CN116731031A - 芬氏唐松草碱衍生物及其应用 - Google Patents
芬氏唐松草碱衍生物及其应用 Download PDFInfo
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- CN116731031A CN116731031A CN202310719633.7A CN202310719633A CN116731031A CN 116731031 A CN116731031 A CN 116731031A CN 202310719633 A CN202310719633 A CN 202310719633A CN 116731031 A CN116731031 A CN 116731031A
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Abstract
本发明公开了一种芬氏唐松草碱衍生物或其药用盐，结构选自以下结构的一种：
Description
技术领域
本发明属于药物化学技术领域，具体地说，涉及芬氏唐松草碱衍生物及其应用。
背景技术
耐药性是导致肿瘤化疗临床失败的主要因素之一。近年研究发现，芬氏唐松草碱是一种天然的AMPK激活剂，具有进一步开发为抗肿瘤或抗肿瘤多药耐药药物的巨大潜力。（Oncotarget. 2017 May 2;8(18):30077-30091）
芬氏唐松草碱是一种双苄基异喹啉生物碱，分离自唐松草属植物中，具有抗癌作用。芬氏唐松草碱区别于其它双苄基异喹啉生物碱的结构特征是，其分子结构中具有C-5位取代的酚羟基（式1），其它此类生物碱，如汉防己甲素和防己诺林碱，其C-5位为不具有取代基，为H原子。
双苄基异喹啉生物碱药理活性广泛，且活性高，具有很高的药用价值。关于芬氏唐松草碱衍生物的研究具有重要价值。经过文献检索，目前尚未发现关于芬氏唐松草碱衍生物的相关报道。
发明内容
本发明的目的是提供一种芬氏唐松草碱衍生物。
本发明的另一个目的是提供一种所述芬氏唐松草碱衍生物在制备抗肿瘤药物中的应用。
为了实现上述目的，本发明采用的技术方案如下：
本发明的第一方面提供了一种芬氏唐松草碱衍生物或其药用盐，结构选自以下结构的一种：
R2选自苯环上的取代基，包括F、Cl、Br、三氟甲基、氨基、氰基、酯基、硝基、甲氧基、羟基，取代基数量为1-3。
R4、R5各自独立的选自C1~C6烷基，或与C、N、O一起形成3元~6元环，环上N可以与甲基、乙基和异丙基连接，环上C原子上的H可以被F、Cl原子单取代或多取代，当R4为H或甲基时，R5选自苯环或取代的苯环，取代基包括F、Cl、Br、三氟甲基、氨基、氰基、酯基、硝基、甲氧基、羟基，取代基数量为1-3。
R6、R7各自独立的选自H、C1~C4烷基，或与C、N、O一起形成3元~6元环；
R8选自H、甲基、乙基。R9选自C1~C5的烷基、、苯基、吡啶基、嘧啶基、呋喃基、噻吩基，其中苯基、吡啶基、嘧啶基、呋喃基、噻吩基上有1-3个取代基，取代基包括F、Cl、Br、三氟甲基、氨基、氰基、硝基、甲氧基、羟基；
所述芬氏唐松草碱衍生物中，R1选自以下结构的一种：
本发明的第二方面提供了一种所述芬氏唐松草碱衍生物或其药用盐在制备抗肿瘤药物中的应用。
所述肿瘤选自白血病、多发性骨髓瘤、淋巴瘤、肝癌、胃癌、乳腺癌、结肠癌、胆管细胞癌、胰腺癌、肺癌、大肠癌、骨肉瘤、黑色素瘤、人宫颈癌、神经胶质瘤、鼻咽癌、喉癌、食管癌、中耳肿瘤或前列腺癌。
本发明的第三方面提供了一种所述芬氏唐松草碱衍生物或其药用盐与其他药物联用，在制备抗肿瘤药物中的应用。
所述其他药物选自阿霉素、紫杉醇。
本发明的第四方面提供了一种所述芬氏唐松草碱衍生物或其药用盐在制备肿瘤耐药逆转剂中的应用。
由于采用上述技术方案，本发明具有以下优点和有益效果：
本发明提供的芬氏唐松草碱衍生物，通过结构改造获得了活性更好的抗肿瘤药物。
本发明的药物逆转肿瘤耐药的活性高于经典的第三代耐药逆转剂Tarquidar，且本身兼具良好的抗肿瘤作用。
本发明提供的芬氏唐松草碱衍生物可以与一线临床抗肿瘤药物联用，提高疗效。
通过细胞实验发现，本发明提供的芬氏唐松草碱衍生物与芬氏唐松草碱相比，具有更好的抗肿瘤活性，对耐药的肿瘤细胞效果良好。同时本发明的化合物与抗肿瘤药联用，可以逆转耐药。
附图说明
图1是本发明的实施例中的芬氏唐松草碱醚类衍生物结构图。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
原料芬氏唐松草碱购自禹捷生物科技（上海）有限公司。制备反应的有机酸、酰氯、卤代烃等试剂全部可以在市场上购买获得。常规的化学转换可用于实施本发明。本领域的技术人员可以决定用于这些化学转换的适当的化学试剂、溶剂和反应条件。
实施例1：TD-01的合成
冰盐浴下，25 mL反应瓶中加入芬氏唐松草碱（200mg，1当量）和5 mL DMF作溶剂，加入1.2当量氢化钠作碱，磁力搅拌反应10分钟，再分批加入1.1当量3-三氟甲基苄溴，自然升温反应2小时，反应结束后加水淬灭。通过硅胶柱色谱层析纯化，收率82%。1H NMR (600MHz, CDCl3) δ 7.75 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz,1H), 7.50 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 7.16 (dd, J =8.4, 2.4 Hz, 1H), 6.87 (s, 2H), 6.82 (dd, J = 8.4, 2.4 Hz, 1H), 6.57 (s, 1H),6.54 (s, 1H), 6.33 (dd, J = 8.4, 1.8 Hz, 1H), 6.03 (s, 1H), 5.10 (ABq, J AB =11.4 Hz, 2H), 3.95 (s, 3H), 3.94 – 3.89 (m, 1H), 3.81 (s, 3H), 3.78 (d, J =9.6 Hz, 1H),3.51 – 3.39 (m, 2H), 3.35 (s, 3H), 3.31 – 3.24 (m, 4H), 3.06 –2.97 (m, 1H), 2.91 (dd, J = 13.2, 6.0 Hz, 2H), 2.86 – 2.62 (m, 7H), 2.53 (d,J = 13.8 Hz, 1H), 2.48 (dd, J = 17.4, 4.5 Hz, 1H), 2.27 (s, 3H). 13C NMR (101MHz, CDCl3) δ 153.75, 149.38, 148.32, 147.11, 144.73, 144.37, 143.82, 143.70,142.53, 139.02, 135.15, 134.69, 132.63, 131.21, 130.13, 130.90 (q, J = 32.0Hz), 128.80, 128.40, 127.87, 125.79, 124.72, 124.68, 124.61, 122.78, 121.95,121.90, 120.27, 116.17, 112.64, 111.51, 73.67, 67.10, 63.78, 61.40, 60.99,60.54, 56.13, 55.59, 45.21, 43.47, 42.65, 42.17, 41.72, 37.76, 25.41, 16.73.HRMS (ESI+) m/e [M+H]+：797.33743，C46H47F3N2O7。
实施例2：TD-02的合成
冰盐浴下，25 mL反应瓶中加入芬氏唐松草碱（200mg，1当量）和5 mL DMSO作溶剂，加入1.2当量氢化钠作碱，磁力搅拌反应10分钟，再分批加入1.1当量4-氰基苄溴，保温反应20分钟，反应结束后加水淬灭。通过硅胶柱色谱层析纯化，收率79%。1H NMR (400 MHz,CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.34 (dd, J =8.2, 1.6 Hz, 1H), 7.14 (dd, J = 8.2, 2.4 Hz, 1H), 6.85 (s, 2H), 6.80 (dd, J =8.2, 2.4 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.31 (dd, J = 8.2, 2.0 Hz, 1H),6.01 (s, 1H), 5.08 (ABq, J AB = 12.4 Hz, 2H), 4.00 – 3.83 (m, 4H), 3.83 – 3.65(m, 4H), 3.46-3.37 (m, 2H), 3.35 (s, 3H), 3.31 – 3.20 (m, 4H), 3.03 – 2.81(m, 4H), 2.79 – 2.60 (m, 6H), 2.51 (d, J = 14.4 Hz, 1H), 2.48 – 2.41 (m, 1H),2.27 (s, 3H). 13C NMR (101 MHz, CH2Cl2) δ 153.76, 149.38, 148.30, 147.12,144.82, 144.27, 143.78, 143.52, 143.50, 142.54, 135.15, 134.63, 132.64,132.20, 130.13, 128.46, 128.01, 127.95, 125.88, 122.77, 121.95, 121.90,121.76, 120.26, 118.80, 116.17, 112.63, 111.53, 73.40, 63.77, 61.38, 61.04,60.55, 56.14, 55.64, 45.21, 43.43, 42.65, 42.23, 41.70, 37.70, 25.44, 16.75.HRMS (ESI+) m/e [M+H]+：754.34604，C46H47N3O7。
实施例3：TD-03的合成
参考TD-01方法，以芬氏唐松草碱和4-氟苄溴为原料，合成TD-03，收率85%。1H NMR(400 MHz, CDCl3) δ 7.39 (t, J = 5.2 Hz, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.14(d, J = 7.0 Hz, 1H), 7.03 (t, J = 8.1 Hz, 2H), 6.85 (s, 2H), 6.79 (d, J = 7.2Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.30 (d, J = 7.5 Hz, 1H), 6.01 (s, 1H),4.99 (d, J = 11.0 Hz, 1H), 4.94 (d, J = 11.0 Hz, 1H), 3.92 (s, 3H), 3.90 –3.85 (m, 1H), 3.79 (s, 3H), 3.73 (d, J = 10.1 Hz, 1H), 3.46-3.40 (m, 2H),3.33 (s, 3H), 3.25 (s, 3H), 3.23-3.17 (m, 1H), 3.03 – 2.68 (m, 6H), 2.64 (s,3H), 2.59 – 2.36 (m, 3H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.33,153.76, 149.37, 148.31, 147.10, 144.63, 144.44, 143.83, 143.75, 142.47,135.16, 134.76, 133.72 (d J = 3.5 Hz), 132.64, 130.17, 130,12, 130.09,128.44, 127.86, 125.72, 122.77, 122.10, 121.95, 121.88, 120.30, 116.20,115.30, 115.09, 112.67, 111.51, 73.74, 63.78, 61.42, 60.94, 60.57, 56.14,55.60, 45.24, 43.52, 42.67, 42.17, 41.78, 37.78, 25.43, 16.76. HRMS (ESI+) m/e [M+H]+：747.34038，C45H47FN2O7。
实施例4：TD-04的合成
参考TD-01方法，以芬氏唐松草碱和2-溴-5-甲氧基苄溴为原料，合成TD-04，收率79%。1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 6.4 Hz,1H), 7.23 (s, 1H), 7.14 (d, J = 5.8 Hz, 1H), 6.85 (s, 2H), 6.80 (d, J = 6.7Hz, 1H), 6.74 (d, J = 6.5 Hz, 1H), 6.54 (d, J = 12.8 Hz, 2H), 6.31 (d, J =6.5 Hz, 1H), 6.02 (s, 1H), 5.03 (s, 2H), 3.92 (s, 3H), 3.90 – 3.86 (m, 1H),3.80 (s, 7H), 3.43-3.37 (m, 2H), 3.37 (s, 3H), 3.26 (s, 3H), 3.10 – 2.66 (m,8H), 2.64 (s, 3H), 2.57 – 2.45 (m, 2H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3)δ 159.07, 153.75, 149.38, 148.38, 147.09, 144.72, 144.47, 144.08, 143.73,142.50, 138.56, 135.17, 134.75, 133.02, 132.64, 130.14, 128.38, 127.86,125.69, 122.79, 122.09, 121.96, 121.90, 120.29, 116.18, 115.07, 114.64,112.77, 112.65, 111.52, 73.74, 63.79, 61.43, 61.10, 60.54, 56.14, 56.14,55.68, 55.60, 45.24, 43.53, 42.66, 42.23, 41.76, 37.81, 25.41, 16.67. HRMS(ESI+) m/e [M+H]+：837.27100，839.27011，C46H49BrN2O8。
