CN110372766A - 喜树碱糖类衍生物及其制备方法与应用 - Google Patents

喜树碱糖类衍生物及其制备方法与应用 Download PDF

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CN110372766A
CN110372766A CN201910542005.XA CN201910542005A CN110372766A CN 110372766 A CN110372766 A CN 110372766A CN 201910542005 A CN201910542005 A CN 201910542005A CN 110372766 A CN110372766 A CN 110372766A
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周文
李茂林
袁思思
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Guangzhou University of Traditional Chinese Medicine
Guangzhou University of Chinese Medicine
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Abstract

本发明涉及喜树碱糖类衍生物及其制备方法与应用，属于生物医药领域。本发明喜树碱糖类衍生物的结构式如下述式(I)所示。本发明喜树碱糖类衍生物能明显增加喜树碱与10‑羟基喜树碱的稳定性和水溶性，对不同肿瘤细胞具有不同敏感性。尤其当上述链接链n＝1时，本发明喜树碱糖类衍生物能明显增加对肿瘤细胞的选择性。

Description

喜树碱糖类衍生物及其制备方法与应用
技术领域
本发明涉及喜树碱糖类衍生物及其制备方法与应用，属于生物医药领域。
背景技术
喜树碱(Camptothecin，CPT)是早期发现的一种有细胞毒性的天然吲哚类生物碱，抑制DNA拓扑异构酶I(Topo I)活性而达到抗肿瘤作用。CPT与Topo iI-DNA复合物可逆性地结合，形成稳定的CPT-Topo I-DNA三元结合体，对可裂解复合物起到稳定作用,阻断DNA合成，进而诱导细胞的凋亡(DNA拓扑异构酶1抑制剂：化学，生物学和界面抑制剂，化学综述，2009，109，2894-2902)。以具有清晰作用靶点的CPT为先导，科学家进行广泛TopoI抑制剂的研发，总结CPT较完善的抗肿瘤构效关系，并得到临床治疗不同肿瘤的CPT衍生物如拓扑替康(Topotecan，TPT)、依立替康(Irinotecan，CPT-11)、贝洛替康(Belotecan，CDK-602)。然而，水溶性差、血浆稳定性差、毒性大一直是困扰喜树碱类化合物广泛应用的主要障碍。
糖靶向药物治疗是治疗肿瘤的一种非常有效的手段，广受关注，它利用酶、抗体、凝集素等受体蛋白介导的含糖结合物，通过细胞内化、胞吞作用，将抗肿瘤药物运输到肿瘤部位后从载体中释放，从而发挥其靶向治疗肿瘤的作用。去唾液酸糖蛋白受体(asialoglycoproteinreceptor，ASGPR)能有效地识别并结合含末端带有非还原半乳糖和乙酰半乳糖胺，有效介导半乳糖类物质内吞与摄取，为靶向肝癌给药提供有效的靶点(半乳糖化脂质体在小鼠体内肝靶向性评价，中国药学杂志，2006，41，1076-1079)。过表达葡萄糖转运蛋白介导的葡萄糖-铂结合物，将抗癌药物顺铂特异性地递送到肿瘤组织中(通过葡萄糖-铂缀合物的位置异构体的化学方法揭示了癌症细胞中葡萄糖转运蛋白介导的体外和体内特异性摄取作用，美国化学学会杂志，2016，138，12541-12551)。博来霉素结构中的二糖片段能特异性识别区分肿瘤细胞和正常细胞(博来霉素二糖部分能提高对癌细胞的摄取，美国化学学会杂志，2014，136，13641-13654)，进一步发现，博来霉素二糖甲酰胺甘露糖部分能选择性靶向肿瘤细胞(博来霉素甲酰胺甘露糖部分能调节选择性靶向肿瘤细胞，生物化学，2014，53，3264-3266)。甘露糖能竞争性地通过葡萄糖转运蛋白介导抑制肿瘤的生长(甘露抑制肿瘤生长并增强化疗，自然，2018，563,719-723.)等等，单糖或二糖可以通过靶向正常细胞与肿瘤细胞受体等差异实现对其选择性，是改善抗肿瘤药物的水溶性、靶向性等的良好配体，然而，目前利用糖基化优化喜树碱的研究报道几乎很少，主要原因喜树碱糖类杂合体制备与分离均极具挑战。
发明内容
本发明的目的在于克服现有技术的不足之处而提供一种水溶性和稳定性好、生物利用度高且肿瘤靶向性强的喜树碱糖类衍生物及其制备方法与应用。
为实现上述目的，本发明采取的技术方案为：一种喜树碱糖类衍生物，其结构式如下述式(I)所示：
所述R1选自
中的任意一种；
所述R2选自：
中的任意一种；
所述R2为H时，所述R1不能为H和OH；
其中，n＝0，1，2；R3为全乙酰化半乳糖、全乙酰化葡萄糖、全乙酰化甘露糖、全乙酰化的3-O-氨基甲酰甘露糖或全乙酰化博来霉素(BLM)二糖等；R4为半乳糖、葡萄糖、甘露糖、3-O-氨基甲酰甘露糖或BLM二糖等。
本发明喜树碱糖类衍生物即为喜树碱糖类杂合体。上述R3的结构式为：
等
上述R4的结构式如下：
等
本发明喜树碱糖类衍生物旨在提高改善喜树碱的水溶性、稳定性、生物利用度以及肿瘤靶向性，从而降低喜树碱的毒性。肿瘤靶向性试验表明，本发明喜树碱糖类衍生物能明显增加喜树碱与10-羟基喜树碱的稳定性和水溶性，对不同肿瘤细胞具有不同敏感性。尤其当上述链接链n＝1时，本发明喜树碱糖类衍生物能明显增加对肿瘤细胞的选择性。
另外，本发明提供了上述喜树碱糖类衍生物的制备方法，其包括以下步骤：
(1)在干燥有机溶剂A中，喜树碱或10-羟基喜树碱与对硝基苯基氯甲酸酯在催化剂A作用下进行酯化反应，得到如下式a所示化合物和式b所示化合物；
(2)在碱性条件下，将不同聚合度的乙二醇胺和氯甲酸苄酯溶于无水四氢呋喃中，反应得到如下式c所示化合物；
(3)在无水醋酸钠的作用下，将不同单糖或寡糖与醋酸酐反应得到全乙酰化糖苷，将全乙酰化糖苷溶于高沸点有机溶剂B，在催化剂B存在的条件下，进行脱端基乙酰基；
(4)将步骤(3)脱端基乙酰基所得化合物和三氯乙腈溶于无水二氯甲烷，在碱性条件下，低温催化反应得到三氯乙酰亚胺活化的酰基糖酯；
(5)将三氯乙酰亚胺活化的酰基糖酯与式c所示化合物溶于无水二氯甲烷，低温条件在偶合剂催化下成醚得到如下式d所示化合物；
(6)将式d所示化合物溶于有机溶剂C中，室温下在钯催化剂催化下脱苄后，在碱作用下，与式a所示化合物进行反应得具以下通式e的喜树碱糖类衍生物；或者将脱苄后所得产物与式b所示化合物溶于有机溶剂D中，在碱催化条件下得到具以下通式h的喜树碱糖类衍生物；
或者将式d所示化合物溶于有机溶剂E中，在甲醇钠作用下，脱去全部乙酰基，然后用阳离子树脂中和置换钠离子，接着用钯催化剂催化下脱苄制备得式f所示化合物；将式f所示化合物与式a所示化合物溶于有机溶剂F中，室温下在碱催化条件下得到具有以下通式g的喜树碱糖类衍生物或将式f所示化合物与式b所示化合物溶于有机溶剂G中，在碱催化条件下成酰胺得到具有以下通式j的喜树碱糖类衍生物；
其中，n＝0，1，2；R3为全乙酰化半乳糖、全乙酰化葡萄糖、全乙酰化甘露糖、全乙酰化的3-O-氨基甲酰甘露糖或全乙酰化BLM二糖；R4为半乳糖、葡萄糖、甘露糖、3-O-氨基甲酰甘露糖或BLM二糖。
本发明喜树碱糖类衍生物的制备方法具有产率高、可操作性强、条件易控、低成本、易纯化、易规模化等优点。
作为本发明所述喜树碱糖类衍生物的制备方法的优选实施方式，所述步骤(1)中，有机溶剂A为二氯甲烷或四氢呋喃；所述催化剂A选自三乙胺、4-二甲氨基吡啶(DMAP)、吡啶或碳酸钾等；所述酯化反应的温度为0-40℃。
作为本发明所述喜树碱糖类衍生物的制备方法的优选实施方式，所述步骤(2)中，碱性条件采用的碱是三乙胺、N,N-二异丙基乙胺(DIPEA)或吡啶等，反应的温度为20℃-45℃，反应的时间为1-3小时。
作为本发明所述喜树碱糖类衍生物的制备方法的优选实施方式，所述步骤(3)中，单糖或寡糖与醋酸酐的摩尔比为1：(6-12)，反应的温度为80-120℃；所述有机溶剂B是N,N-二甲基甲酰胺(DMF)、甲苯或二甲基亚砜(DMSO)；所述催化剂B选自乙酸肼、苄胺或氨水。
作为本发明所述喜树碱糖类衍生物的制备方法的优选实施方式，所述步骤(4)中，碱性条件采用的碱选自1,8-二氮杂二环十一碳-7-烯(DBU)；所述脱端基乙酰基所得化合物、三氯乙腈和1,8-二氮杂二环十一碳-7-烯的摩尔比为脱端基乙酰基所得化合物：三氯乙腈：1,8-二氮杂二环十一碳-7-烯＝1：(1.5-5)：(0.1-0.5)；催化反应的温度为-5-0℃。
作为本发明所述喜树碱糖类衍生物的制备方法的优选实施方式，所述步骤(5)中，耦合剂选自三氟化硼乙醚、三氟甲磺酸三甲基硅酯或三氟甲磺酸盐；所述偶合剂与三氯乙酰亚胺活化的酰基糖酯的摩尔比为(1.0-2.5):1；所述成醚反应温度为-5-0℃；
作为本发明所述喜树碱糖类衍生物的制备方法的优选实施方式，所述步骤(6)中，有机溶剂C、有机溶剂D、有机溶剂F和有机溶剂G各自独立地选自乙酸乙酯、甲醇、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺(DMF)或二甲基亚砜(DMSO)，所述有机溶剂E为甲醇；所述钯催化剂选自钯碳(Pd/C)、氢氧化钯(Pd(OH)2、氧化钯(PdO)或鈀黑；所述碱催化中的碱为N，N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)、三乙胺或吡啶；所述式d所示化合物或式f所示化合物与式a所示化合物反应时，反应的温度为20-45℃，碱催化中的碱与式a所示化合物的摩尔比为(0.5-2):1；所述式d所示化合物或式f所示化合物与式b所示化合物反应时，反应的温度为20-45℃，碱催化中的碱与式b所示化合物的摩尔比为(0.5--2):1；所述阳离子树脂为Dowx50或Amberlite IR-120等。
最后，本发明还提供了一种用于治疗肿瘤的药物，其包含上述喜树碱糖类衍生物。
与现有技术相比，本发明的有益效果为：本发明喜树碱糖类衍生物能明显增加喜树碱与10-羟基喜树碱的稳定性和水溶性以及提高肿瘤靶向性与选择性，它对不同肿瘤细胞具有不同敏感性。尤其当上述链接链n＝1时，本发明喜树碱糖类衍生物能明显增加对肿瘤细胞的选择性。
附图说明
图1为本发明喜树碱或10-羟基喜树碱活化路线路图；
图2为本发明不同链长乙二醇胺苄酯的制备线路图；
图3为本发明喜树碱单糖类杂合物的制备线路图；
图4为本发明喜树碱-博来霉素二糖类杂合物的制备线路图。
具体实施方式
为更好地说明本发明的目的、技术方案和优点，下面将结合具体实施例对本发明作进一步说明。
下述实施例中，喜树碱或10-羟基喜树碱活化路线路如图1所示，不同链长乙二醇胺苄酯的制备线路图如图2所示，喜树碱单糖类杂合体的制备线路如图3所示，喜树碱-博来霉素二糖类杂合体的制备线路如图4所示。
实施例
(1)化合物a的制备
将喜树碱(5g，14.3mmol)与4-二甲氨基吡啶(10.6g，85.8mmol)溶于500mL无水二氯甲烷中，在0℃下，将对硝基苯基氯甲酸酯(11.5g，57.2mmol)逐滴加，滴毕，升温至室温，继续搅拌3小时，TLC监测，直至原料消失。将反应混合物倒入1000mL二氯甲烷中，加入1M盐酸洗涤，直至pH＝7，萃取分离有机相，浓缩干燥，柱层析(乙酸乙酯:二氯甲烷V:V＝1:1)，最终得到淡黄色固体化合物a；产率86％。1H NMR(400MHz,Chloroform-d)δ8.45(s,1H),8.24(dd,J＝17.8,8.6Hz,3H),7.97(d,J＝8.3Hz,1H),7.87(t,J＝7.8Hz,1H),7.71(t,J＝7.6Hz,1H),7.45(s,1H),7.40(d,J＝8.8Hz,2H),7.27(s,1H),5.72(d,J＝17.3Hz,1H),5.43(d,J＝17.3Hz,1H),5.32(d,J＝4.0Hz,2H),2.36(dt,J＝14.9,7.4Hz,1H),2.25(dt,J＝14.1,7.4Hz,1H),1.07(t,J＝7.5Hz,3H).13C NMR(100MHz,CDCl3)δ166.86,157.26,155.06,152.12,151.28,148.89,146.84,145.59,144.97,131.43,130.96,129.56,128.45,128.32,126.24,125.29,121.72,120.36,115.69,95.67,79.33,67.20,50.14,31.91,7.68.
