烷中，加入少量新处理的分子筛，低温冷却到-20℃，滴加溶于二氯甲烷中的三氟化硼乙醚溶液，再用三乙胺、醋酸中和反应体系，过滤除去沉淀，减压除去二氯甲烷，得到粗品，粗品经过硅胶柱层析，用氯仿:甲醇，石油醚:乙酸乙酯洗脱得到鬼臼毒素糖苷物和酰化糖苷物衍生物；或者由4'-O-甲基-4-脱氧-4β-叠氮化合物，4'-O-去甲基-4-脱氧-4β-叠氮化合物与端炔糖苷及酰化端炔糖苷溶于四氢呋喃中，加入1:2的叔丁醇-水和醋酸铜，再滴加抗坏血酸水溶液经过Click反应34小时，反应完全后加入水，用二氯甲烷萃取3次，合并有机相再用饱和食盐水洗涤2次，无水硫酸钠干燥后减压回收二氯甲烷，得到粗品；粗品经硅胶柱层析，用石油醚:丙酮、氯仿:甲醇洗脱得到鬼臼毒素衍生物。
更具体地，本发明提供的鬼臼毒素衍生物I可按如下的方法制备：
鬼臼毒素及由鬼臼毒素制备成4'-O-去甲基鬼臼毒素(1eq.)和不同的糖及酰化糖(1eq.)溶于无水二氯甲烷中，加入少量新处理的分子筛，低温冷却到-20℃，滴加溶于二氯甲烷中的三氟化硼乙醚(0.1eq.)溶液，再用三乙胺(1eq.)、醋酸(1eq.)中和反应体系，过滤除去沉淀，减压除去二氯甲烷，得到粗品；粗品经过硅胶柱层析，用氯仿：甲醇，石油醚：乙酸乙酯洗脱得到鬼臼毒素糖苷物和酰化糖苷物衍生物。或者由4β-叠氮化合物(1eq.)、端炔吡喃糖苷(1eq.)、n-叔丁醇-水(1:2)、醋酸铜(0.1eq.)、抗坏血酸水溶液(1.0M/L的水溶液,3d)，经过Click反应34小时，反应完全后加入水，用二氯甲烷萃取3次，合并有机相再用饱和食盐水洗涤2次，无水硫酸钠干燥后减压回收二氯甲烷，得到粗品；粗品经硅胶柱层析，用氯仿：甲醇，石油醚：乙酸乙酯洗脱得到鬼臼毒素糖苷物和酰化糖苷物衍生物。
体外筛选发现本发明的鬼臼毒素糖苷物和酰化糖苷物衍生物对多种肿瘤细胞株，包括HL-60，SMMC-7721，A-549，MCF-7，SW480等均有较好的抑制增长作用，显示出较依托泊苷更强的细胞毒活性，其中化合物2,6,8,11,12的作用最为突出，对上述细胞株的IC50值在0.49-7.28μM之间。4β-(4"-丁酰化吡喃糖苷取代-1,2,3-三唑)鬼臼毒素衍生物相比于其他的化合物有更高的细胞毒活性，属于短链的脂肪酸的丁酸是脱乙酰酶抑制剂(HDAC)。近年来，由于脱乙酰酶抑制剂能够破坏细胞周期或者通过基因控制选择性的诱导细胞凋亡，使得脱乙酰酶抑制剂能够发展成为抗癌药物受而受到人们更大的关注(Miller,S.J.MiniRev.Med.Chem.2004,4,839-845)。
本发明的技术方案是在总结前人对鬼臼毒素的结构与活性的研究，得出鬼臼毒素的构效关系：间二氧戊环是最佳选择；E环自由旋转和2α、3β构型是活性必需的；4β构型的抗肿瘤活性明显高于4α构型；4位是有效的修饰位点(朱承根等，Drugevaluation,2004,1,4,306-309)。4位上O-，S-和N-取代得到的鬼臼毒素衍生物活性表明O-，S-取代明显低于N-取代的衍生物。在鬼臼毒素结构修饰中引入1,2,3-三唑环，得到的1,2,3-三唑鬼臼毒素衍生物部分化合物可通过抑制DNA拓扑异构酶II的活性，破坏DNA的结构和功能，从而发挥抗肿瘤的作用，活性甚至还要高于依托泊苷(Reddy,D.M.ect.Eur.J.Med.Chem.2011,46,1983.)。基于此，本发明利用鬼臼毒素为先导化合物，通过结构改造，合成了一系列具有抗肿瘤活性的化合物，即一类4β-取代的鬼臼毒素衍生物，主要指4β鬼臼毒素糖苷物和酰化糖苷物衍生物，进而提供了以其为活性成分、抗肿瘤活性较高、毒性较低的抗肿瘤药物组合物，该药物组合物还包括药学上可接受的载体。
本发明所述药学上可接受的载体是指药学领域常规的药物载体，例如：稀释剂、赋形剂如水等，填充剂如淀粉、蔗糖等；黏合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮；湿润剂如甘油；崩解剂如琼脂、碳酸钙和碳酸氢钠；吸收促进剂如季铵化合物；表面活性剂如十六烷醇；吸附载体如高岭土和皂黏土；润滑剂如滑石粉、硬脂酸钙和镁、以及和聚乙二醇等。另外还可以在组合物中加入其他辅剂如香味剂、甜味剂等。
本发明化合物可以组合物的形式通过注射、口服、鼻吸入、直肠或肠胃外给药的方式施用于需要这种治疗的患者。用于口服时，可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等，制成液体制剂如水或油悬浮剂或其他液体制剂如糖浆、酏剂等；用于肠胃外给药时，可将其制成注射用的溶液、水或油性悬浮剂等。优选的形式是片剂、胶囊和注射剂。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合，然后将其制成所需的剂型。
本发明的药物组合物优选含有重量比为0.1%～99.5%的活性成分，最优选含有重量比为0.5%～95%的活性成分。
本发明化合物的施用量可根据用药途径、患者的年龄、体重、所治疗的疾病的类型和严重程度等变化，其日剂量可以是0.01～10mg/kg体重，优选0.1～5mg/kg体重。可以一次或多次施用。
附图说明：
图1为本发明的鬼臼毒素糖苷物和酰化糖苷物衍生物的结构通式（I）；
图2为本发明化合物的合成路线流程图。
具体实施方式：
下面结合附图，用本发明的实施例来进一步说明本发明的实质性内容，但并不以任何方式来限制本发明。
实施例1：
本发明的合成通式为：
实施例2：
化合物4'-O-去甲基-4-脱氧-4β-[(4"-(丁酰化-α-D-半乳糖丙炔三甘醇)-1,2,3-三唑鬼臼毒素(8)的制备：
第一步：制备丙炔三甘醇(ZhaoLigang,etal.JOC.2005,70,10,4059-4063)
将13.5g三甘醇(30mmol)溶解在30ml干燥的四氢呋喃中，冰浴冷却到0℃，1.2g钠(30mmol)预先溶解在15ml干燥的四氢呋喃中缓慢的滴入上述的溶液中，滴完之后再室温下反应0.5小时，然后把3.57g丙炔溴(10mmol)溶解在15ml干燥四氢呋喃溶液中的准备液迅速倒入上述的混合液中，搅拌过夜。用TLC跟踪反应的进行。反应完全后，冷却至室温，向反应中倒入100ml水，再用乙酸乙酯萃取3次，合并有机相并用无水硫酸钠干燥。浓缩后用硅胶色谱纯化(洗脱剂：石油醚/乙酸乙酯=2:1)，得产物III4.5g，收率：80%，黄色油状液体，1HNMR(CDCl3,400MHz)δ4.02(s,2H),3.50(m,10H),3.41(t,2H),3.35(s,1H);13CNMR(CDCl3,100MHz)δ79.4,74.8,72.4,72.4,70.4,70.1,68.8,61.3,58.1;MS-ESIm/z(%):211([M+Na]+,100).