实施例5：TD-06的合成
参考TD-01方法，以芬氏唐松草碱和3，4-二氯苄溴为原料，合成TD-06，收率88%。1HNMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.34 (dd, J =8.1, 2.2 Hz, 1H), 7.27 (dd, J = 8.1, 2.2 Hz, 1H), 7.14 (dd, J = 8.1, 2.2 Hz,1H), 6.85 (s, 2H), 6.79 (dd, J = 8.2, 2.1 Hz, 1H), 6.55 (s, 1H), 6.51 (s,1H), 6.37 – 6.24 (m, 1H), 6.01 (s, 1H), 4.99 (ABq, J AB = 11.6 Hz, 2H), 3.93(s, 3H), 3.91 – 3.86 (m, 1H), 3.77 (s, 3H), 3.74 (d, J = 9.9 Hz, 1H), 3.47(s, 3H), 3.45-3.37 (m, 2H), 3.33 (s, 3H), 3.29 – 3.16 (m, 4H), 3.12 – 2.66(m, 7H), 2.64 (s, 3H), 2.55 – 2.38 (m, 2H), 2.26 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 153.75, 149.38, 148.30, 147.11, 144.76, 144.28, 143.68, 143.64,142.51, 138.25, 135.17, 134.70, 132.64, 132.41, 131.83, 130.32, 130.12,129.91, 129.91, 128.44, 127.92, 127.24, 125.85, 122.78, 121.95, 121.89,121.85, 120.29, 116.19, 112.62, 111.51, 72.93, 63.77, 61.39, 60.98, 60.55,56.14, 55.59, 50.85, 45.22, 43.45, 42.67, 42.19, 41.73, 37.73, 25.44, 16.76.HRMS (ESI+) m/e [M+H]+：797.27124，C45H46Cl2N2O7。
实施例6：TD-07的合成
参考TD-01方法，以芬氏唐松草碱和2-溴-5-甲氧基苄溴为原料，合成TD-07，收率86%。1H NMR (400 MHz, CDCl3) δ 7.49 (t, J = 7.4 Hz, 1H), 7.36-7.26 (m, 2H),7.19 – 7.11 (m, 2H), 7.10 – 7.03 (m, 1H), 6.85 (s, 2H), 6.79 (dd, J = 8.3,2.4 Hz, 1H), 6.56 (s, 1H), 6.52 (s, 1H), 6.30 (dd, J = 8.3, 1.9 Hz, 1H), 6.01(s, 1H), 5.16 – 4.99 (m, 2H),5.07 (ABq, J AB = 16.0 Hz, 2H), 3.92 (s, 3H), 3.91– 3.87 (m, 1H), 3.80 (s, 3H), 3.73 (d, J = 10.5 Hz, 1H), 3.48 – 3.37 (m, 2H),3.35 (s, 3H), 3.30 – 3.19 (m, 4H), 2.95 – 2.66 (m, 6H), 2.63 (s, 3H), 2.60 –2.38 (m, 3H), 2.23 (s, 3H). 13C NMR (101 MHz, CDCl3) δ159.70 (d, J = 246.0Hz), 153.76, 149.36, 148.34, 147.08, 144.68, 144.55, 143.95, 143.79, 142.44,135.15, 134.80, 132.64, 130.81 (d, J = 4.2 Hz), 130.13, 129.85 (d, J = 8.2Hz), 128.35, 127.81, 125.63, 125.07 (d, J = 15.1 Hz), 124.01 (d, J = 3.4 Hz),122.77, 122.24, 121.95, 121.89, 120.31, 116.20, 115.38 (d, J = 21.0 Hz),112.64, 111.51, 68.00, 63.76, 61.42, 60.95, 60.56, 56.14, 55.59, 45.21,43.51, 42.63, 42.14, 41.78, 37.83, 25.37, 16.43. HRMS (ESI+) m/e [M+H]+：747.34162，C45H47FN2O7。
实施例7：TD-08的合成
参考TD-02方法，以芬氏唐松草碱和2，5-二-氟苄溴为原料，合成TD-08，收率82%。1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.1 Hz, 1H), 7.22 (s, 1H), 7.14 (d, J =6.9 Hz, 1H), 6.99 (s, 2H), 6.85 (s, 2H), 6.79 (d, J = 7.1 Hz, 1H), 6.56 (s,1H), 6.52 (s, 1H), 6.30 (d, J = 7.1 Hz, 1H), 6.01 (s, 1H), 5.05 (s, 2H), 3.92(s, 3H), 3.90 – 3.84 (m, 1H), 3.79 (s, 3H), 3.78-3.70 (m, 1H), 3.41 (s, 2H),3.36 (s, 3H), 3.26-3.20 (m, 4H), 2.94 – 2.69 (m, 6H), 2.63 (s, 3H), 2.55-2.41m, 2H), 2.28-2.15 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 162.54 -155.28 (m, 2C),153.75, 149.36, 148.31, 147.09, 144.82, 144.42, 143.71, 143.67, 142.49,135.18, 134.75, 132.64, 130.12, 128.40, 127.90, 126.92 (dd, J = 17.7, 7.8Hz), 125.75, 122.78, 122.06, 121.94, 121.88, 120.31, 116.70, 116.75-115.65(m, 3C), 112.57, 111.51, 67.44, 63.76, 61.39, 60.97, 60.54, 56.13, 55.55,45.23, 43.42, 42.66, 42.12, 41.73, 37.78, 25.42, 16.41. HRMS (ESI+) m/e [M+H]+：765.33134，C45H46F2N2O7。
实施例8：TD-09的合成
参考TD-01方法，以芬氏唐松草碱和3-氯苄溴为原料，合成TD-09，收率74%。1H NMR(400 MHz, CDCl3) δ 7.32 (dd, J = 14.1, 7.7 Hz, 2H), 7.19 (d, J = 7.6 Hz, 1H),7.17 – 7.09 (m, 2H), 7.00 (t, J = 8.4 Hz, 1H), 6.85 (s, 2H), 6.79 (dd, J =8.2, 2.2 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.31 (d, J = 8.2 Hz, 1H), 6.01(s, 1H), 5.00 (ABq, J AB = 12.0 Hz, 2H), 3.92 (s, 3H), 3.91 – 3.85 (m, 1H),3.79 (s, 3H), 3.74 (d, J = 9.7 Hz, 1H), 3.46 – 3.37 (m, 2H), 3.34 (s, 3H),3.30 – 3.15 (m, 4H), 3.02 – 2.66 (m, 6H), 2.64 (s, 3H), 2.59 – 2.35 (m, 3H),2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 161.58(d, J = 244.6 Hz), 153.76,149.37, 148.34, 147.10, 144.69, 144.39, 143.83, 143.74, 142.50, 140.47 (d, J= 7.3 Hz), 135.15, 134.75, 132.64, 130.13, 129.98 (d, J = 7.9 Hz), 127.85,125.72, 122.78, 122.14 (d, J = 2.8 Hz), 122.05, 121.96, 121.89, 120.30,116.20, 115.04 (d, J = 41.1 Hz), 114.83, 114.43 (d, J = 21.1 Hz), 112.62,111.51, 73.65, 63.76, 61.41, 60.98, 60.57, 56.14, 55.57, 45.21, 43.46, 42.64,42.15, 41.74, 37.77, 25.39, 16.70. HRMS (ESI+) m/e [M+H]+：747.34110，C45H47FN2O7。
实施例9：TD-10的合成
参考TD-01方法，以芬氏唐松草碱和4-三氟甲氧基苄溴为原料，合成TD-10，收率83%。1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 8.2, 2.0Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.14 (dd, J = 8.1, 2.5 Hz, 1H), 6.85 (s,2H), 6.79 (dd, J = 8.3, 2.5 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.30 (dd, J= 8.3, 2.0 Hz, 1H), 6.01 (s, 1H), 5.00 (ABq, J AB = 11.3 Hz, 2H), 3.93 (s, 3H),3.92-3.87 (m, 1H), 3.79 (s, 3H), 3.74 (d, J = 9.8 Hz, 1H), 3.46-3.35 (m, 2H),3.34 (s, 3H), 3.29 – 3.21 (m, 4H), 3.01 – 2.69 (m, 6H), 2.64 (s, 3H), 2.61 –2.54 (m, 1H), 2.50 (d, J = 13.7 Hz, 1H), 2.44 (dd, J = 17.3, 4.2 Hz, 1H),2.23 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.77, 149.37, 148.87, 148.33,147.11, 144.68, 144.42, 143.76, 143.72, 142.51, 136.70, 135.12, 134.68,132.63, 130.13, 129.60, 128.37, 127.85, 125.71, 122.78, 122.04, 121.96,121.90, 120.88, 120.29, 116.17, 112.65, 111.52, 73.51, 63.79, 61.42, 60.98,60.58, 56.14, 55.59, 45.23, 43.50, 42.65, 42.14, 41.73, 37.77, 25.41, 16.75.HRMS (ESI+) m/e [M+H]+：813.33337，C46H47F3N2O8。
实施例10：TD-11的合成
参考TD-02方法，以芬氏唐松草碱和3, 5-二氟苄溴为原料，合成TD-11，收率76%。1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.2, 1.5 Hz, 1H), 7.14 (dd, J = 8.1,2.3 Hz, 1H), 6.96 (d, J = 6.0 Hz, 2H), 6.85 (s, 2H), 6.79 (dd, J = 8.3, 2.4Hz, 1H), 6.75 (t, J = 9.1 Hz, 1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.30 (dd, J =8.3, 1.7 Hz, 1H), 6.01 (s, 1H), 4.98 (ABq, J AB = 11.9 Hz, 2H), 3.92 (s, 3H),3.91 – 3.84 (m, 1H), 3.77 (s, 3H), 3.75 (d, J = 10.3 Hz, 1H), 3.47-3.37 (m,2H), 3.35 (s, 3H), 3.30 – 3.18 (m, 4H), 3.02 – 2.70 (m, 6H), 2.64 (s, 3H),2.62 – 2.55 (m, 1H), 2.50 (d, J = 13.8 Hz, 1H), 2.45 (dd, J = 17.7, 4.4 Hz,1H), 2.26 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.20 (d, J = 12.6 Hz), 161.73(d, J = 12.6 Hz), 153.76, 149.38, 148.32, 147.11, 144.80, 144.28, 143.67,143.64, 142.53, 141.99 (t, J = 8.9 Hz), 135.15, 134.69, 132.64, 130.12,128.40, 127.92, 125.81, 122.78, 121.96, 121.89, 120.29, 116.20, 112.58,111.51, 110.56, 110.49(d, J = 12.0 Hz), 110.31, 103.08 (t, J = 26 Hz), 73.08,63.77, 61.38, 61.00, 60.55, 56.13, 55.55, 45.22, 43.41, 42.65, 42.15, 41.70,37.74, 25.43, 16.68. HRMS (ESI+) m/e [M+H]+：765.33129，C45H46F2N2O7。