(2)化合物b的制备
将10-羟基喜树碱(3g，8.2mmol)溶于60mL无水四氢呋喃，在0℃下,分别加入三乙胺(11.5mL，82.3mmol)和对硝基苯基氯甲酸酯(6.6g，32.9mmol)，升温至室温继续搅拌1小时，TLC检测，直至原料消失。浓缩干燥，用乙酸乙酯柱层析，最终得到淡黄色固体化合物b；产率93％。1H NMR(400MHz,Dimethyl sulfoxide-d6)δ8.72(s,1H),8.39(d,J＝12.0Hz,1H),8.28(d,J＝8.0Hz,1H),8.18(s,1H),7.96(d,J＝8.0Hz,1H),7.76(d,J＝12.0Hz,1H),7.35(s,1H),6.55(s,1H),5.43(s,2H),5.30(s,2H),1.87(t,J＝8.0Hz,2H),0.89(t,J＝8.0Hz,3H).13CNMR(100MHz,Dimethyl sulfoxide-d6))δ172.92,157.25,155.51,153.51,151.03,150.46,149.29,146.60,145.98,145.69,131.95,131.31,131.16,128.64,126.66,126.01,125.57,123.21,119.78,119.47,116.26,97.33,72.84,65.72,50.73,30.76,8.25.
(3)化合物c或d或e的制备
将不同聚合度的乙二醇胺c(9.61mmol)溶于60ml四氢呋喃，在室温下,分别加入三乙胺(9.62mmol)与对硝基氯甲酸苯酯(10.62mmol)。混合物在室温下继续反应1小时，TLC点板检测，直至反应完全。倒入100mL乙酸乙酯和20mL水中，萃取有机层，饱和食盐水洗涤，浓缩干燥，柱层析(乙酸乙酯:石油醚V:V＝1:1)，最终得到白色结晶化合物d1(n＝0)或无色油状物化合物d2(n＝1)。
d1：白色结晶化合物，产率,85.2％.1H NMR(400MHz,Chloroform-d)δ7.39-7.27(m,5H),5.45(s,1H),5.08(s,2H),3.65(d,J＝6.3Hz,2H),3.30(d,J＝5.7Hz,2H),2.87(s,1H)；13C NMR(100MHz,CDCl3)δ157.18,136.36,128.55,128.19,128.09,66.91,61.96,43.47.
d2：无色油状物，产率，87.5％.1H NMR(400MHz,Chloroform-d)δ7.39-7.27(m,5H),5.37(s,1H),5.10(s,2H),3.76-3.66(m,2H),3.54(t,J＝5.1Hz,4H),3.39(d,J＝5.4Hz,2H),2.40(s,1H)；13C NMR(100MHz,CDCl3)δ156.70,136.52,128.51,128.12,72.28,70.08,66.74,61.60,40.87.
(4)1,2,3,4,6-五-O-乙酰基-α-吡喃葡萄糖苷(B1)的制备
将A1(50.0g，275mmol)与无水AcONa(20g，244mmol)加入到200mL乙酸酐中。在90℃下,混合物搅拌反应1.5小时后，趁热倒入1kg碎冰剧烈搅拌，直至出现黄色粉末状物体，过滤得土黄色固体，母液用饱和碳酸氢钠水溶液调至pH＝6，乙酸乙酯萃取两次，合并有机相并以饱和碳酸氢钠、食盐水洗涤，无水硫酸钠干燥，浓缩得产物，最后用无水乙醇重结晶得到白色固体B1，产率96.2％.1H NMR(400MHz,Chloroform-d)δ6.32(d,J＝2.9Hz,1H),5.46(t,J＝9.9Hz,1H),5.17–5.06(m,2H),4.26(dd,J＝12.6,4.1Hz,1H),4.14–4.03(m,2H),2.17(s,3H),2.08(s,3H),2.03(s,3H),2.02(s,3H),2.01(s,3H).
(5)2,3,4,6-五-O-乙酰基-α-吡喃葡萄糖(C1)的制备
将B1(33g，84.6mmol)与乙酸肼(10.9g，1.4倍当量，118.4mmol)溶于50mL无水DMF，混合物在50℃下搅拌2小时，TCL点板检测，直至反应结束，加入80ml乙酸乙酯和20ml饱和碳酸氢钠水溶液，萃取分离有机相，干燥浓缩，柱层析(乙酸乙酯:石油醚V:V＝1),最终得到黄色油状物C1，产率76％。1H NMR(400MHz,Chloroform-d)δ5.50(t,J＝9.8Hz,1H),5.42(d,J＝3.7Hz,1H),5.05(t,J＝9.7Hz,1H),4.88–4.82(m,1H),4.26-4.16(m,2H),4.08(dd,J＝6.2,1.7Hz,1H),2.06(s,3H),2.05(s,3H),2.00(s,3H),1.98(s,3H).
(6)三氯乙酰亚胺-2,3,4,6-四-O-乙酰基-α-吡喃葡萄糖苷(D1)的制备
将C1(3.4g,10.0mmoL)溶于10mL无水二氯甲烷，在0℃下加入三氯乙腈(4.33g，30mmoL)和(1,8)-二氮杂双环[5,4,0]十一碳-7-烯。反应混合物继续在0℃下反应2.5小时后，用1％盐酸猝灭，加入30mL乙酸乙酯和10mL水萃取有机层，干燥浓缩，柱层析(乙酸乙酯：石油醚V:V＝1:4)，最终得无色半固体D1(2,3,4,6-四-O-乙酰基-三氯乙酰亚胺-α-吡喃葡萄糖苷),未见纯化直接用于下步反应。
(7)化合物E1、F1、G1的制备
将D1(1mmoL)与化合物c溶于7mL无水二氯甲烷中。在-5℃下，加入三氟甲磺酸三甲基硅酯(1mmoL),持续反应2小时，TLC点板监测，直至反应完全，用少量三乙胺猝灭。加入300mL乙酸乙酯和100mL饱和食盐水萃取有机层，干燥浓缩，柱层析(乙酸乙酯：石油醚v:v＝1:1)，最终得无色透明物。
E1，62.4％：1H NMR(400MHz,Chloroform-d)δ7.39-7.28(m,5H),5.23-5.15(m,2H),5.07(d,J＝13.1Hz,3H),4.96(t,J＝8.9Hz,1H),4.47(d,J＝8.0Hz,1H),4.22(dd,J＝12.7,4.9Hz,1H),4.13(d,J＝12.1Hz,1H),3.92–3.81(m,1H),3.73–3.63(m,2H),3.45–3.29(m,1H),2.04(s,3H),2.01(s,3H),1.99(s,6H)；13C NMR(100MHz,CDCl3)δ170.67,170.24,169.49,169.41,156.36,136.44,128.53,128.18,128.14,101.05,72.64,71.88,71.25,69.54,68.26,66.76,61.83,40.89,20.70,20.60.
F1,71.6％：1H NMR(400MHz,Chloroform-d)δ7.30(ddd,J＝13.1,5.4,2.6Hz,5H),5.34(q,J＝5.3Hz,1H),5.17(td,J＝9.5,2.1Hz,1H),5.07(d,J＝2.7Hz,2H),5.03(dd,J＝9.6,2.4Hz,1H),4.55(dd,J＝7.9,1.8Hz,1H),4.21(ddd,J＝12.3,4.8,2.1Hz,1H),4.09–4.06(m,1H),3.89(ddt,J＝10.9,6.2,3.0Hz,1H),3.66(dtd,J＝14.2,4.9,2.3Hz,2H),3.56(td,J＝4.7,4.3,2.2Hz,2H),3.49(td,J＝5.2,2.2Hz,2H),3.33(tt,J＝7.6,3.7Hz,2H),2.03(d,J＝2.5Hz,3H),1.99–1.94(m,9H)；13C NMR(100MHz,CDCl3)δ170.63,170.19,169.38,156.46,136.62,128.47,128.12,128.05,100.71,72.72,71.79,71.26,70.12,69.93,68.83,68.37,66.61,61.89,40.87,20.69,20.59,20.57.