第二步：制备α-D-半乳糖苷丙炔三甘醇(BimalenduRoy,etal.TetrahedronLetters2007,48,3783-3787)
将0.90gD-半乳糖(5mmol)加到丙炔三甘醇（1.4g,25mmol）中，然后缓慢升高温度至65℃，在这过程中，H2SO4-silica(25mg)催化剂加入到上述的混合液中，继续搅拌直到所有固体全部溶解，大概要2.5小时，用TLC跟踪反应的进行。反应完全后，冷却至室温，反应混合液用硅胶色谱柱先用二氯甲烷把剩余的丙炔三甘醇除去，再用氯仿：甲醇=9:1纯化，得产物IV654mg，收率60%，黄色油状液体，1HNMR(CD3OD,400MHz)δ4.78(d,1H,J=3.7,H-1),4.14(d,2H,J=2.4Hz,CH2-C≡CH),3.74(d,2H,J=1.8Hz),3.61(t,6H,J=1.1Hz),3.55(t,6H,J=3.7Hz,),3.33-3.34(m,4H),3.25(s,4H),2.82(t,1H,J=2.3Hz,C≡CH);13CNMR(CD3OD,100MHz)δ100.2(C-1),80.6(C≡CH),76.1(C≡CH),75.1,73.6(2),71.7,71.4,71.3,70.0,68.1,62.6(C-6),59.0(CH2-C≡CH);MS-ESIm/z(%):373([M+Na]+,100).
第三步：制备丁酰化α-D-半乳糖苷丙炔三甘醇
将227mg化合物IV(0.65mmol)，溶解在2.0ml的吡啶中，然后，冰浴冷却至0℃，0.5ml丁酸酐(2.6mmol)缓慢滴加到上述反应液中，升室温反应2小时。用TLC跟踪反应的进行。反应完全后，减压除去吡啶，剩余的残渣用硅胶色谱纯化(洗脱剂：氯仿：甲醇=9:1)，得产物V400mg，收率：98%，黄色油状液体，1HNMR(CD3OD,400MHz)δ5.48(d,1H,J=9.9Hz,H-3),5.12(d,1H,J=3.2Hz,H-1),5.10(t,1H,J=9.7Hz,H-4),4.82(d,1H,J=3.1Hz,H-2),4.25-4.18(m,3H,H-6a,CH2-C≡CH),4.15-4.10(m,2H,H-6b,H-5),3.68(m,6H,),3.65(m,6H),2.85(s,1H,C≡CH),2.35-2.20(m,8H,),1.65-1.56(m,8H,),0.96-0.91(t,12H,J=7.5Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ174.7,174.0,173.9,173.6(4),97.1(C-1),80.6(C≡CH),76.0(C≡CH),71.7(2),71.6(2),69.6(2),72.1,71.2,69.6,68.6,62.9(C-6),59.0(CH2-C≡CH),36.8,36.7,36.7,36.7(4),19.4,19.3,19.3,19.2(4),14.0(4);MS-ESIm/z(%):521([M+Na]+,100).
第四步：制备4'-O-去甲基鬼臼毒素
将2.07g鬼臼毒素(5mmol)溶解在干燥的二氯甲烷溶液中，碘化钠（2.25g,15mmol）加入到上述的溶液中，搅拌5分钟。冰浴冷却反应液至0℃,1.48甲烷磺酸（15mmol）缓慢的滴加到上述的反应液中继续搅拌，然后在升高到室温继续反应5小时。氮气保护，除去在反应过程中产生的HI气体。然后，在减压下除去上述反应中的溶剂，不做任何处理进行下一步的操作。把上面的粗产物溶解在丙酮-水(25ml-25ml)混合溶剂中，加入碳酸钡（1.98g,10mmol）,在40℃反应条件下反应30分钟，向上述混合溶液中加入100ml二氯甲烷之后，再倒入500ml的10%的硫代硫酸钠的水溶液中，用二氯甲烷萃取出有机相，无水硫酸钠干燥、浓缩得到的粗产物用硅胶色谱纯化(洗脱剂：氯仿：甲醇=92:8)，得产物VII1.8g，收率：90%，白色固体，1HNMR(CDCl3,400MHz)δ7.12(s,1H,C8-H),6.94(s,1H,C5-H),6.33(s,2H,C2',C6'-H),5.93(d,2H,J=12.7Hz,OCH2O),4.58(d,1H,J=5.4Hz,C4-H),4.54(d,1H,J=5.2Hz),4.29(s,1H,C11-CHβ),4.26(d,1H,J=8.2Hz,C11-CHα),3.67(s,6H,3',5'-OMe),3.31(dd,1H,J=10.2Hz,17.3Hz,C2-H),2.87(m,1H,C3-H);13CNMR(CDCl3,100MHz)δ175.6(C-12),148.7(C-7),147.9(C-3'),147.9(C-5'),147.7(C-6),135.9(C-1'),134.2(C-9),133.0(C-10),131.5(C-4'),110.5(C-8),100.5(C-5),109.5(C-2'),109.5(C-6'),102.1(C-13),68.3(C-11),66.7(C-4),56.6(3',5'-OMe),44.6(C-1),41.1(C-2),39.4(C-3);MS-ESIm/z(%):400([M+H]+,100).
第五步：制备4'-O-去甲基-4-脱氧-4β-叠氮鬼臼毒素
将4'-O-去甲基鬼臼毒素(843mg,2.1mmol)和叠氮钠(685mg,10.5mmol)溶解在10ml分析纯的氯仿中，缓慢滴加2.0ml三氟乙酸(TFA,26.4mmol)，反应搅拌1小时，为了避免反应中形成凝胶状的混合物，需要滴加额外的4.0ml三氟乙酸(52.8ml)。用TLC跟踪反应的进行。反应完全后，将反应混合液倒入碳酸氢钠饱和溶液中，再用40ml氯仿萃取2次，合并有机相并用无水硫酸钠干燥、浓缩得到粗产物用硅胶色谱纯化(洗脱剂：乙酸乙酯：丙酮=2:1)，得产物VIII716mg，收率：80%，白色固体，1HNMR(CDCl3,400MHz)δ7.07(s,1H,C5-H),6.60(s,1H,C8-H),6.38(s,2H,C2',C6'-H),6.05(d,2H,J=0.6Hz,OCH2O),4.61(q,2H,J=3.7Hz,5.3Hz,C4-H,C1-H),4.36(dd,2H,J=8.5Hz,10.3Hz,C11-CH2),3.66(s,6H,3',5'-OMe),3.11(dd,1H,J=4.7Hz,14.1Hz,C2-H),2.96(m,1H,C3-H);13CNMR(CDCl3,100MHz)δ174.3(C-12),148.9(C-3'),148.6(C-5'),148.0(C-7),148.0(C-6),136.0(C-1'),133.9(C-4'),131.2(C-9),129.4(C-10),110.8(C-5),109.2(C-2'),109.2(C-6'),107.5(C-8),102.6(C-13),70.9(C-11),63.9(C-4),56.4(3',5'-OMe),45.7(C-1),44.4(C-2),38.6(C-3);MS-ESIm/z(%):448([M+Na]+,100).