实施例11：TD-12的合成
参考TD-01方法，以芬氏唐松草碱和2-溴-5-甲氧基苄溴为原料，合成TD-12，收率79%。1H NMR (400 MHz, CDCl3) δ 7.47 – 7.27 (m, 5H), 7.14 (dd, J = 8.1, 2.5 Hz,1H), 6.85 (s, 2H), 6.79 (dd, J = 8.3, 2.4 Hz, 1H), 6.55 (s, 1H), 6.51 (s,1H), 6.30 (dd, J = 8.3, 1.9 Hz, 1H), 6.01 (s, 1H), 4.97 (ABq, J AB = 11.2 Hz,2H), 3.93 (s, 3H), 3.91 – 3.87 (m, 1H), 3.78 (s, 3H), 3.73 (d, J = 9.9 Hz,1H), 3.46 – 3.37 (m, 2H), 3.32 (s, 3H), 3.29 – 3.18 (m, 4H), 3.01 – 2.68 (m,6H), 2.64 (s, 3H), 2.62-2.55 (m, 1H), 2.50 (d, J = 13.6 Hz, 1H), 2.44 (dd, J= 17.7, 4.5 Hz, 1H), 2.24 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.76, 149.37,148.31, 147.10, 144.65, 144.38, 143.84, 143.74, 142.47, 136.43, 135.16,134.74, 133.75, 132.63, 130.12, 129.54, 128.49, 128.43, 127.87, 125.75,122.77, 122.01, 121.95, 121. 89, 120.30, 116.20, 112.65, 111.51, 73.64,63.78, 61.41, 60.96, 60.56, 56.14, 55.61, 45.24, 43.50, 42.67, 42.17, 41.76,37.78, 25.44, 16.76. HRMS (ESI+) m/e [M+H]+：763.31198，C45H47ClN2O7。
实施例12：TD-21的合成
冰盐浴，25 mL反应瓶中加入芬氏唐松草碱（200mg，1当量）和5 mL DMF作溶剂，加入1.5当量氢化钠，磁力搅拌反应10分钟，再分批加入1.1当量正丁醇对甲苯磺酸酯，自然升温反应2小时，反应结束后加水无水甲醇淬灭。通过氧化铝柱色谱层析纯化，收率88%。 1HNMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 2.4Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3, 2.4 Hz, 1H), 6.56 (s, 1H), 6.51 (s,1H), 6.31 (dd, J = 8.3, 1.9 Hz, 1H), 6.00 (s, 1H), 3.98 – 3.93 (m, 1H), 3.92(s, 3H), 3.90 – 3.85 (m, 1H), 3.82-3.72 (m, 4H), 3.51 – 3.38 (m, 2H), 3.33(s, 3H), 3.30 – 3.15 (m, 4H), 3.01 – 2.69 (m, 8H), 2.65 (s, 3H), 2.57 – 2.44(m, 2H), 2.30 (s, 3H), 1.82 – 1.66 (m, 2H), 1.58-1.45 (m, 2H), 0.98 (t, J =7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 153.72, 149.36, 148.32, 147.06,144.76, 144.42, 144.28, 143.80, 142.40, 135.20, 134.86, 132.62, 130.12,128.41, 127.75, 125.62, 122.76, 121.93, 121.92, 121.86, 120.22, 116.17,112.70, 111.50, 72.78, 63.78, 61.45, 60.86, 60.49, 56.13, 55.62, 45.25,43.66, 42.66, 42.29, 41.81, 37.83, 32.63, 25.39, 19.36, 16.65, 13.98. HRMS(ESI+) m/e [M+H]+：695.36685，C42H50N2O7。
实施例13：TD-22的合成
参考TD-01方法，以烯丙基溴和芬氏唐松草碱为原料，合成TD-22，收率82%。1H NMR(400 MHz, CDCl3) δ 7.34 (dd, J = 8.1, 1.8 Hz, 1H), 7.14 (dd, J = 8.1, 2.4 Hz,1H), 6.86 (s, 2H), 6.80 (dd, J = 8.2, 2.4 Hz, 1H), 6.56 (s, 1H), 6.51 (s,1H), 6.31 (dd, J = 8.2, 1.7 Hz, 1H), 6.13-6.01 (m, 1H), 6.00 (s, 1H), 5.35(dd, J = 17.1, 1.4 Hz, 1H), 5.20 (d, J = 10.5 Hz, 1H), 4.48 (d, J = 4.8 Hz,1H), 3.93 (s, 3H), 3.92 – 3.83 (m, 3H), 3.82-3.72 (m, 4H), 3.50-3.35 (m, 2H),3.33 (s, 3H), 3.28-3.21 (m, 4H), 3.01-2.85 (m, 2H), 2.82 – 2.69 (m, 4H), 2.63(s, 3H), 2.55-2.45 (m, 2H), 2.30 (s, 3H). MS (ESI+) m/e [M+H]+：679.41，C41H46N2O7。
实施例14：TD-23的合成
参考TD-02所述方法，以溴甲基环丙烷和芬氏唐松草碱为原料，合成TD-23，浅黄色粉末，收率81%。1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.2, 2.0 Hz, 1H), 7.14(dd, J = 8.1, 2.5 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3, 2.5 Hz, 1H), 6.56(s, 1H), 6.50 (s, 1H), 6.31 (dd, J = 8.2, 2.0 Hz, 1H), 6.00 (s, 1H), 3.93 (s,3H), 3.89 (dd, J = 11.0, 5.7 Hz, 1H), 3.85-3.78 (m, 1H), 3.76 (s, 3H), 3.75-3.71 (m, 1H), 3.52 – 3.38 (m, 2H), 3.33 (s, 3H), 3.26 (d, J = 5.7 Hz, 1H),3.23 (s, 3H), 3.04 – 2.84 (m, 4H), 2.83-2.66 (m, 4H), 2.63 (s, 3H), 2.59 –2.48 (m, 2H), 2.30 (s, 3H), 1.24 – 1.17 (m, 1H), 0.67 – 0.46 (m, 2H), 0.35 –0.16 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 153.73, 149.37, 148.31, 147.07,144.47, 144.36, 144.35, 143.78, 135.17, 134.83, 132.63, 130.12, 128.36,127.74, 125.54, 122.76, 122.18, 121.94, 121.87, 120.24, 116.17, 112.63,111.51, 77.62, 63.78, 61.48, 60.82, 60.54, 56.14, 55.54, 45.24, 43.69, 42.65,42.27, 41.82, 37.83, 25.39, 16.73, 11.21, 3.14, 2.84. HRMS (ESI+) m/e [M+H]+：693.35137，C42H48N2O7。
实施例15：TD-24的合成
室温条件下，25 mL反应瓶中加入芬氏唐松草碱（200mg，1当量）和5 mL DMF作溶剂，加入2.5当量碳酸钾，磁力搅拌反应10分钟，再分批加入1.2当量氯乙基哌啶盐酸盐，升温至75摄氏度反应2小时，反应结束后减压浓缩去除溶剂。通过氧化铝柱色谱层析纯化，收率72%. 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.2, 2.0 Hz, 1H), 7.14 (dd, J =8.1, 2.5 Hz, 1H), 6.85 (d, J = 5.3 Hz, 2H), 6.79 (dd, J = 8.3, 2.5 Hz, 1H),6.56 (s, 1H), 6.50 (s, 1H), 6.31 (dd, J = 8.3, 2.0 Hz, 1H), 5.99 (s, 1H),4.12-4.01 (m, 2H), 3.92 (s, 3H), 3.88 (dd, J = 11.1, 5.8 Hz, 1H), 3.76 (s,3H), 3.73 (s, 1H), 3.51 – 3.35 (m, 3H), 3.32 (s, 3H), 3.28 – 3.17 (m, 4H),3.03 – 2.83 (m, 4H), 2.83 – 2.67 (m, 6H), 2.63 (s, 3H), 2.55-2.45 (m, 4H),2.31 (s, 3H), 1.61 (dt, J = 11.0, 5.6 Hz, 4H), 1.52 – 1.39 (m, 2H). 13C NMR(101 MHz, CDCl3) δ 153.73, 149.36, 148.31, 147.05, 144.71, 144.39, 144.33,143.74, 142.38, 135.19, 134.83, 132.63, 130.11, 128.41, 127.76, 125.62,122.75, 121.96, 121.93, 121.86, 120.18, 116.17, 112.66, 111.51, 70.28, 63.80,61.45, 60.92, 60.50, 59.10, 56.13, 55.60, 54.96, 45.26, 43.67, 42.68, 42.31,41.85, 37.85, 25.96, 25.41, 24.36, 16.63. HRMS (ESI+) m/e [M+H]+：750.40802，C45H55N3O7。
实施例16：TD-25的合成
参考实施例15所述方法，以氯乙基吗啉盐酸盐和芬氏唐松草碱为原料，合成TD-25，浅黄色粉末，收率74%。 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.3, 1.9 Hz,1H), 7.14 (dd, J = 8.1, 2.5 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3, 2.5 Hz,1H), 6.55 (s, 1H), 6.51 (s, 1H), 6.31 (dd, J = 8.3, 2.1 Hz, 1H), 5.99 (s,1H), 4.13-4.01 (m, 2H), 3.93 (s, 3H), 3.91 – 3.86 (m, 1H), 3.76 (t, J = 4.5Hz, 8H), 3.52-3.38 (m, 2H), 3.35 (s, 3H), 3.27 (d, J = 5.6 Hz, 1H), 3.24 (s,3H), 3.09 – 2.85 (m, 4H), 2.85 – 2.67 (m, 6H), 2.63 (s, 3H), 2.61 – 2.48 (m,5H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.74, 149.38, 148.34, 147.10,144.54, 144.47, 144.35, 143.67, 142.44, 135.11, 134.65, 132.63, 130.13,128.28, 127.73, 125.61, 122.79, 121.95, 121.89, 120.16, 116.11, 114.08,112.62, 111.52, 69.75, 66.96, 63.81, 61.47, 60.96, 60.52, 58.85, 56.13,55.60, 53.99, 45.21, 43.74, 42.62, 42.35, 41.80, 37.79, 25.35, 16.73. HRMS(ESI+) m/e [M+H]+：752.38803，C44H53N3O8。
实施例17：TD-26的合成
参考实施例2方法，以芬氏唐松草碱和溴乙烷为原料合成TD-26，经二氯甲烷-甲醇硅胶柱层析纯化，收率81%。1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.2, 2.0 Hz,1H), 7.14 (dd, J = 8.1, 2.5 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3, 2.5 Hz,1H), 6.56 (s, 1H), 6.51 (s, 1H), 6.31 (dd, J = 8.3, 2.0 Hz, 1H), 6.00 (s,1H), 4.06-3.96 (m, 2H), 3.93 (s, 3H), 3.90 – 3.86 (m, 1H), 3.77 (s, 3H), 3.75(s, 1H), 3.51 – 3.38 (m, 2H), 3.33 (s, 3H), 3.27 (d, J = 5.6 Hz, 1H), 3.24(s, 3H), 3.04 – 2.85 (m, 3H), 2.84 – 2.67 (m, 4H), 2.63 (s, 3H), 2.58 – 2.45(m, 2H), 2.30 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ153.75, 149.38, 148.34, 147.09, 144.58, 144.44, 144.31, 143.82, 142.39,135.12, 134.77, 132.63, 130.13, 128.29, 127.69, 125.53, 122.79, 122.01,121.95, 121.89, 120.22, 116.14, 112.70, 111.51, 68.61, 63.80, 61.50, 60.80,60.51, 56.14, 55.61, 45.24, 43.78, 42.63, 42.32, 41.82, 37.85, 25.35, 16.76,15.87. HRMS (ESI+) m/e [M+H]+：667.33618，C40H46N2O7。