(8)化合物H1、I1、J1的制备
将化合物E1或F1或G1(0.571mmol)溶于5mL乙酸乙酯中，加入100mg10％Pd/C，室温下,通入1个标准大气压氢气。混合物在氢气条件室温搅拌1小时，TLC点板监测，直至原料消耗完。过滤，浓缩干燥，最终得无色透明油状物H1或I1或J1,定量转化，未经纯化直接用于下步反应。
(9)化合物K1、L1、M1的制备
将化合物E1或F1或G1(0.527mmol)溶于5mL无水甲醇中，加入催化量甲醇钠(0.1倍当量)。混合物室温下搅拌1小时，TLC监测，直至原料消失。加入阳离子酸性树脂DOWX50(50mg)，静止10分钟后，过滤，浓缩干燥得到粗品，后者溶于5mL甲醇溶液中，加入70mg10％Pd/C，在室温下,通入1个标准大气压氢气。混合物在氢气环境下，室温搅拌1小时，TLC点板检测，直至原料消耗完。过滤，浓缩干燥，最终分别得无色透明油状物K1或L1或M1；直接用于下步反应。
(10)杂合体T1、U1、V1的制备
将化合物H1或I1或J1(0.5mmoL)与化合物a(0.6mmoL)溶于8mL无水二氯甲烷中，在0℃下，滴加N,N-二异丙基乙胺(0.15mL)，反应升温至室温，继续搅拌3小时，TLC点板监测，直至原料消失。倒入100mL二氯甲烷与20mL饱和氯化铵溶液，合并有机层，饱和氯化钠洗涤，浓缩干燥，柱层析(乙酸乙酯:二氯甲烷V:V＝1:1)，最终得到白色固体化合物T1或U1或V1。
T1：产率66.8％。1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.24(d,J＝8.5Hz,1H),8.10(dd,J＝8.2,1.5Hz,1H),7.84(ddd,J＝8.5,6.8,1.4Hz,1H),7.68(ddd,J＝8.1,6.8,1.2Hz,1H),7.37(s,1H),5.32(s,2H),4.96(t,J＝5.5Hz,1H),4.78(dd,J＝11.7,5.2Hz,1H),4.73–4.66(m,3H),4.63–4.59(m,1H),4.27(t,J＝9.5Hz,1H),3.90(t,J＝5.5Hz,2H),3.85–3.70(m,3H),3.65(dt,J＝14.4,5.0Hz,1H),3.58(dd,J＝12.3,6.4Hz,1H),2.02(s,3H),1.90(s,3H),1.64(s,3H),1.42(s,3H),0.93(t,J＝7.3Hz,3H)；13C NMR(100MHz,DMSO-d6)δ172.95,170.45,169.66,169.46,169.12,161.15,154.11,152.79,148.57,144.62,144.29,131.95,130.71,130.62,130.60,129.76,128.90,128.56,128.05,100.06,97.30,89.20,72.13,71.07,70.82,68.20,65.27,62.33,55.55,51.12,31.45,30.29,20.89,20.68,20.42,20.00,7.91.TOF-MS,m/z:[M+Na+],Calcdfor C37H39N3O15Na+,788.2273,Found,788.2318.
U1：产率57.3％。1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.18(d,J＝8.5Hz,1H),8.13(d,J＝8.1Hz,1H),7.87(ddd,J＝8.5,6.8,1.4Hz,1H),7.81(t,J＝5.8Hz,1H),7.72(ddd,J＝8.2,6.8,1.2Hz,1H),7.03(s,1H),5.44(d,J＝2.6Hz,2H),5.30(s,2H),5.22(t,J＝9.5Hz,1H),4.87(t,J＝9.7Hz,1H),4.79–4.67(m,2H),4.15(dd,J＝12.3,5.0Hz,1H),3.98(dd,J＝12.4,2.5Hz,1H),3.90(ddd,J＝9.9,4.9,2.4Hz,1H),3.71(dd,J＝10.7,5.4Hz,1H),3.58(td,J＝7.0,3.2Hz,1H),3.53–3.47(m,1H),3.44(dd,J＝6.8,3.8Hz,1H),3.41(s,1H),3.06(q,J＝5.4Hz,2H),2.10(h,J＝7.0Hz,2H),1.98(s,3H),1.97(s,3H),1.95(s,3H),1.91(s,3H),0.89(t,J＝7.4Hz,3H)；13C NMR(100MHz,DMSO-d6)δ170.50,170.01,169.75,169.52,168.51,157.12,154.90,152.86,148.35,146.82,146.14,132.12,130.89,130.28,129.42,129.03,128.48,128.18,119.36,99.96,95.33,75.13,72.52,71.31,70.97,69.73,69.41,68.95,68.60,66.69,62.12,50.68,31.62,30.29,20.94,20.84,20.81,20.74,8.01.TOF-MS,m/z:[M+Na+],Calcd for C39H43N3O16Na+,832.2536,Found,832.2548.
V1：产率73.3％。1H NMR(400MHz,Chloroform-d)δ8.39(d,J＝10.2Hz,1H),8.22(d,J＝8.3Hz,1H),7.93(t,J＝9.5Hz,1H),7.83(d,J＝7.2Hz,1H),7.74(s,1H),7.66(d,J＝7.6Hz,1H),5.28(s,2H),5.19(t,J＝9.7Hz,1H),5.05(q,J＝13.2,11.4Hz,3H),4.95(t,J＝9.1Hz,1H),4.59(dd,J＝27.4,8.0Hz,1H),4.26(dq,J＝17.0,5.9,4.7Hz,1H),4.18–4.06(m,2H),3.92–3.47(m,13H),2.44(m,2H),2.07(s,6H),2.01(s,3H),1.98(s,3H),1.05(t,J＝7.5Hz,3H)；13C NMR(100MHz,CDCl3)δ172.28,170.75,170.32,169.49,169.42,162.10,153.85,152.26,148.89,144.74,144.41,131.14,130.68,130.09,129.78,128.43,128.15,128.11,128.06,100.80,98.17,89.16,72.83,71.75,71.27,70.64,70.26,70.14,69.05,68.41,66.59,61.95,58.91,50.20,39.94,32.11,20.78,20.68,20.63,7.67.TOF-MS,m/z:[M+Na+],Calcd for C41H47N3O17Na+,876.2798,Found,876.2806.
(11)杂合体T2、U2、V2制备
实验步骤如同操作(10)，只需分别用H2或I2或J2替代化合物H1或I1或J1。
T2:产率为72.6％，1H NMR(400MHz,Chloroform-d)δ8.42(s,1H),8.23(d,J＝8.7Hz,1H),7.95(d,J＝8.1Hz,1H),7.83(t,J＝8.0Hz,1H),7.75(s,1H),7.67(t,J＝7.7Hz,1H),5.35(q,J＝3.9Hz,3H),5.08(q,J＝7.1,6.4Hz,3H),4.63(d,J＝10.4Hz,1H),4.43(d,J＝8.0Hz,1H),4.06(dt,J＝18.1,9.3Hz,3H),3.84(ddt,J＝31.2,24.3,8.6Hz,4H),2.45(dp,J＝15.1,7.6Hz,2H),2.07(s,3H),2.04(s,3H),2.01(s,3H),1.85(s,3H),1.06(t,J＝7.4Hz,3H).13C NMR(100MHz,CDCl3)δ172.25,170.36,170.17,169.93,169.46,153.57,152.24,148.78,144.53,144.44,131.29,130.71,130.22,129.61,128.75,128.27,128.11,100.98,97.94,89.05,70.79,70.63,68.25,66.89,64.10,61.15,59.08,50.34,40.50,31.96,29.72,29.34,27.23,20.67,20.60,20.44,7.72.TOF-MS,m/z:[M+Na+],Calcd forC37H39N3O15Na+,788.2273,Found,788.2263.
U2:产率为55.3％，1H NMR(400MHz,Chloroform-d)δ8.41(s,1H),8.26(d,J＝8.6Hz,1H),7.93(d,J＝8.2Hz,1H),7.84(t,J＝7.8Hz,1H),7.79(s,1H),7.66(t,J＝7.7Hz,1H),5.34(s,1H),5.30(s,2H),5.18–4.99(m,3H),4.95(d,J＝10.4Hz,1H),4.79(d,J＝5.2Hz,1H),4.46(d,J＝8.0Hz,1H),4.11(q,J＝8.9,7.2Hz,2H),3.93–3.86(m,1H),3.80(d,J＝6.8Hz,3H),3.72(d,J＝5.2Hz,2H),3.66–3.57(m,3H),2.44(hept,J＝7.5Hz,2H),2.13(s,3H),2.04(s,6H),1.97(s,3H),1.06(t,J＝7.9Hz,3H).13C NMR(100MHz,CDCl3)δ172.27,170.43,170.32,170.19,169.54,153.78,152.26,148.84,144.70,144.37,131.28,130.94,130.76,130.18,129.74,128.47,128.17,128.13,101.25,98.16,89.23,70.87,70.58,69.92,68.98,68.79,67.05,66.70,61.23,59.03,50.22,39.97,32.08,29.71,29.33,27.22,20.76,20.72,20.69,20.62,7.67.TOF-MS,m/z:[M+Na+],Calcd for C39H43N3O16Na+,832.2536,Found,832.2531.
V2:产率为71.4％，1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝4.7Hz,1H),8.16(d,J＝8.4Hz,1H),8.06(d,J＝8.0Hz,1H),7.83(t,J＝7.7Hz,1H),7.67(t,J＝7.5Hz,1H),7.38(s,1H),5.75(s,1H),5.24(d,J＝10.9Hz,3H),5.14(dd,J＝10.4,3.5Hz,1H),4.97–4.86(m,2H),4.80(d,J＝5.5Hz,2H),4.68(d,J＝8.0Hz,1H),4.16(d,J＝6.4Hz,1H),4.03(t,J＝7.2Hz,2H),3.78–3.59(m,4H),3.59–3.39(m,7H),2.36(p,J＝7.1Hz,1H),2.11(s,3H),1.99(d,J＝5.6Hz,6H),1.91(s,3H),0.95(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.95,170.44,170.36,170.00,169.62,160.99,154.27,152.78,148.33,144.78,144.43,131.99,130.81,130.21,130.14,129.41,128.89,128.34,128.10,100.47,97.18,89.01,70.71,70.30,70.18,69.86,69.07,68.94,67.79,66.25,61.75,55.41,55.37,50.93,31.80,20.95,20.91,20.85,20.80,7.86.TOF-MS,m/z:[M+Na+],Calcd for C41H47N3O17Na+,876.2798,Found,869.2799.
(12)化合物T3、U3、V3制备
实验步骤如同操作(10)，只需分别用H3或I3或J3替代化合物H1或I1或J1。
T3:产率为78.6％,1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.17(d,J＝8.5Hz,1H),8.12(d,J＝8.2Hz,1H),8.06(t,J＝5.6Hz,1H),7.86(t,J＝7.7Hz,1H),7.71(t,J＝7.5Hz,1H),7.04(s,1H),5.44(d,J＝4.1Hz,2H),5.29(s,2H),5.15(d,J＝10.1Hz,2H),5.06(t,J＝9.7Hz,1H),4.85(s,1H),4.12(dd,J＝12.5,5.7Hz,1H),4.05–3.93(m,2H),3.58(dt,J＝10.8,5.5Hz,1H),3.46(dt,J＝10.8,6.0Hz,1H),3.24–3.07(m,2H),2.13(m,2H),2.08(s,3H),2.00(s,3H),1.93(s,3H),1.89(s,3H),0.89(t,J＝7.5Hz,3H).13C NMR(100MHz,DMSO-d6)δ170.00,169.57,169.49,168.03,156.65,154.57,152.41,147.90,146.15,145.73,131.63,130.36,129.81,128.99,128.55,128.02,127.70,119.03,96.94,94.86,74.80,68.73,68.65,67.80,66.33,65.49,61.85,50.22,30.79,20.61,20.46,20.40,7.55.TOF-MS,m/z:[M+Na+],Calcd for C37H39N3O15Na+,788.2273,Found,788.2264.