第六步：制备4'-O-去甲基-4-脱氧-4β-[(4"-(丁酰化-α-D-半乳糖丙炔三甘醇)-1,2,3-三唑鬼臼毒素(8)
将24.3mg化合物VIII(0.06mmol)和36mg化合物V(0.06mmol)溶解在干燥的1.0ml四氢呋喃中，样品充分溶解后，向上述反应液中加入t-BtOH-H2O(1:2)1.0ml,加入醋酸铜(4.6mg,0.03mmol)，再滴加3滴抗坏血酸水溶液(1.0M/L)，在室温下反应34小时，用TLC跟踪反应的进行。反应完全后，向混合反应液中加入30ml水，再用20ml的乙酸乙酯萃取3次，合并有机相并用无水硫酸钠干燥、浓缩得到粗产物用硅胶色谱纯化(洗脱剂：石油醚：丙酮=1:1)，得产物55mg，收率：92%，白色固体，1HNMR(CD3OD,400MHz)δ8.18(s,1H,C5″-H),6.61(s,1H,C5-H),6.59(s,2H,C2′-H,C6′-H),6.26(s,1H,C8-H),6.02(d,1H,J=10.6Hz,C4-H),5.94(s,2H,OCH2O),5.47(t,1H,J=9.7Hz,C1-H),5.11(d,2H,J=3.7Hz,C1'''-H),5.06(t,1H,J=12.0Hz,C2'''-H),4.23-4.09(m,6H,C11-CH2,C3-H,C3'''-H,C4'''-H,C5'''-H),3.80(s,6H,C3',C5'-OMe),3.72-3.63(m,12H),3.30-3.26(m,3H,C2-H,C6'''-CH2),2.32-2.19(m,8H,COCH2),1.62-1.53(m,8H,CH2CH3),0.93-0.89(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ176.0(C-12),174.8(COCH2),174.1(COCH2),174.1(COCH2),173.6(COCH2),149.7(C-7),149.1(C-6),148.6(C-3',C-5'),134.3(C-1'),131.5(C-9),131.5(C-9),127.2(C-4'),125.5(C-5'),110.9(C-5),109.2(C-2',C-6'),107.2(C-8),103.1(-OCH2O-),97.1(C-1'''),72.1(C-5'''),71.2(C-3'''),69.6(C-2'''),68.7(C-4'''),68.7(C-11),71.7(6),65.1(C-6''),63.9(C-2),62.9(C-6'''),56.8(3',5'-OMe),46.6(C-4),45.2(C-1),39.9(C-3),36.8(4),19.3(4),13.9(4);ESIMS:m/z1078[M+Na]+,HRESIMS:calcdforC52H69N3O20H[M+H]+1056.4547,found1056.4484.
实施例3-22：
化合物3-22的制备：
依照实施例2的方法，将4'-O-甲基-4-脱氧或4'-O-去甲基-4-脱氧-4β-叠氮鬼臼毒素(0.06-0.08mmol)与不同链长的端炔吡喃糖苷(0.006-0.008mmol)溶解在干燥的1.0ml四氢呋喃中，样品充分溶解后，向上述反应液中加入t-BtOH-H2O(1:2)1.0ml,加入醋酸铜(4.6mg,0.03mmol)，再滴加3滴抗坏血酸水溶液(1.0M/L)，在室温下反应34小时，用TLC跟踪反应的进行。反应完全后，向混合反应液中加入30ml水，再用20ml的乙酸乙酯萃取3次，合并有机相并用无水硫酸钠干燥、浓缩得到粗产物用硅胶色谱纯化(洗脱剂：石油醚：丙酮=1:1或者氯仿：甲醇=9:1)，制备以下结构的4β-(4"-吡喃糖苷取代-1,2,3-三唑)鬼臼毒素衍生物：
表1实施例3-22化合物结构
4β-(4"-吡喃糖苷取代-1,2,3-三唑)鬼臼毒素衍生物(实施例3-22)的结构数据：
分子式：C38H41N3O17
分子量：811
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.24(s,1H,C5′′-H),6.60(s,1H,C5-H),6.26(s,1H,C8-H),6.58(s,2H,C2′,6′-CH),5.99(d,1H,J=10.5Hz,C4-H),5.91(d,2H,J=8.1Hz,OCH2O),5.42(t,1H,J=9.9Hz,C1-H),5.24(d,1H,J=3.5Hz,C1'''-H),5.04(t,1H,J=9.4Hz,C2'''-H),4.77(s,2H,C6''-CH2),4.67(d,1H,C11-CHα),4.26-4.00(m,5H,C11-CHβ,C3-H,C3'''-H,C4'''-H,C5'''-H),3.54-3.22(m,3H,C2-H,C6'''-CH2),2.03-1.97(s,12H,COCH3);13CNMR(CD3OD,100MHz)δ176.0(C-12),172.3,171.7,171.5,171.2,149.7(C-7),149.1(C-6),148.6(C-3',C-5'),144.7(C-4''),135.5(C-1'),134.3(C-9),131.6(C-10),129.1(C-4'),126.2(C-5''),110.9(C-5),109.2(C-2',-6'),107.2(C-8),103.1(OCH2O),96.2(C-1'''),72.1(C-5'''),71.3(C-3'''),71.3(C-11),69.8(C-2'''),68.9(C-4'''),63.9(C-2),62.9(C-6''),61.7(C-6'''),56.8(3',5'-OMe),46.6(C-4),45.1(C-1),39.9(C-3),20.5(4);ESIMS:m/z834[M+Na]+,HRESIMS:calcdforC38H41N3O17H[M+H]+812.2509,found812.2480.
分子式：C46H57N3O17
分子量：923
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.21(s,1H,C5′′-H),6.57(s,2H,C2′,C6′-H),6.57(s,1H,C5-H),6.18(s,1H,C5-H),5.91(d,2H,J=6.0Hz,OCH2O),5.88(s,1H,C4-H),5.47(t,1H,J=9.7Hz,C1-H),5.25(d,1H,J=3.0Hz,C1'''-H),5.11(t,1H,J=9.7Hz,C2'''-H),4.84(s,2H,C6''-CH2),4.76(m,1H,C11-CHα),4.23-4.02(m,5H,C11-CHβ,C3-H,C3'''-H,C4'''-H,C5'''-H),3.49-3.04(m,3H,C2-H,C6'''-CH2),2.29-2.14(m,8H,COCH2),1.62-1.47(m,8H,CH2CH3),0.88-0.81(t,12H,J=7.8Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ175.8(C-12),174.7,174.0,173.9,173.5,149.5(C-7),149.0(C-6),148.5(C-3',-5'),144.6(C-4''),135.4(C-1'),134.3(C-9),131.7(C-10),129.0(C-4'),126.2(C-5''),111.0(C-5),109.2(C-2',-6'),107.3(C-8),103.1(OCH2O),96.3(C-1'''),72.0(C-5'''),71.1(C-3'''),69.5(C-2'''),69.1(C-4'''),71.3(C-11),63.8(C-2),62.8(C-6''),61.7(C-6'''),56.9(3',5'-OMe),46.4(C-4),45.0(C-1),39.8(C-3),36.7,36.7(4),19.3(4),14.1(4);ESIMS:m/z946[M+Na]+,HRESIMS:calcdforC46H57N3O17H[M+H]+924.3761,found924.3722.