实施例18：TD-27的合成
参考和实施例15方法，以芬氏唐松草碱和二甲氨基氯乙烷盐酸盐为原料合成TD-27，浅黄色粉末，收率76%。 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 1H),7.14 (d, J = 7.2 Hz, 1H), 6.86 (s, 2H), 6.80 (d, J = 7.6 Hz, 1H), 6.56 (s,1H), 6.50 (s, 1H), 6.31 (d, J = 7.9 Hz, 1H), 6.00 (s, 1H), 4.03 (dt, J =21.1, 7.7 Hz, 2H), 3.92 (s, 3H), 3.90 – 3.86 (m, 1H), 3.77 (s, 3H), 3.74 (s,1H), 3.51 – 3.38 (m, 2H), 3.32 (s, 3H), 3.27-3.18 (m, 4H), 3.01 – 2.86 (m,3H), 2.84 – 2.66 (m, 6H), 2.63 (s, 3H), 2.56-2.47 (m, 2H), 2.34 (s, 6H), 2.29(s, 3H). 13C NMR (101 MHz, CDCl3) δ 153.73, 149.36, 148.31, 147.07, 144.72,144.42, 144.33, 143.73, 142.43, 135.17, 134.79, 132.63, 130.12, 128.38,127.74, 125.62, 122.77, 121.94, 121.90, 121.87, 120.17, 116.15, 112.67,111.51, 70.63, 63.80, 61.46, 60.93, 60.50, 59.43, 56.13, 55.60, 45.81, 45.24,43.64, 42.66, 42.28, 41.80, 37.81, 25.39, 16.66. HRMS (ESI+) m/e [M+H]+：710.37727，C42H51N3O7。
实施例19：TD-28的合成
参考实施例2方法，以芬氏唐松草碱和异丙基溴为原料合成TD-28，白色粉末，收率76%。 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.14 (dd, J =8.1, 2.4 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3, 2.4 Hz, 1H), 6.57 (s, 1H),6.50 (s, 1H), 6.31 (dd, J = 8.2, 1.9 Hz, 1H), 6.00 (s, 1H), 4.48 (dt, J =12.2, 6.1 Hz, 1H), 3.92 (s, 3H), 3.91 – 3.86 (m, 1H), 3.78 (s, 1H), 3.75 (s,3H), 3.47 – 3.37 (m, 2H), 3.32 (s, 3H), 3.27 (d, J = 5.7 Hz, 1H), 3.24 (s,3H), 2.99 – 2.87 (m, 3H), 2.84 – 2.67 (m, 4H), 2.63 (s, 3H), 2.57 – 2.48 (m,2H), 2.29 (s, 3H), 1.33 – 1.29 (d, J = 6.1 Hz, 3H), 1.21 (d, J = 6.1 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 153.75, 149.36, 148.26, 147.08, 144.43, 144.13,143.87, 143.31, 142.45, 135.14, 134.83, 132.63, 130.13, 128.35, 127.65,125.55, 122.78, 122.61, 121.93, 121.87, 120.25, 116.15, 112.72, 111.50,74.40, 63.79, 61.59, 60.53, 60.49, 56.13, 55.47, 45.23, 44.04, 42.64, 42.36,42.00, 37.80, 25.38, 22.83, 22.40, 17.36. HRMS (ESI+) m/e [M+H]+：681.35110，C41H48N2O7。
实施例20：TD-29的合成
冰盐浴条件下，25 mL反应瓶中加入芬氏唐松草碱（200mg，1当量）和5 mL DMF作溶剂，加入1.2当量氢化钠，磁力搅拌反应10分钟，再分批加入三氟甲磺酸三氟乙酯，自然升至室温，反应2小时，反应结束后减压浓缩去除溶剂。通过氧化铝柱色谱层析纯化，收率85%。 1HNMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.2, 2.1 Hz, 1H), 7.14 (dd, J = 8.1, 2.5Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3, 2.5 Hz, 1H), 6.55 (s, 1H), 6.51 (s,1H), 6.31 (dd, J = 8.3, 2.1 Hz, 1H), 6.00 (s, 1H), 4.47-4.30 (m, 2H), 3.92(s, 3H), 3.90 – 3.82 (m, 1H), 3.77 (s, 1H), 3.75 (s, 3H), 3.50 – 3.38 (m,2H), 3.34 (s, 3H), 3.29 – 3.17 (m, 4H), 3.02 – 2.85 (m, 3H), 2.84 – 2.66 (m,4H), 2.63 (s, 3H), 2.56 – 2.45 (m, 2H), 2.30 (s, 3H). 13C NMR (101 MHz, CDCl3)δ 153.76, 149.37, 148.24, 147.13, 145.07, 143.53, 143.42, 143.25, 142.46,135.16, 134.62, 132.65, 130.12, 128.46, 127.98, 126.06, 125.05 (q, J = 277.0Hz), 122.82, 121.95, 121.89, 121.45, 120.20 , 116.15, 112.56, 111.53, 69.48(q, J = 34.0 Hz), 63.76, 61.36, 60.94, 60.56, 56.12, 55.52, 45.19, 43.27,42.64, 42.19, 41.67, 37.61, 25.46, 16.01. HRMS (ESI+) m/e [M+H]+：721.30740，C40H43F3N2O7。
实施例21：TD-51的合成
芬氏唐松草碱(200 mg，1倍量)溶于5 mL二氯甲烷中，加入三乙胺（1.5倍量），滴加烟酰氯 (1.2倍量)的1 mL二氯甲烷溶液，在0 ℃-5 ℃反应5分钟，经薄层色谱和LC-MS检测，反应结束。加入水20 mL，溶液分层，分出二氯甲烷层，水相用20 mL二氯甲烷萃取1次，合并有机相，水洗2次，饱和食盐水洗涤1次，无水硫酸钠干燥，减压浓缩得到粗品，经乙酸乙酯和石油醚重结晶纯化得到化合物TD-51，收率89%。1H NMR (400 MHz, CDCl3) δ 8.87 (d, J= 6.0 Hz, 2H), 8.01 (d, J = 6.0 Hz, 2H), 7.36 (dd, J = 8.2, 2.4 Hz, 1H), 7.16(dd, J = 8.2, 2.4 Hz, 1H), 6.86 (s, 2H), 6.81 (dd, J = 8.4, 2.4 Hz, 1H), 6.57(s, 1H), 6.55 (s, 1H), 6.32 (dd, J = 8.4, 2.0 Hz, 1H), 6.03 (s, 1H), 3.93 (s,3H), 3.90 (d, J = 5.6 Hz, 1H), 3.80 (d, J = 10.0 Hz, 1H), 3.70 (s, 3H), 3.56– 3.35 (m, 5H), 3.28 (s, 3H), 3.25 (d, J = 5.6 Hz, 1H), 3.02-2.87 (m, 3H),2.81-2.71 (m, 4H), 2.63 (s, 3H), 2.55 (d, J = 13.6 Hz, 1H), 2.32 (s, 3H),2.33-2.30(m, 1H).
13C NMR (101 MHz, CDCl3) δ 163.38, 153.79, 150.88, 149.39, 148.28,147.16, 146.83, 143.48, 143.18, 142.50, 136.53, 136.18, 135.15, 134.51,132.66, 130.14, 128.52, 128.12, 125.92, 123.22, 122.80, 121.94, 121.19,120.11, 116.19, 112.65, 111.54, 63.79, 61.30, 60.90, 60.40, 56.14, 55.67,53.45, 45.20, 42.81, 42.67, 42.13, 41.56, 37.60, 25.50, 16.15. HRMS (ESI+) m/e [M+H]+：744.32554，C44H45N3O8。
实施例22：TD-52的合成
参考实施例21所述合成方法，以异烟酰氯和芬氏唐松草碱为原料，合成TD-52，白色粉末，收率88%。1H NMR (400 MHz, CDCl3) δ 9.34 (d, J = 1.6 Hz, 1H), 8.78 (dd, J= 4.8, 1.6 Hz, 1H), 8.38 (dt, J = 8.0, 2.0 Hz, 1H), 7.39 (dd, J = 8.0, 4.8Hz, 1H), 7.28 (dd, J = 8.2, 2.0 Hz, 1H), 7.08 (dd, J = 8.2, 2.4 Hz, 1H), 6.78(s, 2H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 6.50 (s, 1H), 6.47 (s, 1H), 6.25(dd, J = 8.4, 2.0 Hz, 1H), 5.96 (s, 1H), 3.85 (s, 3H), 3.82 (d, J = 5.6 Hz,1H), 3.73 (d, J = 9.6 Hz, 1H), 3.63 (s, 3H), 3.47 – 3.35 (m, 2H), 3.34 (s,3H), 3.20 (s, 3H), 3.19 – 3.15 (m, 1H), 2.98 – 2.77 (m, 3H), 2.76 – 2.59 (m,4H), 2.56 (s, 3H), 2.48 (d, J = 13.6 Hz, 1H), 2.24 (s, 3H), 2.26-2.21 (m,1H). 13C NMR (101 MHz, CDCl3) δ 162.44, 152.97, 152.75, 150.32, 148.35,147.25, 146.11, 145.72, 142.48, 142.26, 141.45, 136.58, 135.18, 134.14,133.52, 131.63, 129.11, 127.50, 127.09, 124.85, 124.32, 122.52, 121.78,120.91, 120.88, 120.30, 119.09, 115.16, 111.64, 110.51, 62.75, 60.28, 59.89,59.37, 55.10, 54.65, 44.18, 41.83,41.65, 41.10, 40.54, 36.59, 24.46, 15.15.HRMS (ESI+) m/e [M+H]+：744.32542，C44H45N3O8。
实施例23：TD-53的合成
参考实施例21所述合成方法，以2-噻吩甲酰氯和芬氏唐松草碱为原料，合成TD-53，白色粉末，收率82%。1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 3.6, 1.2 Hz, 1H),7.57 (dd, J = 5.0, 1.2 Hz, 1H), 7.27 (dd, J = 8.2, 2.0 Hz, 1H), 7.12 – 7.02(m, 2H), 6.78 (s, 2H), 6.72 (dd, J = 8.4, 2.4 Hz, 1H), 6.49 (s, 1H), 6.46 (s,1H), 6.23 (dd, J = 8.4, 2.4 Hz, 1H), 5.95 (s, 1H), 3.84 (s, 3H), 3.81 (d, J =5.6 Hz, 1H), 3.71 (d, J = 10.0 Hz, 1H), 3.64 (s, 3H), 3.51 – 3.33 (m, 2H),3.32 (s, 3H), 3.19 (s, 3H), 3.16 (d, J = 5.6 Hz, 1H), 2.98 – 2.78 (m, 3H),2.76 – 2.59 (m, 4H), 2.56 (s, 3H), 2.47 (d, J = 13.6 Hz, 1H), 2.29 (d, J =4.4 Hz, 1H), 2.23 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.19, 153.80, 149.38,148.32, 147.14, 146.65, 143.64, 142.40, 136.35, 135.17, 134.65, 133.42,132.67, 132.46, 130.14, 128.61, 128.47, 128.11, 128.05, 125.75, 122.82,121.93, 121.91, 121.63, 120.17, 116.25, 112.73, 111.55, 63.79, 61.34, 60.94,60.40, 56.15, 55.71, 45.23, 42.92, 42.68, 42.13, 41.63, 37.73, 25.46, 16.13.HRMS (ESI+) m/e [M+H]+：749.28588，C43H44N2O8S。