U3:产率为72.6％,1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.18(d,J＝8.5Hz,1H),8.12(dd,J＝8.3,1.4Hz,1H),7.93–7.82(m,2H),7.71(ddd,J＝8.1,6.9,1.2Hz,1H),7.04(s,1H),5.44(d,J＝2.7Hz,2H),5.29(s,2H),5.06(d,J＝7.2Hz,3H),4.81(d,J＝1.5Hz,1H),4.11(dd,J＝12.3,5.1Hz,1H),3.98(dd,J＝12.6,2.8Hz,1H),3.92–3.86(m,1H),3.70–3.63(m,1H),3.60–3.50(m,3H),3.39(t,J＝5.9Hz,2H),3.07(tt,J＝6.2,3.8Hz,2H),2.16–2.05(m,5H),2.00(s,6H),1.92(s,3H),0.89(t,J＝7.4Hz,2H).13C NMR(100MHz,DMSO-d6)δ170.49,170.09,169.94,168.49,157.12,154.90,152.86,148.35,146.86,146.14,132.09,130.85,130.27,129.41,129.02,128.47,128.16,119.32,97.06,95.31,75.13,69.44,69.28,69.10,68.21,66.91,66.68,65.80,62.37,50.68,31.11,21.05,20.96,20.89,20.87,8.01.TOF-MS,m/z:[M+Na+],Calcd forC39H43N3O16Na+,832.2536,Found,832.2561.
V3:产率为78.7％,1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.18(d,J＝8.5Hz,1H),8.13(d,J＝8.2Hz,1H),7.90–7.79(m,2H),7.71(t,J＝7.5Hz,1H),7.04(s,1H),5.44(d,J＝2.5Hz,2H),5.30(d,J＝3.0Hz,2H),5.13–5.04(m,3H),4.86(s,1H),4.12(dd,J＝12.3,5.2Hz,1H),4.02(dd,J＝12.1,2.5Hz,1H),3.97–3.91(m,1H),3.70–3.59(m,2H),3.54–3.36(m,8H),3.06(q,J＝5.7Hz,2H),2.13(m,2H),2.09(s,3H),2.00(s,3H),1.99(s,3H),1.92(s,3H),0.89(t,J＝7.5Hz,3H).13C NMR(100MHz,DMSO)δ170.50,170.11,169.94,168.50,157.12,154.88,152.86,148.36,146.85,146.13,132.09,130.86,130.27,129.43,129.01,128.47,128.16,119.34,97.07,95.33,75.10,70.06,70.02,69.51,69.36,69.12,68.18,66.95,66.69,65.81,62.37,50.68,21.05,20.97,20.87,8.00.TOF-MS,m/z:[M+Na+],Calcdfor C41H47N3O17Na+,876.2798,Found,876.2797.
(13)化合物T4、U4、V4制备
实验步骤如同操作(10)，只需分别用H4或I4或J4替代化合物H1或I1或J1。
T4:产率为81.3％。1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.20(d,J＝8.5Hz,1H),8.10(d,J＝8.2Hz,1H),7.94–7.80(m,1H),7.70(t,J＝7.5Hz,1H),7.41(s,1H),6.68(s,1H),6.54(s,1H),5.26(s,2H),5.11–5.06(m,1H),5.03(d,J＝10.1Hz,1H),5.00–4.93(m,1H),4.90(d,J＝7.4Hz,2H),4.82(t,J＝6.4Hz,2H),4.09–3.94(m,3H),3.86(d,J＝9.3Hz,3H),3.78–3.68(m,2H),2.36(dd,J＝14.7,7.5Hz,1H),2.06(s,3H),2.03–1.99(m,13H),0.97(t,J＝7.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.98,170.51,170.01,169.71,160.99,155.72,154.21,152.88,148.38,144.67,144.46,132.05,130.85,130.31,130.10,129.48,128.96,128.41,128.13,97.34,96.89,89.03,69.54,68.77,68.39,66.31,63.34,62.41,55.34,51.00,31.61,21.11,20.95,20.91,8.03；
U4:产率为76.5％，1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.18(d,J＝8.5Hz,1H),8.09(d,J＝8.2Hz,1H),7.84(ddd,J＝8.4,6.8,1.5Hz,1H),7.69(t,J＝7.5Hz,1H),7.40(s,1H),5.25(s,2H),5.10–5.04(m,2H),4.99(dd,J＝10.3,3.5Hz,1H),4.89(t,J＝5.6Hz,1H),4.85–4.74(m,3H),4.11(dd,J＝12.1,5.3Hz,1H),3.96(dd,J＝12.1,2.6Hz,1H),3.90(ddd,J＝9.8,5.3,2.5Hz,1H),3.78–3.54(m,8H),2.50(dq,J＝14.6,7.2Hz,1H),2.36(dq,J＝14.6,7.2Hz,1H),2.09(s,3H),2.02(s,3H),2.01(s,3H),0.96(t,J＝7.3Hz,3H)；13C NMR(100MHz,DMSO-d6)δ172.96,170.51,169.98,169.83,161.01,155.87,154.28,152.85,148.36,144.81,144.46,132.02,130.84,130.28,130.15,129.43,128.94,128.39,128.12,97.25,97.17,89.03,69.68,69.35,68.56,68.37,66.79,66.37,62.57,55.42,55.38,50.97,31.82,21.16,20.98,20.97,7.82.
V4:产率为68.3％，1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.19(d,J＝8.4Hz,1H),8.12–8.07(m,1H),7.85(ddd,J＝8.4,6.7,1.5Hz,1H),7.69(t,J＝7.5Hz,1H),7.39(s,1H),6.74(s,1H),6.58(s,1H),5.75(s,1H),5.26(s,2H),5.11–5.03(m,2H),4.99(dd,J＝10.2,3.5Hz,1H),4.90(t,J＝5.4Hz,1H),4.81(dd,J＝8.9,3.6Hz,2H),4.11(dd,J＝12.1,5.5Hz,1H),4.01–3.97(m,1H),3.91(ddd,J＝8.5,5.4,2.6Hz,1H),3.67(ddt,J＝28.1,9.7,4.4Hz,5H),3.50(qd,J＝9.2,8.5,3.9Hz,7H),2.50(dq,J＝14.5,7.1Hz,2H)),2.36(dq,J＝14.5,7.1Hz,2H)),2.09(s,3H),2.02-2.00(m,6H),0.95(t,J＝7.2Hz,3H)；13C NMR(100MHz,DMSO)δ172.49,170.03,169.53,169.42,160.57,155.43,153.79,152.39,147.91,144.35,144.03,131.58,130.39,129.84,129.70,128.98,128.49,127.94,127.68,96.72,88.57,69.68,69.40,69.32,69.21,68.08,67.93,66.48,65.97,65.86,62.13,54.97,54.92,50.52,31.31,20.70,20.52,20.50,7.41.TOF-MS,m/z:[M+Na+],Calcdfor C40H46N4NaO17 +,877.2750,Found,877.2759.
(14)杂合体N1、O1、P1制备
将化合物K1或L1或M1(1.0mmoL)与化合物a(1.20mmoL)溶于5.0mL无水N,N-二甲基甲酰胺中，在0℃下，滴加N,N-二异丙基乙胺(0.1mL)，升温至室温，继续反应3小时，TLC监测，直至原料消失。浓缩干燥，柱层析(甲醇:二氯甲烷V:V＝1/20)，最终得到白色固体化合物N1或O1或P1。
N1:产率为38.1％,1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.22(d,J＝8.0Hz,1H),8.12(d,J＝8.3Hz,1H),7.86(t,J＝7.8Hz,1H),7.71(t,J＝7.6Hz,1H),7.40(d,J＝1.8Hz,0.6H),7.05(d,J＝2.0Hz,0.4H),5.45(d,J＝3.5Hz,1H),5.28(d,J＝4.7Hz,2H),4.96–4.84(m,1H),4.81–4.66(m,2H),4.56(q,J＝8.2,6.1Hz,1H),4.37(dd,J＝13.7,4.2Hz,1H),4.08(dd,J＝12.9,6.1Hz,1H),3.88(t,J＝7.2Hz,1H),3.71(s,2H),3.60(t,J＝6.1Hz,3H),3.12(d,J＝7.0Hz,3H),2.36(dt,J＝13.8,6.9Hz,0.7H),2.14(dt,J＝21.1,7.1Hz,1.4H),0.95(t,J＝7.3Hz,2H),0.89(t,J＝7.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ173.00,160.97,157.10,154.97,154.28,152.93,152.83,148.37,148.33,146.68,146.19,144.58,144.40,119.40,104.18,103.83,97.69,95.34,88.95,75.72,75.69,75.23,73.90,73.66,71.05,70.80,68.52,68.35,68.00,66.78,64.18,63.54,60.79,60.65,55.36,53.80,50.99,50.67,31.76,8.06,8.01.TOF-MS,m/z:[M+Na+],Calcd forC29H31N3O11Na+,620.1851,Found,620.1855.
O1:产率为41.3％,1H NMR(400MHz,DMSO-d6)δ8.68(d,J＝3.2Hz,1H),8.20(d,J＝8.5Hz,1H),8.11(d,J＝8.2Hz,1H),7.86(t,J＝7.6Hz,1H),7.71(t,J＝7.5Hz,1H),7.40(s,1H),5.27(s,2H),4.98–4.86(m,3H),4.81(t,J＝5.2Hz,1H),4.48(t,J＝5.8Hz,1H),4.16–4.03(m,1H),3.86–3.47(m,7H),3.17(d,J＝5.2Hz,1H),3.12–2.99(m,3H),2.92(td,J＝8.1,4.9Hz,1H),2.36(dd,J＝14.7,7.4Hz,1H),0.96(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.99,161.02,154.31,152.87,148.36,144.77,144.50,132.06,130.88,130.33,130.15,129.47,128.97,128.42,128.15,103.46,97.28,89.04,77.28,77.16,77.14,73.83,70.44,69.81,68.21,66.27,61.49,55.39,51.00,49.07,31.78,7.93.
P1:产率为42.6％,1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.20(t,J＝8.7Hz,1H),8.13(d,J＝8.0Hz,1H),7.92–7.83(m,2H),7.73(d,J＝7.5Hz,0.4H),7.05(d,J＝3.0Hz,0.6H),5.45(t,J＝2.8Hz,1H),5.30(d,J＝4.8Hz,2H),5.02–4.88(m,3H),4.51(t,J＝6.1Hz,1H),4.10(dd,J＝7.8,5.5Hz,1H),3.89–3.40(m,14H),3.21–3.02(m,5H),2.93(td,J＝8.3,4.5Hz,1H),2.18–2.06(m,2H),0.98–0.85(m,3H)；13C NMR(100MHz,DMSO-d6)δ172.95,168.52,157.12,154.90,154.27,152.84,148.35,146.84,146.14,144.82,144.53,132.13,130.91,130.35,130.26,130.15,129.45,129.01,128.47,128.18,119.34,103.42,95.34,89.03,77.34,77.20,75.10,73.82,70.47,70.11,70.05,68.19,61.51,53.89,31.76,8.01.TOF-MS,m/z:[M+Na+],Calcd forC33H39N3O13Na+,708.2375,Found,708.2353.