分子式：C37H47N3O16
分子量：789
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,600MHz)δ7.84(s,1H,C5′′-H),6.70(s,1H,C5-H),6.63(s,1H,C8-H),6.41(s,2H,C2′,C6′-H),6.27(d,1H,J=3.2Hz,C4-H),5.98(d,2H,J=4.8Hz,OCH2O),4.82(d,1H,J=3.5Hz,C1'''-H),4.81(d,1H,J=4.0Hz,C1-H),4.62(s,2H,C6''-CH2),4.40(m,1H,C2'''-H),3.86-3.79(m,2H,C5'''-H,C11-CHα),3.74(s,6H,C3'',C5''-OMe),3.72(s,3H,C4''-OMe),3.69-3.61(m,12H,),3.47-3.14(m,7H,C11-CHβ,C2-H,C3-H,C3'''-H,C4'''-H,C6'''-CH2);13CNMR(CD3OD,150MHz)δ176.0(C-12),154.1(C-3',-5'),150.7(C-7),149.5(C-6),146.1(C-4''),138.4(C-1'),136.9(C-9),134.9(C-10),127.1(C-4'),126.1(C-5''),111.3(C-5),110.0(C-8),109.4(C-2',-6'),103.5(OCH2O),100.5(C-1'''),75.3(C-5'''),73.8(C-3'''),73.8(C-2'''),71.9(C-4'''),71.1(C-11),71.6(4),69.1,68.2,65.1(C-6''),62.8(C-6'''),61.2(4'-OMe),59.9(C-2),56.8(3',5'-OMe),45.1(C-4),42.7(C-1),38.7(C-3);ESIMS:m/z812[M+Na]+,HRESIMS:calcdforC37H47N3O16Na[M+Na]+812.2849,found812.2822.
分子式：C45H55N3O20
分子量：957
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.18(s,1H,C5′′-CH),6.62(s,2H,C2′,C6′-H),6.40(s,1H,C5-H),6.25(s,1H,C8-H),5.96(d,1H,J=5.5Hz,C4-H),5.92(d,2H,J=6.8Hz,OCH2O),5.42(t,1H,J=4.0Hz,C1-H),5.10(d,1H,J=3.1Hz,C1'''-H),5.02(t,1H,J=12.0Hz.C2'''-H),4.69(s,2H,C6''-CH2),4.39-4.06(m,6H,C11-CH2,C3-H,C3'''-H,C4'''-H,C5'''-H),3.78(s,6H,C3'',C5''-OMe),3.72(s,3H,C4''-OMe),3.71-3.60(m,12H,),3.39-3.14(m,3H,C2-H,C6'''-CH2),2.02-1.96(s,12H,COCH3);13CNMR(CD3OD,100MHz)δ175.8(C-12),172.3,171.6,171.6,171.3,153.9(C-3',5'),150.5(C-4''),149.7(C-7),149.3(C-6),136.9(C-1'),134.7(C-9),133.9(C-10),127.0(C-4'),125.6(C-5''),110.9(C-5),109.9(C-8),109.4(C-2',6'),103.2(OCH2O),97.1(C-1'''),72.1(C-5'''),71.6(C-3'''),69.9(C-2'''),68.7(C-11),68.5(C-4'''),71.7(6),64.6(C-6''),63.2(C-6'''),61.1(4'-OMe),56.7(C-2),56.6(3',5'-OMe),45.2(C-4),45.5(C-1),39.9(C-3),20.7(4);ESIMS:m/z980[M+Na]+,HRESIMS:calcdforC45H55N3O20H[M+H]+958.3452,found958.3403.
分子式：C53H71N3O20
分子量：1069
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.17(s,1H,C5′′-H),6.61(s,2H,C2′,C6′-H),6.40(s,1H,C5-H),6.25(s,1H,C8-H),5.95(d,1H,J=6.8Hz,C4-H),5.91(d,2H,J=9.6Hz,OCH2O),5.48(t,1H,J=12.0Hz,C1-H),5.11(d,1H,J=3.2Hz,C1'''-H),5.08(t,1H,J=8.0Hz,C2'''-H),4.60(s,2H,C6''-CH2),4.37-4.08(m,6H,C11-CH2,C3-H,C3'''-H,C4'''-H,C5'''-H),3.77(s,6H,C3'',C5''-OMe),3.71(s,3H,C4''-OMe),3.70-3.59(m,12H),3.39-3.12(m,3H,C2-H,C6'''-CH2),2.31-2.19(m,8H,COCH2),1.63-1.53(m,8H,CH2CH3),0.90(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ175.7(C-12),174.7,174.1,174.0,173.6,153.9(C-3',5'),150.5(C-4''),149.6(C-7),146.2(C-6),137.9(C-9),136.9(C-10),133.9(C-1'),127.0(C-4'),125.6(C-5''),110.9(C-5),109.8(C-8),109.4(C-2',6'),103.2(OCH2O),97.1(C-1'''),72.1(C-5'''),71.2(C-3'''),69.6(C-2'''),68.7(C-4'''),68.6(C-11),71.7(6),65.2(C-6''),63.0(C-6'''),61.1(4'-OMe),56.7(C-2),56.7(3',5'-OMe),45.2(C-4),42.5(C-1),39.9(C-3),36.8(4),19.3(4),14.1(4);ESIMS:m/z1092[M+Na]+,HRESIMS:calcdforC53H71N3O20H[M+H]+1070.4704,found1070.4658.
分子式：C52H69N3O20
分子量：1055
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.18(s,1H,C5′′-H),6.61(s,1H,C5-H),6.59(s,2H,C2′,C6′-H),6.26(s,1H,C8-H),6.02(d,1H,J=10.6Hz,C4-H),5.94(s,2H,OCH2O),5.47(t,1H,J=9.7Hz,C1-H),5.11(d,2H,J=3.7Hz,C1'''-H),5.06(t,1H,J=12.0Hz,C2'''-H),4.23-4.09(m,6H,C11-CH2,C3-H,C3'''-H,C4'''-H,C5'''-H),3.80(s,6H,C3'',C5''-OMe),3.72-3.63(m,12H),3.30-3.26(m,3H,C2-H,C6'''-CH2),2.32-2.19(m,8H,COCH2),1.62-1.53(m,8H,CH2CH3),0.93-0.89(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ176.0(C-12),174.8,174.1,174.1,173.6,149.7(C-7),149.1(C-6),148.6(C-3',5'),134.3(C-1'),131.5(C-9),131.5(C-9),127.2(C-4'),125.5(C-5''),110.9(C-5),109.2(C-2',6'),107.2(C-8),103.1(OCH2O),97.1(C-1'''),72.1(C-5'''),71.2(C-3'''),69.6(C-2'''),68.7(C-4'''),68.7(C-11),71.7(6),65.1(C-6''),63.9(C-2),62.9(C-6'''),56.8(3',5'-OMe),46.6(C-4),45.2(C-1),39.9(C-3),36.8(4),19.3(4),13.9(4);ESIMS:m/z1078[M+Na]+,HRESIMS:calcdforC52H69N3O20H[M+H]+1056.4547,found1056.4484.
分子式：1089
分子量：C5lH67N3O23
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.21(s,1H,C5′′-H),6.62,(s,2H,C2′,C6′-H),6.60(s,1H,C5-H),6.25(s,1H,C5-H),6.02(d,1H,J=8.0Hz,C4-H),5.93(d,2H,J=1.7Hz,OCH2O),5.42(t,1H,J=4.0Hz,C1-H),5.11(d,1H,J=3.5Hz,C1'''-H),5.02(t,1H,J=8.0Hz,C2'''-H),4.70(s,2H,C6''-CH2),4.25-4.07(m,6H,C11-CH2,C3-H,C3'''-H,C4'''-H,C5'''-H),3.79(s,6H,C3'',C5''-OMe),3.72(s,3H,C4''-OMe),3.64-3.57(m,24H),3.35-3.30(m,3H,C2-H,C6'''-CH2),2.04-1.97(s,12H,COCH3);13CNMR(CD3OD,100MHz)δ175.8(C-12),172.3,171.7,171.7,171.3,153.9(C-3',5'),153.9(C-7),149.7(C-6),149.2(C-4''),137.9(C-1'),137.0(C-9),133.9(C-10),129.3(C-4'),125.7(C-5''),110.9(C-5),109.3(C-2',C-6'),107.2(C-8),103.2(OCH2O),97.1(C-1'''),72.1(C-5'''),71.5(C-3'''),69.9(C-2'''),68.5(C-4'''),68.6(C-11),71.5(20),71.2,70.0,65.1(C-6''),63.8(C-2),63.2(C-6'''),61.1(4'-OMe),56.7(3',5'-OMe),45.5(C-4),45.3(C-1),39.9(C-3),20.6(4);ESIMS:m/z1090[M+H]+,HRESIMS:calcdforC51H67N3O23H[M+H]+1090.4238,found1090.4177.