实施例24：TD-54的合成
参考实施例21所述合成方法，以2-呋喃甲酰氯和芬氏唐松草碱为原料，合成TD-54，白色粉末，收率78%。1H NMR (400 MHz, CDCl3) δ 7.68 (s, 1H), 7.39 (d, J = 3.6Hz, 1H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H), 7.16 (dd, J = 8.0, 2.4 Hz, 1H), 6.85(s, 2H), 6.80 (dd, J = 8.2, 2.4 Hz, 1H), 6.60 (dd, J = 3.2, 1.6 Hz, 1H), 6.57(s, 1H), 6.53 (s, 1H), 6.37 – 6.24 (m, 1H), 6.02 (s, 1H), 3.93 (s, 3H), 3.91– 3.85 (m, 1H), 3.78 (d, J = 10.0 Hz, 1H), 3.72 (s, 3H), 3.56 – 3.41 (m, 2H),3.39 (s, 3H), 3.27 (s, 3H), 3.24 (d, J = 5.6 Hz, 1H), 3.05 – 2.87 (m, 3H),2.83-2.70 (m, 4H), 2.64 (s, 3H), 2.55 (d, J = 13.6 Hz, 1H), 2.36-2.33 (m,1H), 2.30 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.59, 153.80, 149.37, 148.29,147.13, 146.73, 143.84, 143.60, 143.48, 142.42, 135.85, 135.16, 134.64,132.66, 130.13, 128.48, 128.04, 125.78, 122.80, 121.93, 121.58, 120.13,119.33, 116.21, 112.69, 112.18, 111.54, 63.79, 61.34, 60.88, 60.37, 56.14,55.66, 45.24, 42.92, 42.69, 42.11, 41.64, 37.70, 25.48, 16.12. HRMS (ESI+) m/e [M+H]+：733.30987，C43H44N2O9。
实施例25：TD-55的合成参考实施例21所述合成方法，以苯甲酰氯和芬氏唐松草碱为原料，合成TD-55，白色粉末，收率92%。1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.2Hz, 2H), 7.64 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.35 (dd, J =8.2, 2.0 Hz, 1H), 7.16 (dd, J = 8.2, 2.4 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J =8.2, 2.4 Hz, 1H), 6.58 (s, 1H), 6.54 (s, 1H), 6.32 (dd, J = 8.2, 2.0 Hz, 1H),6.04 (s, 1H), 3.93 (s, 3H), 3.89 (d, J = 5.6 Hz, 1H), 3.80 (d, J = 9.8 Hz,1H), 3.71 (s, 3H), 3.63 – 3.42 (m, 2H), 3.41 (s, 3H), 3.28 (s, 3H), 3.24 (d,J = 5.6 Hz, 1H), 3.07 – 2.86 (m, 3H), 2.85 – 2.66 (m, 4H), 2.64 (s, 3H), 2.56(d, J = 13.6 Hz, 1H), 2.36-2.34 (m, 1H), 2.32 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 164.73, 153.80, 149.38, 148.33, 147.14, 146.53, 143.66, 143.48,142.45, 136.69, 135.19, 134.68, 133.59, 132.67, 130.20, 130.14, 129.30,128.63, 128.52, 128.06, 125.77, 122.82, 121.94, 121.91, 121.52, 120.17,116.25, 112.75, 111.55, 63.80, 61.36, 60.91, 60.40, 56.15, 55.74, 45.25,42.95, 42.70, 42.14, 41.64, 37.73, 25.48, 16.18. HRMS (ESI+) m/e [M+H]+：743.33100，C45H46N2O8。
实施例26：TD-56的合成
参考实施例21所述合成方法，以环丙基甲酰氯和芬氏唐松草碱为原料，合成TD-56，白色粉末，收率84%。1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.0, 1.5 Hz, 1H),7.14 (dd, J = 8.0, 2.5 Hz, 1H), 6.89 – 6.82 (m, 2H), 6.82 – 6.75 (dd, J =8.0, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 6.31 (dd, J = 8.0, 1.7 Hz, 1H), 6.00(s, 1H), 3.92 (s, 3H), 3.91 – 3.84 (m, 1H), 3.78 (d, J = 8.0, 1H), 3.70 (s,3H), 3.51-3.37 (m, 2H), 3.35 (s, 3H), 3.25 (s, 3H), 3.23 – 3.17 (m, 1H),3.01-2.85 (m, 3H), 2.86 – 2.65 (m, 4H), 2.63 (s, 3H), 2.52 (d, J = 13.6 Hz,1H), 2.29 (s, 3H), 2.25 (d, J = 4.4 Hz, 1H), 1.95 – 1.81 (m, 1H), 1.24 – 1.11(m, 2H), 1.04-0.99 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 172.99, 153.75, 149.37,148.29, 147.12, 146.32, 143.62, 143.37, 142.34, 136.53, 135.16, 134.65,132.64, 130.13, 128.46, 127.97, 125.61, 122.79, 121.93, 121.89, 121.44,120.12, 116.17, 112.73, 111.51, 63.75, 61.30, 60.77, 60.35, 56.14, 55.68,45.20, 42.94, 42.65, 42.10, 41.57, 37.65, 25.43, 16.06, 12.70, 8.97. HRMS(ESI+) m/e [M+H]+：707.33089，C42H46N2O8。
实施例27：TD-57的合成
参考实施例21所述合成方法，以丙烯酰氯和芬氏唐松草碱为原料，合成TD-57，白色粉末，收率85%。1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.0, 1.3 Hz, 1H), 7.15(dd, J = 8.0, 2.4 Hz, 1H), 6.91 – 6.83 (m, 2H), 6.79 (dd, J = 8.2, 2.4 Hz,1H), 6.62 (d, J = 17.2 Hz, 1H), 6.56 (s, 1H), 6.52 (s, 1H), 6.42 – 6.33 (m,1H), 6.31 (d, J = 9.5 Hz, 1H), 6.01 (t, J = 5.6 Hz, 2H), 3.93 (s, 3H), 3.88(d, J = 5.6 Hz, 1H), 3.77 (d, J = 10.0 Hz, 1H), 3.70 (s, 3H), 3.52 – 3.39 (m,2H), 3.37 (s, 3H), 3.26 (s, 3H), 3.23 (d, J = 5.6 Hz, 1H), 3.05-2.87 (m, 3H),2.86 – 2.65 (m, 4H), 2.63 (s, 3H), 2.53 (d, J = 13.6 Hz, 1H), 2.30 (s, 3H),2.24 (d, J = 4.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 164.16, 153.77, 149.37,148.28, 147.12, 146.50, 143.60, 143.29, 142.39, 136.34, 135.17, 134.65,132.65, 132.55, 130.13, 128.50, 128.03, 127.49, 125.74, 122.79, 121.93,121.90, 121.35, 120.13, 116.19, 112.71, 111.53, 63.78, 61.32, 60.82, 60.36,56.14, 55.66, 45.23, 42.93, 42.69, 42.11, 41.60, 37.69, 25.47, 16.08. HRMS(ESI+) m/e [M+H]+：693.31486，C41H44N2O8。
实施例28：TD-58的合成
参考实施例21所述合成方法，以乙酰氯和芬氏唐松草碱为原料，合成TD-58，白色粉末，收率92%。1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 8.2, 1.9 Hz, 1H), 7.16(dd, J = 8.2, 2.4 Hz, 1H), 6.87 (s, 2H), 6.81 (dd, J = 8.3, 2.4 Hz, 1H), 6.55(s, 1H), 6.54 (s, 1H), 6.32 (dd, J = 8.3, 2.0 Hz, 1H), 6.02 (s, 1H), 3.97 (d,J = 5.4 Hz, 1H), 3.93 (s, 3H), 3.78 (d, J = 9.9 Hz, 1H), 3.71 (s, 3H), 3.53 –3.43 (m, 2H), 3.39 (s, 3H), 3.35 – 3.30 (m, 1H), 3.26 (s, 3H), 3.13 – 2.89(m, 4H), 2.87 – 2.72 (m, 3H), 2.68 (s, 3H), 2.66 – 2.58 (m, 1H), 2.54 (d, J =13.7 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.06,153.86, 149.31, 148.46, 147.14, 146.34, 143.66, 143.24, 142.34, 136.60,134.71, 134.46, 132.64, 130.17, 127.58, 125.52, 122.86, 121.98, 121.26,120.11, 116.13, 112.62, 111.50, 63.83, 61.35, 60.80, 60.37, 56.12, 55.61,45.80, 45.13, 43.03, 42.49, 42.12, 41.55, 37.81, 25.11, 16.13. HRMS (ESI+) m/e [M+H]+：681.31527，C40H44N2O8。
实施例29：TD-59的合成
参考实施例21所述合成方法，以肉桂酰氯和芬氏唐松草碱为原料，合成TD-59，白色粉末，收率86%。1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 16.0 Hz, 1H), 7.62 (dd,J = 6.2, 2.9 Hz, 2H), 7.51 – 7.41 (m, 3H), 7.37 (dd, J = 8.2, 1.9 Hz, 1H),7.18 (dd, J = 8.1, 2.4 Hz, 1H), 6.88 (s, 2H), 6.82 (dd, J = 8.2, 2.4 Hz, 1H),6.70 (d, J = 16.0 Hz, 1H), 6.59 (s, 1H), 6.55 (s, 1H), 6.34 (dd, J = 8.3, 1.9Hz, 1H), 6.05 (s, 1H), 3.95 (s, 3H), 3.94 – 3.88 (m, 1H), 3.81 (d, J = 9.9Hz, 1H), 3.74 (s, 3H), 3.49 (m, 2H), 3.41 (s, 3H), 3.29 (s, 3H), 3.26 (d, J =5.5 Hz, 1H), 2.98 (m, 3H), 2.78 (m, 4H), 2.66 (s, 3H), 2.57 (d, J = 13.7 Hz,1H), 2.37-2.32 (m, 1H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.09,153.72, 149.35, 148.29, 147.08, 146.70, 146.48, 143.62, 143.38, 142.38,136.55, 135.19, 134.64, 134.15, 132.67, 130.78, 130.16, 129.03, 128.43,128.34, 127.99, 125.71, 122.78, 121.97, 121.94, 121.46, 120.15, 116.75,116.15, 112.68, 111.44, 63.74, 61.34, 60.90, 60.40, 56.13, 55.68, 45.19,42.95, 42.69, 42.12, 41.62, 37.70, 25.44, 16.15. HRMS (ESI+) m/e [M+H]+：769.34573，C47H48N2O8。