(15)化合物N2、O2、P2的制备
实验步骤如同操作(14)，只需分别用K2或L2或M2替代化合物K1或L1或M1。
N2:产率为48.6％,1H NMR(400MHz,DMSO-d6)δ8.67(d,J＝3.2Hz,1H),8.19(dd,J＝8.6,5.2Hz,1H),8.15–8.07(m,1H),7.85(ddd,J＝8.5,6.8,1.5Hz,1H),7.75–7.66(m,1H),7.38(s,0.5H),7.04(s,0.5H),5.44(d,J＝3.0Hz,1H),5.26(d,J＝3.9Hz,2H),4.95–4.86(m,1H),4.85–4.65(m,2H),4.55(q,J＝5.9Hz,1H),4.36(dd,J＝13.1,4.5Hz,1H),4.09(td,J＝13.3,12.7,6.0Hz,2H),3.70(d,J＝3.6Hz,1H),3.59(h,J＝3.9Hz,2H),3.46(dt,J＝14.6,5.6Hz,2H),3.32–3.24(m,2H),3.16(d,J＝5.1Hz,1H),3.12(dp,J＝10.6,3.5Hz,2H),2.20–1.98(m,2H),0.92(dt,J＝19.6,7.3Hz,2H).TOF-MS,m/z:[M+Na+],Calcd forC29H31N3O11Na+,620.1851,Found,620.1866.
O2:产率为39.4％,1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),8.17(d,J＝8.5Hz,1H),8.07(d,J＝8.0Hz,1H),7.84(t,J＝7.7Hz,1H),7.67(t,J＝7.6Hz,1H),7.37(s,1H),5.23(s,2H),4.91(t,J＝5.4Hz,1H),4.79(t,J＝4.7Hz,2H),4.69(d,J＝5.5Hz,1H),4.58(t,J＝5.7Hz,1H),4.37(d,J＝4.8Hz,1H),4.13(q,J＝5.3Hz,1H),4.03(d,J＝7.2Hz,1H),3.80–3.47(m,10H),3.25(dt,J＝12.5,5.8Hz,2H),3.16(d,J＝5.0Hz,2H),3.08(dt,J＝14.1,7.8Hz,1H),2.35(dt,J＝14.6,7.3Hz,1H),0.95(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.98,161.00,154.31,152.80,148.32,144.77,144.45,132.02,130.84,130.25,130.13,129.42,128.91,128.36,128.11,104.06,97.26,89.03,75.60,73.90,70.95,69.82,68.50,68.10,66.28,60.79,55.40,53.76,50.96,49.06,31.81,7.91.TOF-MS,m/z:[M+Na+],Calcd for C31H35N3O12Na+,664.2113,Found,664.2090.
P2:产率为45.8％,1H NMR(400MHz,DMSO-d6)δ8.59(d,J＝7.6Hz,1H),8.11(d,J＝8.5Hz,1H),8.00(d,J＝8.3Hz,1H),7.81(t,J＝7.7Hz,1H),7.64(t,J＝7.5Hz,1H),7.40(s,1H),5.18(s,2H),4.99(d,J＝5.8Hz,2H),4.89(d,J＝5.6Hz,1H),4.83–4.71(m,3H),4.48(d,J＝4.7Hz,1H),3.63–3.56(m,5H),3.47(q,J＝5.2,4.7Hz,3H),3.32–3.21(m,3H),2.47–2.40(m,0H),2.37–2.26(m,1H),0.92(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.98,161.23,154.40,152.43,148.15,145.20,144.41,132.21,131.05,129.97,129.67,129.18,128.90,128.30,128.26,103.68,97.67,89.05,75.41,73.68,70.91,70.04,69.98,69.73,68.60,68.06,66.14,60.92,55.44,50.94,31.83,7.77.TOF-MS,m/z:[M+Na+],Calcd forC33H39N3O13Na+,708.2375,Found,708.2344.
(16)化合物N3、O3、P3的制备
实验步骤如同操作(14)，只需分别用K3或L3或M3替代化合物K1或L1或M1。
N3:产率为41.2％,1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.19(d,J＝8.5Hz,1H),8.09(d,J＝8.2Hz,1H),7.84(t,J＝7.7Hz,1H),7.69(t,J＝7.5Hz,1H),7.40(s,1H),5.25(s,2H),4.90(t,J＝5.4Hz,1H),4.81(d,J＝5.5Hz,2H),4.70(d,J＝4.2Hz,2H),4.63(s,1H),4.53(d,J＝4.7Hz,1H),4.41(t,J＝6.0Hz,1H),3.78(q,J＝6.7,4.8Hz,2H),3.70–3.54(m,3H),3.53–3.48(m,1H),3.21(d,J＝7.3Hz,1H),2.36(dt,J＝14.7,7.3Hz,1H),0.95(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.99,161.01,154.22,152.88,148.36,144.75,144.50,132.02,130.82,130.30,130.04,129.48,128.93,128.39,128.11,99.89,97.15,88.93,74.54,71.22,70.55,67.14,62.25,61.46,55.39,50.97,31.88,7.97.TOF-MS,m/z:[M+Na+],Calcd for C29H31N3O11Na+,620.1851,Found,620.1844.
O3:产率为46.4％,1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.18(d,J＝8.5Hz,1H),8.11(dd,J＝8.4,1.4Hz,1H),7.91–7.81(m,2H),7.75–7.64(m,1H),7.04(s,1H),5.44(d,J＝2.2Hz,2H),5.27(s,2H),4.70(dd,J＝11.3,4.8Hz,2H),4.61–4.52(m,2H),4.44(t,J＝6.0Hz,1H),3.68–3.48(m,6H),3.42(qd,J＝9.1,7.5,3.2Hz,4H),3.28(ddd,J＝9.0,6.2,2.0Hz,1H),3.09(dddd,J＝18.9,8.8,6.6,3.2Hz,2H),2.09(hept,J＝7.2Hz,2H),0.90(t,J＝7.4Hz,3H).13CNMR(100MHz,DMSO-d6)δ168.53,157.11,154.91,152.81,148.32,146.87,146.12,132.10,130.89,130.22,129.41,128.98,128.44,128.15,119.32,100.41,95.36,75.14,74.39,71.37,70.70,69.81,69.40,67.41,66.69,66.10,61.71,53.84,50.66,31.11,8.03.TOF-MS,m/z:[M+Na+],Calcdfor C31H35N3O12Na+,664.2113,Found,664.2120.
P3:产率为38.6％,1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.16(d,J＝8.5Hz,1H),8.06(d,J＝8.0Hz,1H),7.83(t,J＝7.7Hz,1H),7.67(q,J＝7.4,6.2Hz,2H),7.38(s,1H),5.22(s,2H),4.91(t,J＝5.4Hz,1H),4.79(d,J＝5.0Hz,2H),4.73(dd,J＝11.9,4.7Hz,2H),4.60(d,J＝5.5Hz,2H),4.44(t,J＝6.1Hz,1H),4.12(t,J＝4.6Hz,1H),3.78–3.41(m,15H),3.29(d,J＝7.4Hz,1H),3.09(h,J＝5.3Hz,1H),2.35(dq,J＝14.7,7.3Hz,1H),0.95(t,J＝7.3Hz,3H).13CNMR(100MHz,DMSO-d6)δ172.94,161.00,154.27,152.75,148.32,144.81,144.43,132.17,132.05,130.82,130.19,130.12,129.40,129.12,128.90,128.34,128.10,100.41,97.22,89.02,74.36,72.75,71.41,70.71,70.15,69.94,69.87,67.85,67.41,66.27,66.09,61.70,60.72,55.42,50.94,31.80,7.88.TOF-MS,m/z:[M+Na+],Calcd forC33H39N3O13Na+,708.2375,Found,708.2365.
(17)化合物N4、O4、P4的制备
实验步骤如同操作(14)，只需分别用K4或L4或M4替代化合物K1或L1或M1。
N4:产率为55.1％,1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.21(d,J＝8.5Hz,1H),8.12(d,J＝8.2Hz,1H),7.95(d,J＝5.5Hz,1H),7.87(t,J＝7.6Hz,1H),7.71(t,J＝7.5Hz,1H),7.05(s,1H),6.42(s,2H),5.45(d,J＝2.1Hz,2H),5.29(s,2H),4.68–4.55(m,2H),3.93–3.31(m,10),3.24–3.13(m,1H),3.07(dt,J＝14.2,6.5Hz,1H),2.24–2.03(m,J＝7.5,7.1Hz,2H),0.89(t,J＝7.4Hz,3H)；13C NMR(100MHz,DMSO-d6)δ168.52,157.11,154.98,152.85,148.33,146.69,146.16,132.10,130.88,130.27,129.49,128.98,128.46,119.39,100.69,95.37,75.19,74.69,74.17,68.49,66.75,65.94,64.72,61.37,50.68,31.21,8.01.TOF-MS,m/z:[M+Na+],Calcdfor C30H32N4O12Na+,663.1909,Found,663.1903.
O4:产率为42.3％,1H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.17(d,J＝8.5Hz,1H),8.10(d,J＝8.2Hz,1H),7.86(ddt,J＝8.7,6.6,3.6Hz,2H),7.69(t,J＝7.5Hz,1H),7.04(d,J＝2.4Hz,1H),6.44(s,2H),5.48–5.41(m,2H),5.26(s,2H),5.00(d,J＝5.5Hz,1H),4.87(d,J＝6.7Hz,1H),4.59(dd,J＝9.9,2.5Hz,1H),4.52(t,J＝6.0Hz,1H),3.78–3.72(m,1H),3.70–3.42(m,9H),3.09(dt,J＝12.2,5.6Hz,3H),2.09(p,J＝6.9Hz,2H),0.90(t,J＝7.4Hz,3H).13CNMR(100MHz,DMSO-d6)δ168.53,157.16,157.10,154.92,152.80,148.32,146.88,146.12,132.08,130.90,130.20,129.41,128.97,128.43,128.14,119.30,100.60,95.36,75.12,74.62,74.20,69.76,69.36,68.51,66.68,66.10,64.63,61.43,53.75,50.65,31.12,8.03.TOF-MS,m/z:[M+Na+],Calcd for C32H36N4O13Na+,707.2171,Found,707.2158.
P4:产率为68.4％,1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.21(d,J＝8.3Hz,1H),8.12(d,J＝8.4Hz,1H),7.87(dd,J＝8.4,6.7Hz,1H),7.71(t,J＝7.5Hz,1H),7.41(s,1H),6.44(s,2H),5.28(s,2H),5.00(d,J＝5.5Hz,1H),4.90(d,J＝5.4Hz,1H),4.87–4.84(m,1H),4.81(d,J＝6.1Hz,2H),4.62–4.57(m,2H),4.50(q,J＝6.3Hz,1H),3.76–3.40(m,13H),2.50(dt,J＝14.7,7.2Hz,1H),2.37(dt,J＝14.7,7.2Hz,1H),0.96(t,J＝7.2Hz,3H).13CNMR(100MHz,DMSO-d6)δ172.95,161.04,157.15,154.26,152.88,148.38,144.83,144.51,132.09,130.89,130.34,130.15,129.46,128.98,128.42,128.17,100.58,97.22,89.03,74.60,74.22,70.09,69.88,69.83,68.52,66.27,66.09,64.67,61.46,55.42,51.01,49.07,46.12,31.77,7.89.TOF-MS,m/z:[M+Na+],Calcd for C33H40N4NaO14 +,751.2433,Found,751.2422.