分子式：C59H83N3O23
分子量：1201
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.20(s,1H,C5′′-H),6.62(s,2H,C2′,C6′-H),6.59(s,1H,C5-H),6.25(s,1H,C8-H),6.02(d,1H,J=10.5Hz,C4-H),5.93(d,2H,J=4.3Hz,OCH2O),5.48(t,1H,J=12.0Hz,C1-H),5.12(d,1H,J=4.0Hz,C1'''-H),5.07(t,1H,J=12.0Hz,C2'''-H),4.69(s,2H,C6''-CH2),4.40-4.07(m,5H,C11-CH2,C3-H,C3'''-H,C4'''-H,C5'''-H),3.79(s,6H,C3'',C5''-OMe),3.72(s,3H,C4''-OMe),3.70-3.59(m,24H,),3.27-3.12(m,3H,C2-H,C6'''-CH2),2.33-2.20(m,8H,COCH2),1.65-1.53(m,8H,CH2CH3),0.94-0.88(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ175.8(C-12),174.7,174.1,174.0,173.6,153.9(C-3',5'),149.7(C-7),149.2(C-6),146.3(C-4''),137.9(C-1'),136.9(C-9),133.9(C-10),129.3(C-4'),125.8(C-5''),110.9(C-5),109.4(C-2',6'),107.3(C-8),103.2(OCH2O),97.1(C-1'''),72.1(C-5'''),71.2(C-3'''),69.6(C-2'''),68.7(C-11),68.6(C-4'''),71.5(10),71.2,71.0,65.2(C-6''),63.8(C-2),62.9(C-6'''),61.1(4'-OMe),56.7(3',5'-OMe),46.5(C-4),45.2(C-1),39.9(C-3),36.7(4),19.3(4),14.0(4);ESIMS:m/z1224[M+Na]+,HRESIMS:calcdforC59H83N3O23H[M+H]+1202.5490,found1202.5423.
分子式：C58H81N3O23
分子量：1187
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.18(s,1H,C5′′-H),6.62(s,1H,C5-H),6.59(s,2H,C2′-H,C6′-CH),6.25(s,1H,C8-H),6.02(d,1H,J=8.5Hz,C4-H),5.94(s,2H,OCH2O),5.37(t,1H,J=8.0Hz,C1-H),5.11(d,2H,J=2.8Hz,C1'''-H),4.97(t,1H,J=8.0Hz,C2'''-H),4.70(s,2H,C6''-CH2),4.13-3.99(m,5H,C11-CH2,C3'''-H,C4'''-H,C5'''-H),3.80(s,6H,C3'',C5''-OMe),3.53-3.51(m,24H),3.62-3.55(m,4H,C2-H,C3-H,C6'''-CH2),2.24-2.10(m,8H,COCH2),1.56-1.43(m,8H,CH2CH3),0.85-0.79(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ176.0(C-12),174.8,174.0,174.0,173.6,149.7(C-7),149.1(C-6),148.6(C-3',5'),146.2(C-4''),135.6(C-1'),134.3(C-9),131.6(C-9),129.2(C-4'),125.6(C-5''),110.0(C-5),109.1(C-2',6'),107.1(C-8),103.0(OCH2O),97.1(C-1'''),72.0(C-5'''),71.2(C-3'''),69.5(C-2'''),68.6(C-4'''),68.6(C-11),71.6(10),71.2,70.0,65.1(C-6''),63.8(C-2),62.9(C-6'''),56.8(3',5'-OMe),46.7(C-4),45.1(C-1),39.9(C-3),36.8(4),19.3(4),14.0(4);ESIMS:m/z1210[M+Na]+,HRESIMS:calcdforC58H81N3O23H[M+H]+1188.5334,found1188.5298.
分子式：C47H59N3O17
分子量：937
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.87(s,1H,C5′′-H),6.71(s,1H,C5-H),6.61(s,1H,C8-H),6.44(s,2H,C2′,C6′-H),6.26(d,1H,J=3.9Hz,C4-H),5.97(d,2H,J=7.8Hz,OCH2O),5.49(d,1H,J=2.6Hz,C1-H),5.26(d,1H,J=2.9Hz,C1'''-H),5.34(dd,1H,J=4.0,12.0Hz),5.05(dd,1H,J=4.0,12.0Hz),4.77(s,2H,C6''-CH2),4.69-4.65(m,1H),4.37-4.35(m,1H),4.15-4.02(m,2H,C11-CH2),3.81-3.79(m,3H,C3-H,C6'''-CH2),3.75(s,6H,C3'',C5''-OMe),3.73(s,3H,C4''-OMe),3.47-3.40(m,1H,C2-H),3.29-3.19(t,8H,J=8.0Hz,COCH2),1.69-1.51(m,8H,CH2CH3),0.97-0.87(t,12H,J=8.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ174.2(C-12),173.0,172.7,172.6,172.3,152.4(C-3',5'),149.0(C-7),147.7(C-6),143.1(C-4''),136.7(C-1'),135.2(C-9),133.2(C-10),125.4(C-4'),124.8(C-5''),109.7(C-5),108.3(C-8),107.8(C-2',6'),101.8(OCH2O),95.0(C-1'''),67.7(C-5'''),67.6(C-3'''),67.2(C-2'''),66.3(C-4'''),67.3(C-11),60.9(C-6''),59.9(C-6'''),59.5(4'-OMe),58.3(C-2),55.1(3',5'-OMe),43.4(C-4),41.0(C-1),37.0(C-3),35.1(4),17.8(4),12.4(4);ESIMS:m/z960[M+Na]+,HRESIMS:calcdforC47H59N3O17H[M+H]+938.3917,found938.3915.
分子式：C30H33N3O13
分子量：643
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ8.23(s,1H,C5′′-H),6.62(s,1H,C5-H),6.59(s,2H,C2′,C6′-H),6.27(s,1H,C8-H),6.02(d,1H,J=10.6Hz,C4-H),5.93(d,2H,J=2.5Hz,OCH2O),4.97(d,1H,J=3.8Hz,C1'''-H),4.71-4.68(m,2H),4.25-4.19(m,2H,C11-CH2),3.80(s,6H,C3'',C5''-OMe),3.89-3.70(m,4H,C3-H,C2-H,C6'''-CH2);13CNMR(CD3OD,100MHz)δ176.1(C-12),149.8(C-7),149.2(C-6),148.8(C-3',5'),145.9(C-4''),134.3(C-9),131.7(C-10),129.9(C-1'),129.2(C-4'),125.7(C-5''),111.0(C-5),109.6(C-2',6'),107.3(C-8),103.1(OCH2O),100.2(C-1'''),72.8(C-5'''),71.5(C-3'''),71.3(C-2'''),70.2(C-4'''),70.2(C-11),64.1(C-2),62.9(C-6''),61.8(C-6'''),57.0(3',5'-OMe),46.8(C-4),45.2(C-1),40.0(C-3);ESIMS:m/z966[M+Na]+,HRESIMS:calcdforC30H33N3O13Na[M+Na]+666.1906,found666.1900.