实施例30：TD-60的合成
参考实施例21所述合成方法，以2-溴异丁酰溴和芬氏唐松草碱为原料，合成TD-60，白色粉末，收率84%。1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J = 8.2, 1.8 Hz, 1H),7.17 (dd, J = 8.1, 2.4 Hz, 1H), 6.87 (s, 2H), 6.82 (dd, J = 8.3, 2.4 Hz, 1H),6.57 (s, 1H), 6.54 (s, 1H), 6.33 (dd, J = 8.3, 1.8 Hz, 1H), 6.03 (s, 1H),3.95 (s, 3H), 3.96-3.90 (m, 1H), 3.79 (d, J = 10.1 Hz, 1H), 3.72 (s, 3H),3.55 – 3.42 (m, 2H), 3.39 (s, 3H), 3.30 (d, J = 5.6 Hz, 1H), 3.27 (s, 3H),2.96 (m, 3H), 2.87 – 2.67 (m, 4H), 2.66 (s, 3H), 2.54 (d, J = 13.7 Hz, 1H),2.40-2.34 (m, 1H), 2.32 (s, 3H), 2.11 (d, J = 1.7 Hz, 6H). 13C NMR (101 MHz,CDCl3) δ 169.94, 153.75, 149.34, 148.29, 147.10, 146.67, 143.51, 143.12,142.44, 136.23, 135.08, 134.51, 132.67, 130.15, 128.28, 127.97, 125.76,122.78, 121.98, 121.95, 121.35, 120.13, 116.14, 112.59, 111.45, 63.72, 61.26,61.00, 60.42, 56.12, 55.62, 55.07, 53.48, 45.11, 42.78, 42.61, 42.07, 41.53,37.64, 31.01, 25.37, 15.88. MS (ESI+) m/e [M+H]+：787.25581, 789.25496，C42H47BrN2O8。
实施例31：TD-61的合成
参考实施例21所述合成方法，以3,5-二甲氧基苯甲酰氯和芬氏唐松草碱为原料，合成TD-61，白色粉末，收率88%。1H NMR (600 MHz, CDCl3) δ 7.40-7.36 (m, 3H), 7.18(dd, J = 8.2, 2.5 Hz, 1H), 6.88 (s, 2H), 6.82 (dd, J = 8.3, 2.5 Hz, 1H), 6.75(t, J = 2.3 Hz, 1H), 6.59 (s, 1H), 6.57 (s, 1H), 6.34 (dd, J = 8.3, 2.0 Hz,1H), 6.06 (s, 1H), 3.97 (d, J = 5.8 Hz, 1H), 3.95 (s, 3H), 3.87 (s, 6H),3.85-3.82 (m, 1H), 3.73 (s, 3H), 3.53 – 3.46 (m, 2H), 3.45 (s, 3H), 3.33 (dd,J = 12.6, 5.5 Hz, 1H), 3.29 (s, 3H), 3.05 – 2.99 (m, 1H), 2.94 (dd, J = 14.3,6.4 Hz, 2H), 2.86-2.74 (m, 4H), 2.68 (s, 3H), 2.58 (d, J = 13.9 Hz, 1H),2.40-2.32 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 164.56, 160.83, 153.87, 149.36,148.46, 147.18, 146.47, 143.73, 143.49, 142.44, 136.70, 134.87, 134.53,132.66, 131.03, 130.16, 127.98, 127.77, 125.66, 122.86, 121.96, 121.45,120.18, 116.21, 112.74, 111.55, 107.75, 106.33, 104.18, 63.83, 61.37, 60.94,60.40, 56.14, 55.74, 55.66, 45.16, 42.99, 42.54, 42.15, 41.59, 37.79, 25.23,16.22. HRMS (ESI+) m/e [M+H]+：803.34987，C47H50N2O10。
实施例32：TD-62的合成
参考实施例21所述合成方法，以3,5-二氟苯甲酰氯和芬氏唐松草碱为原料，合成TD-62，白色粉末，收率80%。1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 5.2 Hz, 2H),7.28 (d, J = 7.7 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 8.1 Hz, 1H),6.78 (s, 2H), 6.73 (d, J = 8.2 Hz, 1H), 6.49 (s, 1H), 6.47 (s, 1H), 6.25 (d,J = 8.1 Hz, 1H), 5.96 (s, 1H), 3.85 (s, 3H), 3.85-3.78 (m, 1H), 3.72 (d, J =9.8 Hz, 1H), 3.62 (s, 3H), 3.45-3.35 (m, 2H), 3.34 (s, 3H), 3.20 (s, 3H),3.19-3.14 (m, 1H), 2.96 – 2.78 (m, 3H), 2.77 – 2.59 (m, 4H), 2.57 (s, 3H),2.47 (d, J = 13.8 Hz, 1H), 2.27-2.17 (m, 4H). 13C NMR (101 MHz, CDCl3) δ164.15 (d, J = 11.7 Hz), 162.62, 161.66 (d, J = 11.9 Hz), 153.79, 149.39,148.29, 147.16, 146.78, 143.51, 143.22, 142.48, 136.24, 135.15, 134.54,132.66, 132.45(t, J = 9.4 Hz), 130.14, 128.50, 128.10, 125.87, 122.81,121.95, 121.23, 120.12, 116.20, 113.35, 113.27 (d, J = 11.7 Hz), 113.08,112.65, 111.54, 109.05 (t, J = 26.0 Hz), 63.79, 61.31, 60.90, 60.39, 56.14,55.67, 45.21, 42.85, 42.67, 42.13, 41.56, 37.62, 25.49, 16.14. HRMS (ESI+) m/e [M+H]+：779.31118，C45H44F2N2O8。
实施例33：TD-63的合成
芬氏唐松草碱(200 mg，1倍量)溶于3 mL二氯甲烷中，加入吡喃-4-甲酸(1.2倍量)，以二环己基碳二亚胺滴（1.5倍量）为缩合剂，25 ℃反应6小时，过滤。加入水和二氯甲烷各20 mL，溶液分层，分出二氯甲烷层，饱和食盐水洗涤1次，无水硫酸钠干燥，减压浓缩得到粗品，经硅胶柱层析分离得到化合物TD-63，收率81%。1H NMR (600 MHz, CDCl3) δ 7.36(dd, J = 8.2, 2.0 Hz, 1H), 7.17 (dd, J = 8.1, 2.5 Hz, 1H), 6.91 – 6.84 (m,2H), 6.81 (dd, J = 8.3, 2.5 Hz, 1H), 6.57 (s, 1H), 6.54 (s, 1H), 6.33 (dd, J= 8.3, 2.1 Hz, 1H), 6.03 (s, 1H), 4.05 (dt, J = 11.5, 3.5 Hz, 2H), 3.95 (s,3H), 3.92 (dd, J = 11.0, 5.7 Hz, 1H), 3.79 (d, J = 10.1 Hz, 1H), 3.70 (s,3H), 3.54 (td, J = 11.3, 2.7 Hz, 2H), 3.51 – 3.40 (m, 2H), 3.38 (s, 3H), 3.32– 3.23 (m, 4H), 3.05 – 2.85 (m, 4H), 2.84 – 2.70 (m, 3H), 2.66 (s, 3H), 2.64– 2.59 (m, 1H), 2.54 (d, J = 13.7 Hz, 1H), 2.31 (s, 3H), 2.25 (d, J = 17.2Hz, 1H), 2.06 – 1.96 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 172.56, 153.78,149.36, 148.32, 147.14, 146.40, 143.57, 143.11, 142.41, 136.35, 135.04,134.55, 132.64, 130.13, 128.28, 127.90, 125.71, 122.80, 121.92, 121.90,121.13, 120.10, 116.16, 112.69, 111.52, 67.01, 63.74, 61.27, 60.73, 60.34,56.13, 55.67, 45.12, 42.88, 42.56, 42.09, 41.52, 40.00, 37.62, 28.76, 25.35,16.09. HRMS (ESI+) m/e [M+H]+：751.35617，C44H50N2O9。
实施例34：TD-64的合成
参考实施例33所述合成方法，以4-三氟甲氧基苯甲酸和芬氏唐松草碱为原料，合成TD-64，白色粉末，收率75%。 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H),7.38-7.32 (m, 3H), 7.16 (dd, J = 8.1, 2.4 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J= 8.3, 2.4 Hz, 1H), 6.57 (s, 1H), 6.54 (s, 1H), 6.32 (dd, J = 8.3, 1.7 Hz,1H), 6.03 (s, 1H), 3.93 (s, 3H), 3.92 – 3.85 (m, 1H), 3.80 (d, J = 9.9 Hz,1H), 3.70 (s, 3H), 3.55 – 3.42 (m, 2H), 3.40 (s, 3H), 3.27 (s, 3H), 3.24 (d,J = 5.7 Hz, 1H), 3.04-2.85 (m, 3H), 2.85 – 2.66 (m, 4H), 2.64 (s, 3H), 2.56(d, J = 13.7 Hz, 1H), 2.38-2.25 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 163.57,153.79, 153.12, 149.39, 148.30, 147.15, 146.65, 143.58, 143.36, 142.47,136.44, 135.17, 134.59, 132.66, 132.21, 130.14, 128.53, 128.09, 127.66,125.83, 122.80, 121.94, 121.92, 121.38, 120.49, 120.14, 116.21, 112.70,111.53, 63.79, 61.33, 60.90, 60.39, 56.14, 55.71, 45.23, 42.90, 42.69, 42.14,41.60, 37.66, 25.50, 16.18. HRMS (ESI+) m/e [M+H]+：827.31139，C46H45F3N2O9。
实施例35：TD-81的合成
芬氏唐松草碱(100 mg，1倍量)溶于5 mL二氯甲烷中，加入三乙胺（2.5倍量），加入二(对硝基苯)碳酸酯(1.2倍量), 4-二甲氨基吡啶 (0.1倍量)，室温搅拌反应2小时。加入吗啉（2.5倍量），继续反应2小时。加入水20 mL，溶液分层，分出二氯甲烷层，水洗2次，饱和食盐水洗涤1次，无水硫酸钠干燥，减压浓缩得到粗品，经硅胶柱层析得产物，收率82%。1HNMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.2, 1.9 Hz, 1H), 7.15 (dd, J = 8.2, 2.5Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3, 2.4 Hz, 1H), 6.56 (s, 1H), 6.53 (s,1H), 6.32 (dd, J = 8.3, 1.9 Hz, 1H), 6.02 (s, 1H), 3.93 (s, 3H), 3.90 (d, J =5.6 Hz, 1H), 3.79-3.74 (m, 7H), 3.73 (s, 3H), 3.62-3.55 (m, 2H), 3.54-3.40(m, 2H), 3.38 (s, 3H), 3.32 – 3.20 (m, 4H), 3.08 – 2.82 (m, 4H), 2.82 – 2.66(m, 4H), 2.64 (s, 3H), 2.53 (d, J = 13.7 Hz, 1H), 2.31 (s, 3H). 13C NMR (101MHz, CDCl3) δ 153.74, 153.40, 149.34, 148.32, 147.08, 146.22, 143.66, 142.31,136.88, 135.14, 134.63, 132.65, 130.14, 128.38, 127.95, 125.51, 122.77,121.94, 121.91, 121.73, 120.15, 116.18, 112.71, 111.47, 66.73, 63.74, 61.30,60.88, 60.38, 56.12, 55.72, 45.19, 44.40, 42.95, 42.67, 42.12, 41.60, 37.70,25.41, 15.98. HRMS (ESI+) m/e [M+H]+：752.35178，C43H49N3O9。