(18)杂合体X2制备
将化合物I2(0.5mmoL)与化合物b(0.6mmoL)溶于5ml无水二氯甲烷中，在0℃条件下滴加三乙胺(0.15mL)，升温至室温，继续反应3小时，TLC点板检测，直至原料消失。倒入100mL二氯甲烷与20mL饱和氯化铵溶液，萃取有机层，饱和氯化钠洗涤，浓缩干燥，柱层析(乙酸乙酯:二氯甲烷V:V＝2:1)，最终得到白色固体化合物X2。
X2:产率78.4％。1H NMR(400MHz,Chloroform-d)δ8.28(s,1H),8.18(d,J＝9.2Hz,1H),7.69(d,J＝2.5Hz,1H),7.64(s,1H),7.60(dd,J＝9.2,2.5Hz,1H),5.97(t,J＝5.7Hz,1H),5.71(d,J＝16.4Hz,1H),5.43–5.36(m,1H),5.33–5.18(m,3H),5.05(dd,J＝10.5,3.4Hz,1H),4.81(s,1H),4.57(d,J＝7.9Hz,1H),4.21(dd,J＝11.2,6.4Hz,1H),4.13(dd,J＝11.2,6.9Hz,1H),4.02(ddd,J＝10.7,4.7,3.1Hz,1H),3.94(t,J＝6.7Hz,1H),3.76(ddd,J＝10.4,6.0,3.8Hz,1H),3.71–3.62(m,3H),3.50(dq,J＝9.8,5.0,4.6Hz,1H),2.10(s,2H),2.09(s,2H),2.04(s,2H),1.97(s,2H),1.89(dt,J＝16.6,7.2Hz,1H),1.02(t,J＝7.4Hz,3H)；13C NMR(100MHz,CDCl3)δ173.86,170.48,170.24,170.18,169.77,157.60,154.28,152.01,150.17,150.10,146.50,146.18,130.90,130.67,129.00,128.52,126.22,118.72,118.37,101.41,98.12,72.80,70.80,70.00,69.87,69.07,68.95,67.00,66.31,61.27,50.05,41.17,31.64,20.88,20.71,20.63,20.60,7.84.
(19)化合物Z2制备
将化合物L2(1mmoL)与化合物b(1.2mmoL)溶于5mL无水N,N-二甲基甲酰胺中，在0℃下,滴加0.1mL N,N-二异丙基乙胺，升温至室温，继续反应3小时，TLC点板监测，直至原料消失。浓缩干燥，柱层析(甲醇:二氯甲烷V:V＝1:20)，最终得到白色固体化合物Z2。
Z2：产率38.7％，1H NMR(400MHz,Methanol-d4)δ8.29(s,1H),7.87(d,J＝9.2Hz,1H),7.55(d,J＝2.7Hz,1H),7.46–7.42(m,1H),7.41(s,1H),5.47(d,J＝16.2Hz,1H),5.28(d,J＝16.2Hz,1H),5.00(d,J＝4.1Hz,2H),4.30(d,J＝7.6Hz,1H),4.10–3.98(m,1H),3.82(d,J＝3.2Hz,1H),3.74(dddd,J＝16.7,11.2,7.4,3.5Hz,5H),3.64(t,J＝5.3Hz,2H),3.59–3.45(m,3H),3.39(t,J＝5.4Hz,2H),3.27(p,J＝1.7Hz,2H),1.89(dt,J＝8.5,6.7Hz,2H),0.96(t,J＝7.3Hz,3H)；13C NMR(101MHz,MeOD)δ174.78,158.97,156.48,152.89,152.45,151.47,146.94,146.89,132.49,130.96,130.91,129.96,127.37,120.35,119.64,105.08,99.45,76.71,74.91,74.15,72.54,71.28,70.67,70.29,69.79,66.69,62.53,51.34,41.93,32.13,8.15.
(20)化合物BLMD-1的制备
将博来霉素二糖(5g,7.4mmoL)与无水AcONa(665mg，8.1mmoL)加入到20mL乙酸酐中。在90℃下，混合物搅拌反应1.5小时后，TLC点板监测，直至反应完全，浓缩干燥，柱层析(石油醚:乙酸乙酯V:V＝1:1)，最终得白色固体BLMD-1,产率95.4％。1H NMR(400MHz,Chloroform-d)δ5.37(t,J＝3.6Hz,1H),5.30(dd,J＝3.3,1.8Hz,1H),5.25(d,J＝1.8Hz,1H),5.22(d,J＝10.2Hz,1H),5.05(d,J＝8.1Hz,1H),4.99(dd,J＝10.6,3.5Hz,2H),4.96(s,2H),4.93(dd,J＝3.7,1.3Hz,1H),4.28-4.21(m,1H),4.21-4.18(m,1H),4.14(dd,J＝11.3,5.8Hz,1H),4.11-4.04(m,3H),3.78(dd,J＝8.1,3.6Hz,1H),2.18(s,3H),2.12(s,3H),2.12(s,3H),2.07(s,6H),2.04(s,3H).13C NMR(100MHz,Chloroform-d)δ170.72,170.67,170.25,169.53,155.71,98.23,94.36,73.14,70.35,69.93,69.63,69.37,68.78,68.19,65.71,62.61,62.00,20.92,20.87,20.77,20.74,20.69；TOF-MS,m/z:[M+Na+],Calcd for C25H35NaO18 +660.1746,Found:660.1726.
(21)化合物BLMD-2的制备
将化合物BLMD-1(6g，9.3mmoL)溶入在40mL无水四氢呋喃中，并加入分子筛，温度降至-78℃下，往溶液中加入8.8mL浓度为1.6M正丁基锂的己烷溶液(14.0mmoL),搅拌10min后，加入3.9mL氯磷酸二苯酯(18.8mmoL),再继续搅拌40分钟。将所得混合物倒入200mL乙酸乙酯和100mL饱和氯化铵溶液的混合物中。将有机层用100Ml饱和食盐水洗涤，经无水硫酸钠干燥、过滤，然后在减压条件下浓缩，得到粗品，经硅胶色谱柱，用石油醚和乙酸乙酯混合物(V/V＝1/1)为流动相，进一步纯化得到6.2g化合物BLMD-2，白色固体，收率72.1％；TLC Rf＝0.26(PE:EA＝1:2,V/V)；1H NMR(400MHz,Chloroform-d)δ7.31(m,4H),7.19(m,6H),5.74-5.62(m,1H),5.42(d,J＝3.7Hz,1H),5.28(s,1H),5.25-5.19(m,1H),5.13(s,1H),5.04(d,J＝9.9Hz,1H),4.98(d,J＝3.7Hz,1H),4.69(s,2H),4.29(m,2H),4.15-4.02(m,4H),4.01-3.95(m,1H),2.22(s,3H),2.15(s,3H),2.08(s,6H),2.01(s,3H),1.98(s,3H).13C NMR(100MHz,Chloroform-d)δ169.58,169.40,169.17,168.44,168.27,168.20,128.83,128.65,124.57,124.53,119.26,119.21,119.04,118.99,97.63,96.38,96.32,70.91,70.81,70.49,68.69,68.55,68.23,67.69,66.55,64.88,61.60,60.15,19.82,19.71,19.63；TOF-MS,m/z:[M+Na+],Calcd for C37H44NNaO21P+,892.2036,Found,892.1998.
(22)化合物BLMD-3、BLMD-4、BLMD-5的制备
向含有1.0g化合物BLMD-2(1.1mmol)和分子筛，混合在30mL无水二氯甲烷的搅拌溶液中加入257mg(1.3mmol)的化合物c或d。将反应混合物在0℃下搅拌30分钟，然后加入活化剂三氟甲磺酸三甲基硅酯(0.2mL,1.1mmol)。在相同温度下，将反应混合物继续搅拌1小时后，用足量的三乙胺淬灭。反应液中用40mL乙酸乙酯萃取，有机层依次用水(30mL)和饱和盐水(15mL)洗涤，用无水硫酸钠干燥。减压浓缩滤液，得到残余物，将其通过硅胶快速柱色谱法纯化，用石油醚和乙酸乙酯(V:V＝1:1)的混合物洗脱，分别得到化合物BLMD-3或BLMD-4。
BLMD-3：白色泡沫状物，产率75.3％。1H NMR(400MHz,Chloroform-d)δ7.38-7.27(m,5H),5.77(d,J＝6.1Hz,1H),5.36(t,J＝3.6Hz,1H),5.28(d,J＝9.6Hz,1H),5.23(m,1H),5.19(t,J＝4.2Hz,1H),5.15(d,J＝3.1Hz,1H),5.09–5.06(m,1H),5.03(dd,J＝10.3,2.6Hz,1H),4.93(dd,J＝7.0,3.9Hz,1H),4.67(s,2H),4.42(td,J＝6.3,2.5Hz,1H),4.27(ddd,J＝17.6,12.2,4.9Hz,1H),4.10(dddd,J＝18.2,11.5,6.9,2.5Hz,5H),3.95(ddd,J＝9.9,6.0,3.1Hz,1H),3.83(ddd,J＝16.1,7.3,3.2Hz,1H),3.70(tt,J＝7.5,3.0Hz,1H),3.58(ddd,J＝10.0,6.7,3.1Hz,1H),3.51–3.33(m,2H),2.19(s,3H),2.13(s,3H),2.10(s,3H),2.07(s,6H),2.03(s,3H).13C NMR(100MHz,CDCl3)δ170.58,170.50,170.20,170.02,169.95,169.68,169.44,156.60,155.14,136.77,128.47,128.45,128.06,127.90,100.77,97.83,96.73,96.02,72.18,70.91,70.53,70.38,70.25,69.55,69.35,69.21,68.68,68.17,67.66,66.48,65.92,65.71,62.61,62.32,62.04,61.68,60.41,41.00,29.70,20.85,20.82,20.74,20.72,20.72,20.67.
BLMD-4：白色泡沫状物，产率67.3％。1H NMR(400MHz,Chloroform-d)δ7.34-7.30(m,5H),5.52-5.49(m,1H),5.36-5.34(t,J＝4.0Hz,1H),5.27-5.25(m,2H),5.36-5.34(d,J＝8.0Hz,1H),5.12-5.04(m,2H),5.02-4.89(m,3H),4.80(m,1H),4.78-4.70(brs,2H),4.26-4.22(m,1H),4.15-4.02(m,5H),3.98-3.90(m,1H),3.85-3.79(m,1H),3.78-3.70(m,1H),3.69-3.45(m,5H),3.40-3.31(m,2H),2.16(s,3H),2.09(s,6H),2.06(s,3H),2.05(s,3H),2.04(s,3H)；13C NMR(100MHz,Chloroform-d)δ170.60,170.49,170.18,170.04,169.47,169.42,156.55,155.31,136.66,128.51,128.16,128.10,100.84,98.13,71.92,70.25,70.19,70.02,69.71,69.68,69.31,68.92,68.71,68.09,67.6,66.62,65.82,62.64,62.01,61.69,40.83,20.86,20.75,20.71,20.68,20.66；TOF-MS,m/z:[M+Na+],Calcd forC37H50N2Na O21 +,881.2798,Found,881.2843.