分子式：C46H57N3O17
分子量：923
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,500MHz)δ8.24(s,1H,C5′′-H),6.61(s,3H,C5-H,C2′,C6′-H),6.24(s,1H,C8-H),5.97(d,1H,J=8.5Hz,C4-H),5.91(d,2H,J=10.6Hz,OCH2O),5.51(d,1H,J=2.5Hz,C1-H),5.32(d,1H,J=2.9Hz,C1'''-H),5.41(dd,1H,J=4.0Hz,8.0Hz,C2'''-H),5.13(dd,1H,J=4.0,12.0Hz,C5'''-H),4.91(s,2H,C6''-CH2),4.80(d,1H,J=12.0Hz,C4'''-H),4.66(d,1H,J=4.0Hz,C11-CHα),4.43(t,1H,J=8.0Hz,C3'''-H),4.36-4.06(m,5H,C11-CHβ,C2-H,C3-H,C6'''-CH2),3.79(s,6H,C3',C5''-OMe),2.44-2.20(m,8H,COCH2),1.71-1.52(m,8H,CH2CH3),1.00–0.86(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,125MHz)δ175.9(C-12),174.6,174.3,174.2,173.9,149.7(C-7),149.1(C-6),148.7(C-3',5'),144.9(C-4''),135.8(C-1'),134.3(C-9),131.7(C-10),1229.0(C-4'),125.8(C-5''),111.0(C-5),109.5(C-2',6'),107.3(C-8),103.1(OCH2O),95.9(C-1'''),71.3(C-11),69.3(C-5'''),69.3(C-3'''),68.9(C-2'''),68.0(C-4'''),64.0(C-2),62.5(C-6''),61.8(C-6'''),57.0(3',5'-OMe),46.6(C-4),45.1(C-1),40.0(C-3),36.7(4),19.5,19.4,19.3,19.2,14.0(4);ESIMS:m/z946[M+Na]+,HRESIMS:calcdforC46H57N3O17Na[M+Na]+946.3580,found946.3555.
分子式：C37H47N3O16
分子量：789
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.82(s,1H,C5′′-H),6.68(s,1H,C5-H),6.62(s,1H,C8-H),6.40(s,2H,C2′,C6′-H),6.25(d,1H,J=4.8Hz,C4-H),5.97(d,2H,J=4.8Hz,OCH2O),4.83(d,1H,J=7.4Hz,C1-H),4.79(d,1H,J=4.0Hz,C1'''-H),4.61(s,2H,C6''-CH2),3.87-3.80(m,2H,C2'''-H,C11-CHα),3.73(s,6H,C3'',C5''-OMe),3.71(s,3H,C4''-OMe),3.69-3.60(m,19H,OCH2,C11-CHβ,C3-H,C3'''-H,C4'''-H,C5'''-H,C6'''-CH2),3.46-3.41(m,1H,C2-H);13CNMR(CD3OD,100MHz)δ175.9(C-12),153.9(C-3',5'),150.6(C-7),149.3(C-6),150.0(C-4''),138.3(C-1'),136.8(C-9),134.8(C-10),127.0(C-4'),126.0(C-5''),111.2(C-5),109.8(C-8),109.4(C-2',6'),103.3(OCH2O),100.6(C-1'''),72.8(C-5'''),71.6(C-3'''),71.1(C-2'''),70.4(C-4'''),68.9(C-11),71.5(4),68.9,68.0,65.0(C-6''),62.8(C-6'''),61.1(4'-OMe),59.8(C-2),56.6(3',5'-OMe),44.9(C-4),42.5(C-1),38.6(C-3);ESIMS:m/z812[M+Na]+,HRESIMS:calcdforC37H47N3O16H[M+H]+790.3029,found790.3013.
分子式：C36H45N3O16
分子量：775
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.82(s,1H,C5′′-H),6.68(s,1H,C5-H),6.64(s,1H,C8-H),6.37(s,2H,C2′,C6′-H),6.25(d,1H,J=4.7Hz,C4-H),5.97(d,2H,J=5.0Hz,OCH2O),4.85(d,1H,J=7.4Hz,C1'''-H),4.78(d,1H,J=4.7Hz,C1-H),4.62(s,2H,C6''-CH2),4.39(m,1H,C2'''-H),3.87-3.81(m,2H,C5'''-H,C11-CHα),3.74(s,6H,C3'',C5''-OMe),3.69-3.60(m,15H,OCH2,C11-CHβ,C3'''-H,C4'''-CH),3.43-3.14(m,4H,C2-H,C3-H,C6'''-CH2);13CNMR(CD3OD,100MHz)δ176.0(C-12),150.5(C-7),149.2(C-6),148.7(C-3',5'),145.9(C-4''),135.1(C-9),131.3(C-10),127.0(C-4'),126.0(C-5''),111.2(C-5),109.7(C-8),109.3(C-2',6'),103.2(OCH2O),100.6(C-1'''),72.4(C-5'''),71.6(C-3'''),70.1(C-2'''),70.4(C-4'''),71.4(C-11),71.4(4),68.9,68.1,64.9(C-6''),62.8(C-6'''),59.9(C-2),56.7(3',5'-OMe),44.7(C-4),42.7(C-1),38.5(C-3);ESIMS:m/z798[M+Na]+,HRESIMS:calcdforC36H45N3O16H[M+H]+776.2873,found776.2861.
分子式：C53H71N3O20
分子量：1069
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.80(s,1H,C5′′-H),6.69(s,1H,C5-H),6.63(s,1H,C8-H),6.41(s,2H,C2′,C6′-H),6.25(d,1H,J=4.9Hz,C4-H),5.97(d,2H,J=4.9Hz,OCH2O),5.23(d,1H,J=4.0Hz,C1'''-H),5.14(dd,1H,J=4.0Hz,12.0Hz,C2'''-H),4.80-4.78(m,3H,C6''-CH2,C1-H),4.44-4.24(m,3H,C11-CHα,C5'''-H,C4'''-H),3.94-3.79(m,4H,C11-CHβ,C3'''-H,C6'''-CH2),3.73(s,6H,C3'',C5''-OMe),3.72(s,3H,C4''-OMe),3.65-3.60(m,12H),3.45-3.13(m,2H,C2-H,C3-H),2.35-2.27(t,8H,J=4.0Hz,COCH2),1.68-1.56(m,8H,CH2CH3),0.97-0.92(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ176.2(C-12),175.8,175.0,174.4,174.0,154.7(C-4''),154.0(C-3',5'),150.6(C-7),149.3(C-6),140.6(C-1'),138.3(C-9),136.8(C-10),127.0(C-4'),125.9(C-5''),111.2(C-5),109.9(C-8),109.4(C-2',6'),103.3(OCH2O),99.0(C-1'''),73.1(C-5'''),72.1(C-3'''),70.7(C-2'''),66.0(C-4'''),70.9(C-11),71.6,71.5(2),71.2,68.9,68.1,65.1(C-6''),64.1(C-6'''),61.1(4'-OMe),59.8(C-2),56.6(3',5'-OMe),44.9(C-4),42.5(C-1),38.6(C-3),36.8(4),19.5(4),14.0(4);ESIMS:m/z1092[M+Na]+,HRESIMS:calcdforC53H71N3O20H[M+H]+1070.4704,found1070.4703.