实施例36：TD-82至TD-91的合成
参考实施例35所述合成方法，合成TD-82、TD-83、TD-84、TD-85、TD-86、TD-87、TD-88、TD-89、TD-90、TD-91。
TD-82，白色粉末，收率76%。1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.1,1.7 Hz, 1H), 7.16 (dd, J = 8.1, 2.4 Hz, 1H), 6.86 (s, 2H), 6.81 (dd, J = 8.3,2.3 Hz, 1H), 6.56 (s, 1H), 6.53 (s, 1H), 6.32 (dd, J = 8.3, 1.7 Hz, 1H), 6.02(s, 1H), 5.31 (s, 1H), 3.94 (s, 3H), 3.94-3.87 (m, 1H), 3.81-3.75 (m, 3H),3.73 (s, 3H), 3.64-3.58 (m, 2H), 3.50-3.42 (m, 2H), 3.38 (s, 3H), 3.28 (d, J= 5.8 Hz, 1H), 3.26 (s, 3H), 2.99-2,93 (m, 3H), 2.81-2.72 (m, 4H), 2.65 (s,3H), 2.53 (d, J = 13.7 Hz, 1H), 2.51-2.43 (m, 4H), 2.36 (s, 3H), 2.32 (s,3H), 2.26-2.21 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 153.74, 153.28, 149.34,148.35, 147.09, 146.11, 143.74, 143.69, 142.29, 137.02, 135.11, 134.65,132.64, 130.13, 128.33, 127.90, 125.44, 122.77, 121.95, 121.91, 121.82,120.17, 116.17, 112.74, 111.47, 63.75, 61.31, 60.88, 60.38, 56.13, 55.75,54.94, 54.78, 46.25, 45.19, 44.69, 44.11, 42.98, 42.65, 42.13, 41.60, 37.74,25.37, 16.00. HRMS (ESI+) m/e [M+H]+：765.38230，C44H52N4O8。
TD-83，浅黄色粉末，收率71%。1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.1,1.8 Hz, 1H), 7.16 (dd, J = 8.1, 2.4 Hz, 1H), 6.86 (s, 2H), 6.80 (dd, J = 8.3,2.4 Hz, 1H), 6.57 (s, 1H), 6.53 (s, 1H), 6.32 (dd, J = 8.2, 1.9 Hz, 1H), 6.02(s, 1H), 3.94 (s, 3H), 3.93 – 3.87 (m, 1H), 3.78 (d, J = 10.0 Hz, 1H), 3.74(s, 3H), 3.57 – 3.41 (m, 2H), 3.38 (s, 3H), 3.28-3.22 (m, 4H), 3.15 (s, 3H),3.03 (s, 3H), 3.00 – 2.86 (m, 3H), 2.79 – 2.68 (m, 4H), 2.64 (s, 3H), 2.54(d, J = 13.7 Hz, 1H), 2.37-2.32 (m, 1H), 2.32 (s, 3H). 13C NMR (101 MHz,CDCl3) δ 154.50, 153.71, 149.33, 148.34, 147.05, 146.07, 143.85, 143.73,142.27, 137.19, 135.18, 134.70, 132.65, 130.13, 128.38, 127.92, 125.43,122.75, 121.95, 121.90, 121.86, 120.19, 116.18, 112.76, 111.42, 63.72, 61.30,60.91, 60.36, 56.11, 55.78, 45.19, 42.96, 42.67, 42.12, 41.62, 38.63, 37.74,36.90, 36.58, 25.39, 15.97. HRMS (ESI+) m/e [M+H]+：710.34141，C41H47N3O8。
TD-84，浅黄色粉末，收率73%。1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 6.8Hz, 1H), 7.16 (dd, J = 8.1, 2.2 Hz, 1H), 6.86 (s, 2H), 6.81 (dd, J = 8.2, 2.1Hz, 1H), 6.56 (s, 1H), 6.53 (s, 1H), 6.32 (d, J = 6.7 Hz, 1H), 6.02 (s, 1H),5.01 (d, J = 7.9 Hz, 1H), 3.94 (s, 3H), 3.92 – 3.82 (m, 2H), 3.82-3.75 (m,1H), 3.75 (s, 3H), 3.53 – 3.40 (m, 2H), 3.37 (s, 3H), 3.31 – 3.13 (m, 4H),3.05 – 2.86 (m, 3H), 2.81-2.72 (m, 4H), 2.64 (s, 3H), 2.54 (d, J = 13.8 Hz,1H), 2.41 – 2.33 (m, 1H), 2.33-2.21 (m, 4H), 1.24 (d, J = 6.3 Hz, 6H). 13C NMR(151 MHz, CDCl3) δ 153.76, 153.53, 149.37, 148.36, 147.10, 146.13, 143.97,143.68, 142.26, 136.67, 135.12, 134.69, 132.64, 130.13, 128.35, 127.88,125.42, 122.81, 122.18, 121.93, 121.90, 120.11, 116.16, 112.82, 111.53,63.77, 61.32, 60.83, 60.35, 56.14, 55.77, 45.19, 43.52, 43.04, 42.63, 42.14,41.60, 37.71, 25.36, 22.95, 16.07. HRMS (ESI+) m/e [M+H]+：724.35773，C42H49N3O8。
TD-85，白色粉末，收率70%。1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 6.9 Hz,1H), 7.16 (d, J = 6.4 Hz, 1H), 6.86 (s, 2H), 6.80 (d, J = 7.3 Hz, 1H), 6.57(s, 1H), 6.53 (s, 1H), 6.31 (d, J = 6.9 Hz, 1H), 6.02 (s, 1H), 3.93 (s, 3H),3.92 – 3.85 (m, 1H), 3.82-3.76 (m, 1H), 3.76 (s, 3H), 3.63-3.58 (m, 2H),3.51-3.42 (m, 4H), 3.38 (s, 3H), 3.30-3.19 (m, 4H), 3.10 – 2.88 (m, 3H), 2.86– 2.68 (m, 4H), 2.64 (s, 3H), 2.54 (d, J = 13.6 Hz, 1H), 2.41-2.34 (m, 1H),2.31 (s, 3H), 1.96 (dd, J = 12.8, 6.2 Hz, 4H). 13C NMR (151 MHz, CDCl3) δ153.81, 152.79, 149.35, 148.40, 147.11, 146.05, 143.98, 143.83, 142.29,137.17, 135.08, 134.75, 132.64, 130.12, 128.29, 127.84, 125.43, 122.80,121.97, 121.91, 121.88, 120.21, 116.26, 112.85, 111.54, 63.78, 61.36, 60.88,60.34, 56.14, 55.81, 46.52, 46.42, 45.22, 43.07, 42.63, 42.14, 41.67, 37.81,25.91, 25.35, 25.04, 16.09. HRMS (ESI+) m/e [M+H]+：736.35657，C43H49N3O8。
TD-86，浅黄色粉末，收率66%。1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 8.1,1.9 Hz, 1H), 7.16 (dd, J = 8.1, 2.5 Hz, 1H), 6.87 (s, 2H), 6.81 (dd, J = 8.3,2.4 Hz, 1H), 6.56 (s, 1H), 6.53 (s, 1H), 6.32 (dd, J = 8.3, 1.9 Hz, 1H), 6.02(s, 1H), 3.94 (s, 3H), 3.93 – 3.83 (m, 3H), 3.81 – 3.77 (m, 1H), 3.74 (s,3H), 3.55 (s, 1H), 3.52 – 3.41 (m, 2H), 3.39 (s, 3H), 3.30-3.22 (m, 4H), 3.22(s, 1H), 3.09 (s, 1H), 3.03 – 2.88 (m, 3H), 2.81-2.72 (m, 4H), 2.65 (s, 3H),2.56-2.50 (m, 1H), 2.35 (d, J = 7.2 Hz, 1H), 2.31 (s, 3H), 2.02 (s, 3H). 13CNMR (151 MHz, CDCl3) δ 155.76, 153.76, 149.37, 148.36, 147.11, 146.16,144.19, 143.64, 142.19, 137.03, 135.14, 134.67, 132.63, 130.13, 128.42,127.96, 125.50, 122.80, 121.94, 121.91, 121.81, 120.17, 116.19, 112.74,111.52, 63.77, 61.30, 60.88, 60.75, 60.34, 56.14, 55.79, 52.21, 45.21, 42.98,42.66, 42.15, 41.59, 37.71, 35.80, 25.41, 16.11. HRMS (ESI+) m/e [M+H]+：740.35187，C42H49N3O9。
TD-87，浅黄色粉末，收率79%。1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 8.1,1.7 Hz, 1H), 7.16 (dd, J = 8.1, 2.4 Hz, 1H), 6.87 (s, 2H), 6.81 (dd, J = 8.3,2.3 Hz, 1H), 6.56 (s, 1H), 6.53 (s, 1H), 6.33 (dd, J = 8.3, 1.8 Hz, 1H), 6.02(s, 1H), 5.49 (t, J = 5.3 Hz, 1H), 4.15-4.05 (m, 2H), 3.94 (s, 3H), 3.5-3.87(m, 1H), 3.79 (d, J = 10.0 Hz, 1H), 3.75 (s, 3H), 3.57 – 3.42 (m, 2H), 3.39(s, 3H), 3.30 (d, J = 5.6 Hz, 1H), 3.26 (s, 3H), 2.99-2.90 (m, 3H), 2.81-2.72(m, 4H), 2.66 (s, 3H), 2.54 (d, J = 13.8 Hz, 1H), 2.39-2.35 (m, 1H), 2.31 (s,3H), 2.14 (s, 1H). 13C NMR (151 MHz, CDCl3) δ 153.97, 153.79, 149.37, 148.37,147.14, 146.32, 143.88, 143.63, 142.29, 136.51, 135.02, 134.58, 132.64,130.14, 128.21, 127.85, 125.46, 122.83, 121.99, 121.95, 121.93, 120.11,116.15, 112.76, 111.53, 79.36, 71.97, 63.79, 61.32, 60.94, 60.37, 56.14,55.72, 45.16, 43.00, 42.58, 42.14, 41.57, 37.70, 31.20, 25.31, 16.06. HRMS(ESI+) m/e [M+H]+：720.32626，C42H45N3O8。