(23)化合物BLMD-6、BLMD-7、BLMD-8的制备
将1mmoL的BLMD-3或BLMD-4或BLMD-5溶于5mL的乙酸乙酯溶液中，加入50mg10％Pd/C，在一个大气压的氢气气氛下,搅拌2小时后，过滤除去钯碳，真空干燥分别得化合物BLMD-6或BLMD-7或BLMD-8，直接用于下一步反应。
(24)化合物BLMD-9、BLMD-10、BLMD-11的制备
将化合物BLMD-6或BLMD-7或BLMD-8(0.37mmoL)溶于5mL无水甲醇溶液中,然后加入15mg的甲醇钠,室温下将混合物搅拌反应1.5小时后，加入适量的酸性阳离子交换树脂DOWX50，反应继续搅拌10min，过滤，真空浓缩分别得化合物BLMD-9或BLMD-10或BLMD-11，直接用于下一步反应。
(25)杂合体BLMD-12、BLMD-13、BLMD-14制备
将0.25mmol的化合物BLMD-6或BLMD-7或BLMD-8与喜树碱活化物a混溶于5.0mL无水二氯甲烷溶液中，低温条件下缓慢加入N,N-二异丙基乙二胺(0.1mL),温度升至室温，反应继续4小时后，加入0.1％盐酸淬灭，依次用100mL的二氯甲烷和30mL水、20mL饱和食盐水洗涤，合并有机层，经无水硫酸钠干燥，浓缩后，硅胶柱层析纯化(乙酸乙酯/二氯甲烷(V/V)＝2/1)分别得到黄白色固体化合物BLMD-12或BLMD-13或BLMD-14。
BLMD-12：产率为80.4％，1H NMR(400MHz,DMSO-d6)δ8.70(s,1H),8.17(d,J＝8.8Hz,1H),7.91-7.81(m,1H),7.77-7.66(m,2H),7.06(s,1H),6.67(s,1H),6.54(s,1H),5.44(t,J＝3.5Hz,2H),5.30(s,2H),5.12-5.01(m,4H),4.96(dd,J＝10.3,3.4Hz,1H),4.89(tt,J＝9.1,5.1Hz,1H),4.29(t,J＝6.5Hz,1H),4.15-3.86(m,6H),3.74-3.58(m,1H),3.42(dd,J＝16.7,6.8Hz,1H)，3.22(dq,J＝15.6,8.9,7.9Hz,1H),3.08(q,J＝7.3Hz,3H),2.15-1.97(m,18H),0.88(t,J＝7.3,3H).13C NMR(100MHz,DMSO-d6)δ170.46,170.09,170.03,169.91,169.71,168.46,164.42,157.10,155.80,154.88,152.85,148.38,146.64,146.17,140.06,132.11,130.88,130.22,129.44,129.00,128.49,128.17,126.01,123.19,119.42,96.29,95.85,95.25,75.18,75.11,69.63,68.97,68.22,67.00,66.80,66.34,63.27,62.60,62.37,60.23,50.64,46.03,31.62,31.29,30.29,29.49,29.29,29.17,22.56,21.23,21.10,21.02,20.99,20.89,20.73,14.55,14.42,9.01,7.96.TOF-MS,m/z:[M+Na+],Calcd for C48H54N4O23Na+,1077.3071,Found,1077.3067.
BLMD-13：产率为72.6％，1H NMR(400MHz,DMSO-d6)δ8.67(s,1H),8.19(d,J＝8.4Hz,1H),8.11(d,J＝8.1Hz,1H),7.85(t,J＝7.7Hz,1H),7.70(t,J＝7.5Hz,1H),6.71(s,1H),6.55(s,1H),5.26(s,2H),5.18-5.00(m,4H),4.97-4.87(m,3H),4.81(dt,J＝6.2,3.2Hz,2H),4.17-3.91(m,7H),3.85-3.49(m,9H),3.05(q,J＝6.8,1H)，2.35(ddt,J＝15.7,8.3,4.2Hz,1H),2.18-1.95(m,18H),0.96(tt,J＝7.4,3.5Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.98,172.94,170.48,170.14,170.06,170.01,169.95,169.85,169.79,169.74,161.03,155.86,155.79,154.28,154.27,152.88,148.37,144.82,144.78,144.53,144.48,132.05,130.85,130.32,130.17,129.44,128.97,128.41,128.14,100.61,97.40,97.28,97.18,95.82,95.56,89.00,71.04,70.28,69.77,69.66,69.39,69.09,68.78,68.62,68.26,68.11,66.67,66.28,66.19,63.26,62.77,62.65,62.28,62.19,,55.42,50.99,46.13,31.84,31.76,21.13,21.07,21.05,20.99,20.91,20.89,7.85.TOF-MS,m/z:[M+Na+],Calcd for C50H58N4O24Na+,1121.3333,Found,1121.3314.
BLMD-14：产率为76.3％，1H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.20(d,J＝8.3Hz,1H),8.13(d,J＝8.1Hz,1H),7.89-7.84(m,1H),7.71(t,J＝7.5Hz,1H),7.41(s,1H),6.66(s,1H),6.55(s,1H),5.44(s,1H),5.29(d,J＝4.1Hz,3H),5.17-5.03(m,4H),4.92(ddd,J＝21.0,12.0,3.5Hz,3H),4.80(dd,J＝7.4,4.5Hz,2H),4.30(d,J＝6.6Hz,1H),4.16-4.06(m,2H),3.99(dd,J＝10.3,2.3Hz,1H),3.78–3.57(m,3H),3.55–3.40(m,5H),3.07(dt,J＝9.6,4.8Hz,4H),2.35(dd,J＝14.7,7.3Hz,1H),2.16–1.99(m,18H),0.95(t,J＝7.2Hz,3H).13C NMR(100MHz,DMSO-d6)δ172.94,170.82,170.48,170.05,169.94,169.77,168.50,161.05,155.84,155.76,154.25,152.91,148.40,144.81,144.53,132.09,130.88,130.36,130.17,129.48,129.01,128.44,128.17,97.23,95.75,95.56,89.02,70.31,70.08,69.90,69.79,69.64,69.38,68.86,68.62,68.23,68.11,67.86,66.32,66.21,60.23,55.42,51.01,45.99,31.78,21.24,21.10,21.07,21.03,20.99,20.97,20.89,9.00,7.86.TOF-MS,m/z:[M+Na+],Calcd for C52H62N4O25Na+,1165.3595,Found,1165.3603.
(26)杂合体BLMD-18、BLMD-19、BLMD-20的制备
将0.3mmoL的化合物BLMD-9或BLMD-10或BLMD-11与喜树碱活化物a混溶于5.0mL无水DMSO溶液中，低温下,缓慢加入N,N-二异丙基乙二胺(0.1mL),室温下继续反应4小时后，加入0.1％盐酸淬灭，依次用100mL的二氯甲烷和30mL水、20mL饱和食盐水洗涤，合并有机层，经无水硫酸钠干燥，浓缩后，硅胶柱层析纯化(乙酸乙酯/二氯甲烷(V/V)＝2/1)分别得到黄白色固体化合物BLMD-18或BLMD-19或BLMD-20。
BLMD-19，产率分别为38.2％,1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.18(d,J＝8.5Hz,1H),8.08(d,J＝8.1Hz,1H),7.84(t,J＝7.7Hz,1H),7.68(t,J＝7.5Hz,1H),7.39(s,1H),6.44(s,2H),5.24(s,2H),5.04(d,J＝5.7Hz,1H),4.93(dt,J＝14.6,4.0Hz,2H),4.83–4.77(m,7H),4.69(dd,J＝9.6,3.3Hz,1H),4.60(q,J＝8.0,7.0Hz,1H),4.54–4.47(m,1H),4.19–4.11(m,1H),3.94–3.46(m,10H),3.16(s,2H),2.36(dt,J＝14.7,7.2Hz,1H),0.94(t,J＝7.3Hz,3H).13C NMR(101MHz,DMSO)δ172.99,161.01,157.16,154.33,152.83,148.32,144.84,144.47,132.05,130.87,130.29,130.11,129.43,128.94,128.38,128.14,99.79,97.30,97.24,89.01,88.98,74.58,74.14,71.33,70.33,69.80,69.52,68.75,67.71,67.23,67.16,66.48,64.58,61.17,60.89,60.68,55.36,51.00,49.07,31.80,31.76,31.61,30.27,29.50,27.01,22.58,20.45,14.44,7.89.TOF-MS,m/z:[M+Na+],Calcd forC38H46N4O18Na+,869.2699,Found,869.2647.
(27)化合物BLMD-15、BLMD-16、BLMD-17制备
将(0.233mmol)化合物BLMD-6或BLMD-7或BLMD-8与化合物b混溶于8mL的无水二氯甲烷溶液中，在低温条件下将三乙胺(0.10mL)加入到反应混合物中，并在室温下搅拌4小时，并通过TLC分析消耗完原料。将反应混合物用100mL的二氯甲烷和30mL饱和氯化铵溶液稀释。有机相依次用20mL水和20mL盐水洗涤，干燥(无水硫酸钠)过滤，然后在减压条件下除去二氯甲烷，得到黄色粗产物，快速通过硅胶柱层析纯化，得到化合物BLMD-15或BLMD-16或BLMD-17。黄色固体，产率分别为81.2％、76％、72％。
BLMD-16：1H NMR(400MHz,Chloroform-d)δ8.33(s,1H),8.20(d,J＝8.0Hz,1H),7.73(s,1H),7.66(s,1H),7.62(d,J＝8.0Hz,1H),6.09(t,J＝8.0Hz,1H),5.74(d,J＝16.0Hz,1H),5.40(t,J＝4.0Hz,1H),5.36-5.23(m,5H),5.09-5.02(m,1H),4.95(d,J＝4.0Hz,1H),4.84(d,J＝12.0Hz,1H),4.75(s,2H),4.27(m,1H),4.17-3.97(m,6H),3.97-3.87(m,2H),3.77-3.60(m,5H),3.54-3.45(m,2H),2.21(s,3H),2.16(s,3H),2.10(s,3H),2.08(s,9H),1.91(m,J＝2H),1.04(t,J＝8.0Hz,3H).TOF-MS,m/z:[M+H+],Calcd forC50H59N4O25 +,1115.3458,Found,1115.3377.