分子式：C52H69N3O20
分子量：1055
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.80(s,1H,C5′′-H),6.67(s,1H,C5-H),6.62(s,1H,C8-H),6.38(s,2H,C2′,C6′-H),6.23(d,1H,J=4.6Hz,C4-H),5.96(d,2H,J=5.5Hz,OCH2O),5.23(d,1H,J=4.0Hz,C1'''-H),5.14(dd,1H,J=4.0Hz,12.0Hz,C2'''-H),4.90(s,2H,C6''-CH2),4.76(d,1H,C1-H),4.43-4.24(m,3H,C11-CHα,C5'''-H,C4'''-H),3.94-3.78(m,2H,C11-CHβ,C3'''-H),3.73(s,6H,C3''-O,C5''-OMe),3.65-3.60(m,12H),3.42-3.12(m,4H,C2-H,C3-H,C6'''-CH2),2.35-2.27(t,8H,J=4.0Hz,COCH2),1.69-1.51(m,8H,CH2CH3),0.97-0.89(t,12H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ176.2(C-12),175.9,175.1,174.4,174.0,150.5(C-7),149.2(C-6),148.7(C-3',5'),146.1(C-4''),136.0(C-1'),135.1(C-9),131.4(C-10),126.9(C-4'),125.9(C-5''),111.3(C-5),109.9(C-8),109.4(C-2',6'),103.3(OCH2O),99.0(C-1'''),73.1(C-5'''),72.1(C-3'''),70.7(C-2'''),66.0(C-4'''),70.9(C-11),71.7,71.5(2),71.2,68.9,68.1,65.1(C-6''),64.1(C-6'''),59.9(C-2),56.8(3',5'-OMe),44.6(C-4),42.7(C-1),38.6(C-3),36.8(4),19.5(4),14.0(4);ESIMS:m/z1078[M+Na]+,HRESIMS:calcdforC52H69N3O20H[M+H]+1056.4547,found1056.4509.
分子式：C42H51N3O15
分子量：837
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.86(s,1H,C5′′-H),6.86(s,1H,C5-H),6.59(s,1H,C8-H),6.41(s,2H,C2′,C6′-H),6.24(d,1H,J=4.7Hz,C4-H),5.95(d,2H,J=7.8Hz,OCH2O),5.44(t,1H,J=8.0Hz,C4'''-H),5.13(d,1H,J=3.4Hz,C1'''-H),5.00-4.62(m,5H,C2'''-H,C3'''-H,C6''-CH2,C11-CHβ),4.53-4.35(m,1H,C11-CHα),3.80-3.78(m,1H,C5'''-CH2),3.73(s,6H,C3'',C5''-OMe),3.71(s,3H,C4''-OMe),3.46-3.14(m,2H,C2-H,C3-H),2.24-2.19(t,6H,J=8.0Hz,COCH2),1.60-1.49(m,6H,CH2CH3),0.90(t,9H,J=12.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ175.7(C-12),174.1,174.0,173.9,154.0(C-3',5'),150.6(C-4''),149.3(C-7),144.6(C-6),138.3(C-1'),136.7(C-9),134.7(C-10),127.0(C-4'),126.4(C-5''),111.2(C-5),109.9(C-8),109.4(C-2',6'),103.3(OCH2O),96.1(C-1'''),72.2(C-3'''),70.5(C-2'''),70.3(C-4'''),68.9(C-11),61.3(C5'''-CH2),61.2(4'-OMe),59.8(C-2),59.6(C-6''),56.6(3',5'-OMe),44.9(C-4),42.5(C-1),38.6(C-3),36.8(3),19.3(3),14.0(3);ESIMS:m/z860[M+Na]+,HRESIMS:calcdforC42H51N3O15H[M+H]+838.3393,found838.3367.
分子式：C36H45N3O15
分子量：759
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.82(s,1H,C5′′-H),6.68(s,1H,C5-H),6.63(s,1H,C8-H),6.41(s,2H,C2′,C6′-H),6.24(d,1H,J=4.8Hz,C4-H),5.95(d,2H,J=5.7Hz,OCH2O),4.77(d,1H,J=5.0Hz,C1-H),4.75(m,1H,J=3.6Hz,C1'''-H),4.61(s,2H,C6''-CH2),4.42-4.14(m,2H,C2'''-H,C11-CHα),3.73(s,6H,C3'',C5''-OMe),3.71(s,3H,C4''-OMe),3.66-3.60(m,12H),3.53-3.14(m,7H,C3'''-H,C4'''-H,C5'''-H2,C11-CHβ,C2-H,C3-H);13CNMR(CD3OD,100MHz)δ175.8(C-12),154.0(C-3',5'),150.6(C-7),149.3(C-6),146.0(C-4''),138.3(C-1'),136.8(C-9),134.8(C-10),127.0(C-4'),126.0(C-5''),111.2(C-5),109.9(C-8),109.4(C-2',6'),103.3(OCH2O),101.6(C-1'''),75.3(C-3'''),73.7(C-2'''),71.5(C-4'''),70.9(C-11),71.5(2),71.4,71.3,68.9,68.2,65.0(C5'''-CH2),63.1(C-6''),61.1(4'-OMe),59.8(C-2),56.6(3',5'-OMe),44.9(C-4),42.5(C-1),38.6(C-3);ESIMS:m/z782[M+Na]+,HRESIMS:calcdforC36H45N3O15H[M+H]+760.2923,found760.2914.
分子式：C48H63N3O18
分子量：969
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.77(s,1H,C5′′-H),6.68(s,1H,C5-H),6.60(s,1H,C8-H),6.41(s,2H,C2′，C6′-H),6.25(d,1H,J=4.6Hz,C4-H),5.96(d,2H,J=5.3Hz,OCH2O),5.46(t,1H,J=9.8Hz,C2'''-H),5.06(d,1H,J=3.2Hz,C1'''-H),4.96-4.81(m,2H,C3'''-H,C11-CHα),4.77(d,1H,J=4.7Hz,C1-H),4.60(s,2H,C6''-CH2),4.36(t,1H.J=8.0Hz,C4'''-H),3.80-3.78(m,3H,C5'''-CH2,C11-CHβ),3.43-3.12(2H,C2-H,C3-H),3.24(t,6H,J=8.0Hz,COCH2),1.60-1.53(m,6H,CH2CH3),0.90(t,9H,J=12.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ175.7(C-12),174.1,174.1,174.0,154.0(C-3',5'),150.5(C-7),149.3(C-6),146.1(C-4''),138.3(C-1'),136.7(C-9),134.8(C-10),127.0(C-4'),125.8(C-5''),111.2(C-5),109.9(C-8),109.4(C-2',6'),103.3(OCH2O),97.3(C-1'''),72.2(C-3'''),70.7(C-2'''),70.5(C-4'''),71.0(C-11),71.7,71.5(2),71.3,68.9,68.6,65.1(C5'''-CH2),59.4(C-6''),61.1(4'-OMe),59.8(C-2),56.7(3',5'-OMe),44.9(C-4),42.5(C-1),38.6(C-3),36.7(3),19.3(3),14.0(3);ESIMS:m/z992[M+Na]+,HRESIMS:calcdforC48H63N3O18H[M+H]+970.4179,found970.4167.