(28)杂合体BLMD-21、BLMD-22、BLMD-23制备
将0.21mmoL化合物BLMD-9或BLMD-10或BLMD-11与10羟基喜树碱化合物b混溶于10Ml无水二甲基亚砜中，搅拌，加入三乙胺(0.10mL)。室温下，混合物搅拌24小时，TLC监测，直至原料消耗完全。在减压下除去溶剂DMSO，得到黄色粗产物，将其通过硅胶柱层析纯化，得到化合物BLMD-21或BLMD-22或BLMD-11，为黄色固体。
BLMD-22：产率31.0％，1H NMR(400MHz,Dimethyl sulfoxide-d6)δ8.64-8.40(m,1H),8.17(d,J＝8.0Hz,1H),8.80-7.96(m,1H),7.87(s,1H),7.65(d,J＝8.0Hz,1H),7.33(s,1H),7.25(s,1H),6.54(s,1H),5.42(s,1H),5.26(d,J＝20.0Hz,2H),4.98-4.36(m,10H),4.01-3.11(m,20H),1.92(m,J＝2H),0.98(m,3H).13C NMR(100MHz,Dimethylsulfoxide-d6)δ173.04,157.28,154.69,152.58,150.56,150.12,149.81,146.36,145.89,143.65,131.53,131.06,130.66,130.32,129.71,128.75,126.78,123.52,119.17,109.26,97.14,74.63,74.19,73.86,72.86,71.54,70.08,69.40,68.47,67.34,66.98,65.71,64.72,60.82,49.07,41.00,30.75,8.25.TOF-MS,m/z:[M+Na+],Calcd for C38H46N4O19Na+,885.2654,Found,885.2608。
(29)杂合体BLMD-22、O4、O3的稳定性
通过体外细胞增殖抑制实验选择一些活性相对好的目标化合物。参照文献[99-102]，在稳定性实验中，考察了其在缓冲液(pH＝7.4)的稳定性，主要利用HPLC检测其羧酸盐形式与内酯环形式的比例来判断化合物的稳定性，分别在0min，15min，30min，1h，2h，3h，4h，8h，16h，24h取样分析。稳定性实验的前期工作，应设定好色谱条件与方法，并为目标化合物的测定建立一条标准曲线，通过HPLC分析出来的峰面积计算其浓度，此外配置新鲜的缓冲液等等。喜树碱在缓冲液培养中，在50min内已经降解成90％的羧酸盐形式，保留时间为1.924min；化合物BLMD-22、O4、O3在测定时间都没有降解成羧酸盐形式，因此将间隔时间延长到48h和72h。由于化合物BLMD-22、O4、O3都存在异构体形式，因此液相分析图谱中会出现α与β两种构型的峰。但是仍然发现在72小时，化合物BLMD-22、O4、O3都没有降解成喜树碱或其羧酸盐形式，因此可以表明在喜树碱的20位经酰胺酯键连接上糖基，可以提高其稳定性。
(30)杂合体BLMD-22、O4、O3的溶解度
化合物的溶解度大小会直接影响药物在体内的抗肿瘤效果。除了考察目标化合物的稳定性之外，我们将进一步对稳定性较好的目标化合物进行溶解度检测，参考相关喜树碱糖类衍生物文献,将待测物过饱和溶解在pH＝7.4的磷酸缓冲溶液中，分别通过HPLC测其溶解度大小。将化合物BLMD-22称量1mg稀释到0.1mg/mL、0.2mg/mL、0.5mg/mL、1mg/mL，进样10μL分别测定其峰面积，得到相应的标准曲线方程。化合物O4和O3以相同的方法测得其标准曲线，然后将待测物过饱和溶于pH＝7.4的缓冲溶液中，超声处理，置于室温25℃放置24小时，经离心，稀释合适浓度，进样10μL，测得其最强吸收波长(254nm)下的峰面积,从而代入相应的标准曲线方程，算得其溶解度分别为20.2mg/mL、17.0mg/mL、17.4mg/mL。
(31)杂合体体外靶向抗肿瘤活性
采用MTT法对目标化合物进行体外细胞毒性测试。检测的原理是MTT能与活细胞产生琥珀酸脱氢酶反应生成一种不溶性的蓝紫色甲臜。加入二甲基亚砜使甲臜溶解成蓝紫色溶液后，利用酶标仪在设定好的波长下测其吸光值，吸光值大小与活细胞数量成正比。在实验进行前，我们对四种细胞株胰腺癌SW-1990、正常肾细胞HEK 293、肝癌细胞HEPG 2、结肠癌细胞HCT 116的贴壁生长情况进行观察，防止细胞过多影响敏感性，细胞过少影响观察。然后在目标化合物的浓度设定时，我们参考大量有关喜树碱糖类衍生物细胞毒性实验的文献，设定了较大范围的初筛浓度(0.02μM，0.2μM，1μM，5μM，12.5μM，25μM)。而时间点设定在细胞增殖抑制最明显的时间，综合之前研究的文献数据，我们选择了给药后72小时测其活细胞数抑制情况，结果如表1。
表1：简单糖-喜树碱杂合体对胰腺癌SW 1990、肝癌HEPG 2、结肠癌HCT 116和正常肾细胞HEK 293
由表1可知，相对于喜树碱而言，简单糖-喜树碱杂合体对正常细胞和肿瘤细胞表现出选择性，但又不像前药拓扑替康完全无细胞毒，与连接器长度有关，当n＝1时，连接有利于区分正常细胞与肿瘤细胞，n＝0时,连接反而不利于对肿瘤细胞选择性杀伤，n＝2时，可能链太长，与喜树碱一样，无选择性，而且所测试简单糖-喜树碱杂合体对肿瘤细胞敏感性不同，肝癌HPG2最敏感，其次结肠癌HCT116，最不敏感是胰腺癌SW1990。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (9)

1.一种喜树碱糖类衍生物，其特征在于，所述喜树碱糖类衍生物的结构式如下述式(I)所示：
所述R1选自
H、OH、中的任意一种；
所述R2选自：
H、中的任意一种；
所述R2为H时，所述R1不能为H和OH；
其中，n＝0，1,2；R3为全乙酰化半乳糖、全乙酰化葡萄糖、全乙酰化甘露糖、全乙酰化的3-O-氨基甲酰甘露糖或全乙酰化博来霉素二糖；R4为半乳糖、葡萄糖、甘露糖、3-O-氨基甲酰甘露糖或BLM二糖。
2.如权利要求1所述喜树碱糖类衍生物的制备方法，其特征在于，包括以下步骤：
(1)在有机溶剂A中，喜树碱或10-羟基喜树碱与对硝基苯基氯甲酸酯在催化剂A作用下进行酯化反应，得到如下式a所示化合物和式b所示化合物；
(2)在碱性条件下，将不同聚合度的乙二醇胺和氯甲酸苄酯溶于无水四氢呋喃中，反应得到如下式c所示化合物；
(3)在无水醋酸钠的作用下，将不同单糖或寡糖与醋酸酐反应得到全乙酰化糖苷，将全乙酰化糖苷溶于有机溶剂B，在催化剂B存在的条件下，进行脱端基乙酰基；
(4)将步骤(3)脱端基乙酰基所得化合物和三氯乙腈溶于无水二氯甲烷，在碱性条件下，催化反应得到三氯乙酰亚胺活化的酰基糖酯；
(5)将三氯乙酰亚胺活化的酰基糖酯与式c所示化合物溶于无水二氯甲烷，在偶合剂催化下成醚得到如下式d所示化合物；
(6)将式d所示化合物溶于有机溶剂C中，室温下在钯催化剂催化下脱苄后，在碱作用下，与式a所示化合物进行反应得具以下通式e的喜树碱糖类衍生物；或者将脱苄后所得产物与式b所示化合物溶于有机溶剂D中，在碱催化条件下得到具以下通式h的喜树碱糖类衍生物；
或者将式d所示化合物溶于有机溶剂E中，在甲醇钠作用下，脱去全部乙酰基，然后用阳离子树脂中和置换钠离子，接着用钯催化剂催化下脱苄制备得式f所示化合物；将式f所示化合物与式a所示化合物溶于有机溶剂F中，室温下在碱催化条件下得到具有以下通式g的喜树碱糖类衍生物或将式f所示化合物与式b所示化合物溶于有机溶剂G中，在碱催化条件下成酰胺得到具有以下通式j的喜树碱糖类衍生物；
其中，n＝0，1，2；R3为全乙酰化半乳糖、全乙酰化葡萄糖、全乙酰化甘露糖、全乙酰化的3-O-氨基甲酰甘露糖或全乙酰化BLM二糖；R4为半乳糖、葡萄糖、甘露糖、3-O-氨基甲酰甘露糖或BLM二糖。
3.如权利要求2所述的喜树碱糖类衍生物的制备方法，其特征在于，所述步骤(1)中，有机溶剂A为二氯甲烷或四氢呋喃；所述催化剂A选自三乙胺、4-二甲氨基吡啶、吡啶或碳酸钾；所述酯化反应的温度为0-40℃。
4.如权利要求2所述的喜树碱糖类衍生物的制备方法，其特征在于，所述步骤(2)中，碱性条件采用的碱是三乙胺、N,N-二异丙基乙胺或吡啶，反应的温度为20℃-45℃，反应的时间为1-3小时。
5.如权利要求2所述的喜树碱糖类衍生物的制备方法，其特征在于，所述步骤(3)中，单糖或寡糖与醋酸酐的摩尔比为1：(6-12)，反应的温度为80-120℃；所述有机溶剂B是N,N-二甲基甲酰胺、甲苯或二甲基亚砜；所述催化剂B选自乙酸肼、苄胺或氨水。
6.如权利要求2所述的喜树碱糖类衍生物的制备方法，其特征在于，所述步骤(4)中，碱性条件采用的碱选自1,8-二氮杂二环十一碳-7-烯；所述脱端基乙酰基所得化合物、三氯乙腈和1,8-二氮杂二环十一碳-7-烯的摩尔比为脱端基乙酰基所得化合物：三氯乙腈：1,8-二氮杂二环十一碳-7-烯＝1：(1.5-5)：(0.1-0.5)；催化反应的温度为-5-0℃。
7.如权利要求2所述的喜树碱糖类衍生物的制备方法，其特征在于，所述步骤(5)中，耦合剂选自三氟化硼乙醚、三氟甲磺酸三甲基硅酯或三氟甲磺酸盐；所述偶合剂与三氯乙酰亚胺活化的酰基糖酯的摩尔比为(1.0-2.5):1；所述成醚反应温度为-5-0℃。
8.如权利要求2所述的喜树碱糖类衍生物的制备方法，其特征在于，所述步骤(6)中，有机溶剂C、有机溶剂D、有机溶剂F和有机溶剂G各自独立地选自乙酸乙酯、甲醇、二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺或二甲基亚砜，所述有机溶剂E为甲醇；所述钯催化剂选自钯碳、氢氧化钯、氧化钯或鈀黑；所述碱催化中的碱为N，N-二异丙基乙胺、4-二甲氨基吡啶、三乙胺或吡啶；所述式d所示化合物或式f所示化合物与式a所示化合物反应时，反应温度为20-45℃，碱催化中的碱与式a所示化合物的摩尔比为(0.5-2):1；所述式d所示化合物或式f所示化合物与式b所示化合物反应时，反应的温度为20-45℃，碱催化中的碱与式b所示化合物的摩尔比为(0.5-2):1；所述阳离子树脂为Dowx50或Amberlite IR-120。
9.一种用于治疗肿瘤的药物，其特征在于，包含权利要求1所述喜树碱糖类衍生物。
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