分子式：C48H63N3O18
分子量：969
性状：白色无定型粉末
波谱数据：
1HNMR(CD3OD,400MHz)δ7.80(s,1H,C5′′-H),6.69(s,1H,C5-H),6.62(s,1H,C8-H),6.42(s,2H,C2,C6′-H),6.25(d,1H,J=4.8Hz,C4-H),5.97(d,2H,J=5.6Hz,OCH2O),5.46(t,1H,J=9.2Hz,C2'''-H),4.87-4.84(m,1H,C3'''-H),3.80(d,1H,J=4.0Hz,C1-H),4.65(d,2H,J=8.0Hz,C1'''-H),4.62(s,2H,C6''-CH2O),4.41-4.34(m,1H,C11-CHα),4.87-4.39(m,C4'''-H),4.06-4.02(m,C11-CHβ),3.74(s,6H,C3'',C5''-OMe),3.72(s,3H,C4''-OMe),3.66-3.57(m,12H,OCH2CH2O),3.46-3.13(m,4H,C5'''-CH2,C2-H,C3-H),2.26-2.21(t,6H,J=4.0Hz,COCH2),1.61-1.54(m,6H,CH2CH3),0.91-0.89(t,9H,J=4.0Hz,CH2CH3);13CNMR(CD3OD,100MHz)δ175.8(C-12),174.0,174.0,173.7,154.0(C-3',5'),150.6(C-7),149.3(C-6),146.1(C-4''),138.3(C-1'),136.7(C-9),134.8(C-10),127.0(C-4'),125.8(C-5''),111.2(C-5),109.9(C-8),109.4(C-2',6'),103.3(OCH2O),102.3(C-1'''),73.1(C-3'''),72.3(C-2'''),70.3(C-4'''),70.9(C-11),71.6,71.5,71.4,69.9,68.9,65.0(C5'''-CH2),63.3(C-6''),61.1(4'-OMe),59.8(C-2),56.6(3',5'-OMe),44.9(C-4),42.5(C-1),38.6(C-3),36.8(3),19.3(3),14.0(3);ESIMS:m/z992[M+Na]+,HRESIMS:calcdforC48H63N3O18H[M+H]+970.4179,found970.4162.
实施例23：
化合物23的制备：
按上述实施例的方法制备4-脱氧-4β-糖苷化、酰化糖苷化鬼臼毒素，其中糖和酰化糖为：D-葡萄糖、乙酰化葡萄糖、丁酰化葡萄糖、D-半乳糖、乙酰化半乳糖、丁酰化半乳糖、D-甘露糖、乙酰化甘露糖、丁酰化甘露糖、D-木糖、乙酰化木糖、丁酰化木糖。
实施例24：
化合物24的制备：
按上述实施例的方法制备4'-O-去甲基-4-脱氧-4β-糖苷化、酰化糖苷化鬼臼毒素，其中糖和酰化糖为：D-葡萄糖、乙酰化葡萄糖、丁酰化葡萄糖、D-半乳糖、乙酰化半乳糖、丁酰化半乳糖、D-甘露糖、乙酰化甘露糖、丁酰化甘露糖、D-木糖、乙酰化木糖、丁酰化木糖。
实施例25：
鬼臼毒素糖苷物和酰化糖苷物衍生物对不同肿瘤细胞的体外抑制作用：
1.实验材料
细胞株：人白血病细胞株HL-60，人肝癌细胞株SMMC-7721，人肺癌细胞株A-549，人乳腺癌细胞株MCF-7，人结肠癌细胞株SW480。
检测原理：MTT法检测细胞活性
2.试验方法
1).接种细胞：用含10％胎牛血清的培养液（DMEM或者RMPI1640）配成单个细胞悬液，以每孔5000-10000个细胞接种到96孔板，每孔体积100μl，贴壁细胞提前12小时接种培养。
2).加入待测化合物溶液（固定浓度40μM初筛，在该浓度对肿瘤细胞生长抑制在50%附近的化合物设5个浓度进入梯度复筛），每孔终体积200μl，每种处理均设3个复孔。
3).显色：37摄氏度培养48小时后，每孔加MTT溶液20μl。继续孵育4小时，终止培养，吸弃孔内培养上清液，每孔加200μl的SDS溶液（10%），过夜孵育（温度37℃），使结晶物充分融解。
4).比色：选择595nm波长，酶联免疫检测仪（Bio-Rad680）读取各孔光吸收值，记录结果，以浓度为横坐标，细胞存活率为纵坐标绘制细胞生长曲线，应用两点法（ReedandMuench法）计算化合物的IC50值。
3.实验结果
表2.本发明合成的20个4β-(4"-吡喃糖苷取代-1,2,3-三唑)鬼臼毒素衍生物
对不同肿瘤细胞的IC50(μM)值
结果表明：化合物4,8,10,13,14对五种受试肿瘤细胞株均有较依托泊苷更强的细胞毒活性，对上述细胞株的IC50值在0.49-7.28μM之间。
实施例26：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，用少量的DMSO溶解后，按常规加注射用水，精滤，封装制成注射液。
实施例27：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，用少量的DMSO溶解后，将其溶于无菌注射用水，再无菌精滤，低温冷冻干燥后无菌封装得粉针剂。
实施例28：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，按其与赋形剂重量比为9:1的比例加入赋形剂制成粉剂。
实施例29：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，其与赋形剂重量比为5:1的比例加入赋形剂制成粒压片。
实施例30：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，按常规口服液制法制成口服液。
实施例31：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，其与赋形剂重量比为5:1的比例加入赋形剂制成胶囊。
实施例32：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，其与赋形剂重量比为3:1的比例加入赋形剂制成胶囊。
实施例33：
按实施例2-24制备的鬼臼毒素糖苷物和酰化糖苷物衍生物，按其与赋形剂重量比为5:1的比例加入赋形剂制成颗粒剂。
Claims (6)
1.下述结构式(I)所示的鬼臼毒素丁酰化糖苷物衍生物:
化合物4：R＝H,n＝0,m＝4；糖为葡萄糖；
化合物8：R＝H,n＝3,m＝4；糖为葡萄糖；
化合物10：R＝CH3,n＝6,m＝4；糖为葡萄糖；
化合物14：R＝H,n＝0,m＝4；糖为半乳糖。
2.药物组合物，其中含有治疗有效量的权利要求1所述的鬼臼毒素丁酰化糖苷物衍生物和药学上可接受的载体。
3.权利要求1中所述的鬼臼毒素丁酰化糖苷物衍生物在制备药物中的应用。
4.权利要求1中所述的鬼臼毒素丁酰化糖苷物衍生物在制备抗肿瘤抑制剂中的应用。
5.权利要求1中所述的鬼臼毒素丁酰化糖苷物衍生物在制备抗肿瘤药物中的应用。
6.制备权利要求1所述的通式I的鬼臼毒素丁酰化糖苷物衍生物的方法，其特征在于由三甘醇、六甘醇得到不同链长度的端炔醇与不同的糖醚化后得到端炔糖苷，再丁酰化后得到不同的端基丁酰化糖苷；然后由鬼臼毒素及由鬼臼毒素制备成4'-O-去甲基鬼臼毒素和不同的端炔丁酰化糖苷溶于无水二氯甲烷中，加入少量新处理的分子筛，低温冷却到-20℃，滴加溶于二氯甲烷中的三氟化硼乙醚溶液，再用三乙胺、醋酸中和反应体系，过滤除去沉淀，减压除去二氯甲烷，得到粗品，粗品经过硅胶柱层析，用氯仿:甲醇，石油醚:乙酸乙酯洗脱得到鬼臼毒素丁酰化糖苷物衍生物；或者由4'-O-甲基-4-脱氧-4β-叠氮化合物，4'-O-去甲基-4-脱氧-4β-叠氮化合物与丁酰化端炔糖苷溶于四氢呋喃中，加入叔丁醇-水1:2和醋酸铜，再滴加抗坏血酸水溶液经过Click反应34小时，反应完全后加入水，用二氯甲烷萃取3次，合并有机相再用饱和食盐水洗涤2次，无水硫酸钠干燥后减压回收二氯甲烷，得到粗品；粗品经硅胶柱层析，用石油醚：丙酮、氯仿：甲醇洗脱得到鬼臼毒素衍生物。
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