TD-88，白色粉末，收率80%。1H NMR (400 MHz, CDCl3) δ 7.41 – 7.31 (m, 1H),7.16 (dd, J = 8.1, 2.3 Hz, 1H), 6.86 (s, 2H), 6.81 (dd, J = 8.2, 2.2 Hz, 1H),6.57 (s, 1H), 6.53 (s, 1H), 6.37 – 6.28 (m, 1H), 6.02 (s, 1H), 4.38 – 4.25(m, 1H), 3.97-3.91 (m, 4H), 3.93-3.88 (m, 1H), 3.85-3.76 (m, 2H), 3.75 (s,3H), 3.69-3.64 (m, 1H), 3.58 – 3.41 (m, 3H), 3.38 (s, 3H), 3.31-3.25 (m, 1H),3.23 (s, 3H), 3.03 – 2.87 (m, 3H), 2.81-2.72 (m, 4H), 2.65 (s, 3H), 2.54 (d,J = 13.8 Hz, 1H), 2.36-2.28 (m, 4H), 2.17-2.13 (m, 2H), 1.97-1.93 (m, 2H). 13CNMR (151 MHz, CDCl3) δ 153.78, 153.29, 149.37, 148.37, 147.13, 146.15,143.75, 143.69, 142.31, 136.96, 135.08, 134.64, 132.64, 130.13, 128.34,127.91, 125.48, 122.81, 121.93, 121.90, 121.79, 120.17, 116.20, 112.81,111.53, 63.77, 61.31, 60.84, 60.36, 56.43, 56.14, 55.77, 45.20, 42.99, 42.63,42.14, 41.75, 41.58, 37.70, 35.06, 34.71, 25.37, 16.05. MS (ESI+) m/e [M+H]+：784.33280，C40H50ClN3O8。
TD-89，浅黄色粉末，收率72%。1H NMR (400 MHz, CDCl3) δ 7.37 – 7.22 (m,6H), 7.13 (dd, J = 8.1, 2.4 Hz, 1H), 6.84 (s, 2H), 6.78 (dd, J = 8.2, 2.3 Hz,1H), 6.55 (s, 1H), 6.52 (s, 1H), 6.30 (dd, J = 8.2, 1.7 Hz, 1H), 6.00 (s,1H), 5.37 (s, 1H), 4.28 (s, 2H), 3.91 (s, 3H), 3.92-3.85 (m, 1H), 3.79 (d, J= 9.7 Hz, 1H), 3.70 (s, 3H), 3.53 – 3.37 (m, 2H), 3.35 (s, 3H), 3.29 – 3.15(m, 4H), 3.04 – 2.64 (m, 7H), 2.61 (s, 3H), 2.52 (d, J = 13.9 Hz, 1H), 2.40-2.32 (m, 1H), 2.27 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 158.79, 153.64, 149.34,148.45, 147.10, 146.04, 143.93, 143.55, 142.25, 138.26, 136.67, 134.93,134.41, 132.61, 130.21, 128.68, 127.95, 127.64, 127.55, 127.36, 125.35,122.91, 121.99, 121.95, 121.90, 120.03, 115.91, 112.70, 111.55, 63.56, 61.27,60.85, 60.32, 56.10, 55.63, 44.80, 44.20, 42.92, 42.28, 42.07, 41.36, 37.28,25.04, 16.31. MS (ESI+) m/e [M+H]+：772.44，C46H49N3O8。
TD-90，白色粉末，收率78%。1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.8 Hz,2H), 7.36 (dd, J = 8.1, 1.6 Hz, 1H), 7.26 (t, J = 4.8 Hz, 1H), 7.16 (dd, J =8.1, 2.3 Hz, 1H), 6.87 (s, 2H), 6.81 (dd, J = 8.3, 2.3 Hz, 1H), 6.57 (s, 1H),6.53 (s, 1H), 6.39 (t, J = 4.7 Hz, 1H), 6.32 (dd, J = 8.3, 1.6 Hz, 1H), 6.03(s, 1H), 4.76 (d, J = 4.8 Hz, 2H), 3.94 (s, 3H), 3.93-2.87 (m, 1H), 3.83 –3.65 (m, 4H), 3.55 – 3.41 (m, 2H), 3.38 (s, 3H), 3.31 – 3.14 (m, 4H), 3.02(s, 1H), 3.00 – 2.86 (m, 3H), 2.84-2.71 (m, 4H), 2.65 (s, 3H), 2.55 (d, J =13.8 Hz, 1H), 2.42 (dd, J = 17.3, 4.5 Hz, 1H), 2.31 (s, 3H). 13C NMR (151 MHz,CDCl3) δ 165.76, 157.22, 154.38, 153.79, 149.36, 148.35, 147.10, 146.26,144.03, 143.72, 142.27, 136.70, 135.12, 134.73, 132.64, 130.12, 128.36,127.91, 125.45, 122.80, 122.19, 121.93, 121.90, 120.15, 119.66, 116.21,112.78, 111.54, 63.80, 61.36, 60.96, 60.38, 56.14, 55.73, 46.79, 45.25,43.08, 42.67, 42.16, 41.66, 37.80, 25.39, 16.05. HRMS (ESI+) m/e [M+H]+：774.34722，C44H47N5O8。
TD-91，浅黄色粉末，收率73%。1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 6.9Hz, 1H), 7.17 (d, J = 5.6 Hz, 2H), 6.87 (s, 2H), 6.81 (dd, J = 9.4, 3.4 Hz,2H), 6.57 (s, 1H), 6.54 (s, 1H), 6.32 (d, J = 6.7 Hz, 1H), 6.03 (s, 1H), 4.82(s, 1H), 4.67 (s, 1H), 4.01 (s, 1H), 3.94 (s, 3H), 3.95-3.87 (m, 2H), 3.79(d, J = 9.9 Hz, 1H), 3.71 (d, J = 8.9 Hz, 3H), 3.50-3.40 (m, 2H), 3.40 (s,3H), 3.34 – 3.16 (m, 4H), 3.09 – 2.87 (m, 5H), 2.87 – 2.68 (m, 4H), 2.65 (s,3H), 2.54 (d, J = 13.8 Hz, 1H), 2.5-2.40 (m, 1H), 2.32 (s, 3H). 13C NMR (151MHz, CDCl3) δ 153.81, 149.36, 148.37, 147.11, 146.20, 143.77, 142.32, 137.00,135.12, 134.71, 133.44, 132.90, 132.65, 132.14, 131.56, 130.13, 128.39,127.94, 125.51, 124.99, 124.71, 123.52, 123.34, 122.81, 121.92, 120.19,116.25, 112.79, 111.55, 63.78, 61.33, 60.86, 60.37, 56.15, 55.77, 45.23,44.98, 44.87, 42.99, 42.66, 42.14, 41.63, 37.78, 29.71, 25.40, 16.04. HEMS(ESI+) m/e [M+H]+：804.32768，C46H49N3O8S。
实施例37：TD-93的合成
芬氏唐松草碱(100 mg，1倍量)溶于5 mL二氯甲烷中，加入三乙胺（1.2倍量），加入4-三氟甲氧基苯异氰酸酯（1.2倍量）, 4-二甲氨基吡啶 (0.1倍量)，室温搅拌反应10小时。加入水20 mL，溶液分层，分出二氯甲烷层，水洗2次，饱和食盐水洗涤1次，无水硫酸钠干燥，减压浓缩得到粗品，经硅胶柱层析得产物，收率88%。1H NMR (400 MHz, CDCl3) δ 7.52 (d,J = 8.2 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.19 (s,2H), 6.86 (s, 2H), 6.81 (d, J = 6.9 Hz, 1H), 6.56 (s, 1H), 6.55 (s, 1H), 6.33(d, J = 8.5 Hz, 1H), 6.01 (s, 1H), 3.97-3.89 (m, 4H), 3.85 (d, J = 9.7 Hz,1H), 3.75 (s, 3H), 3.55 – 3.42 (m, 2H), 3.40 (s, 3H), 3.32-3.18 (m, 4H),3.05-2.95 (m, 3H), 2.86 – 2.66 (m, 4H), 2.62 (s, 3H), 2.55 (d, J = 14.2 Hz,1H), 2.41 (dd, J = 17.4, 4.1 Hz, 1H), 2.29 (s, 3H). MS (ESI+) m/e [M+H]+：842.41，C46H46F3N3O9。
实施例38：芬氏唐松草碱衍生物抗肿瘤活性
实验材料和试剂：K562（人慢性髓原白血病细胞）、MCF-7（人乳腺癌细胞）、A549（人非小细胞肺癌细胞）、HepG-2（人肝癌细胞）、HT-29（人结肠癌细胞）和Hela（人宫颈癌细胞）来源于贵州中医药大学基础医学院；Capan-1（人胰腺癌细胞）来源于复旦大学胰腺肿瘤研究所；K562/ADR（人白血病细胞阿霉素耐药株）、MCF-7/ADR（人乳腺癌细胞阿霉素耐药株）和A549/Taxol（人非小细胞肺癌细胞紫杉醇耐药株）来源于华东理工大学药学院。对照药物芬氏唐松草碱来源于禹捷生物科技上海有限公司，紫杉醇和阿霉素购自上海阿拉丁生化科技股份有限公司，其它常规试剂购买自各大生物医药试剂公司。
实验方法：对处于对数生长期的肿瘤细胞配成固定浓度的细胞悬液，并用细胞计数仪对其进行计数，按每孔5000个细胞的浓度在96孔板中将耐药细胞孵育。待细胞贴壁后，向实验孔中加入不同浓度芬氏唐松草碱衍生物，浓度分别为50、25、12.5、6.25、3.125、1.56、0.78 μM的衍生物，每个浓度设3个复孔。以芬氏唐松草碱为阳性药物对照组，另设空白组。加药后于培养箱中孵育48小时。通过cck8法用酶标仪测定各孔在450 nm波长下的吸光度，利用GraphPad软件计算各衍生物的IC50值。结果见表1和表2，单位：μM/L。
表1 芬氏唐松草碱衍生物抗肿瘤细胞增殖活性IC50
| K562 | MCF-7 | A549 | HepG-2 | HT-29 | |
| TD-01 | 6.32 | 12.56 | 6.04 | 15.45 | 2.64 |
| TD-02 | 10.84 | 12.26 | 8.65 | 22.06 | 5.43 |
| TD-03 | 6.51 | 10.05 | 4.22 | 9.78 | 6.54 |
| TD-04 | 10.21 | 5.25 | 5.95 | 12.80 | 8.45 |
| TD-06 | 5.65 | 6.86 | 12.45 | 18.31 | 5.34 |
| TD-07 | 18.86 | 12.45 | 21.89 | 33.54 | 12.62 |
| TD-08 | 8.46 | 10.21 | 6.56 | 8.37 | 5.23 |
| TD-09 | 6.54 | 15.31 | 8.15 | 13.24 | 6.12 |
| TD-10 | 4.36 | 12.74 | 7.55 | 10.65 | 6.37 |
| TD-11 | 5.84 | 6.34 | 7.38 | 12.56 | 8.32 |
| TD-12 | 28.05 | 22.67 | ＞50 | ＞50 | 17.32 |
| TD-21 | 5.52 | 4.87 | 3.24 | 4.74 | 2.64 |
| TD-22 | 6.02 | 6.75 | 15.88 | 5.36 | 9.03 |
| TD-23 | 4.46 | 5.23 | 6.46 | 12.34 | 5.75 |
| TD-24 | 2.94 | 4.34 | 10.98 | 8.64 | 1.06 |
| TD-25 | 15.49 | 8.27 | 13.58 | 14.31 | 6.23 |
| TD-26 | 35.28 | 16.89 | 24.87 | 35.38 | 25.49 |
| TD-27 | 3.64 | 9.36 | 8.42 | 6.45 | 2.36 |
| TD-28 | 44.04 | 18.33 | ＞50 | 19.38 | 20.06 |
| TD-29 | 2.97 | 0.83 | 1.15 | 1.32 | 0.86 |
| TD-51 | 4.25 | 3.17 | 8.56 | 2.30 | 3.45 |
| TD-52 | 7.26 | 20.32 | 21.05 | 23.89 | 11.23 |
| TD-53 | 5.76 | 6.39 | 5.36 | 5.66 | 3.45 |
| TD-54 | 12.91 | 20.08 | 5.37 | 8.34 | 5.32 |
| TD-55 | 4.55 | 12.87 | 19.96 | 11.06 | 8.21 |
| TD-56 | 2.49 | 6.28 | 3.54 | 1.34 | 0.85 |
| TD-57 | 15.12 | 8.26 | 10.53 | 10.45 | 5.74 |
| TD-58 | 22.13 | 12.53 | 18.51 | 18.76 | 5.34 |
| TD-59 | 3.06 | 3.56 | 2.02 | 8.62 | 1.44 |
| TD-60 | 8.35 | 9.28 | 9.76 | 7.38 | 3.10 |
| TD-61 | 6.06 | 2.67 | 1.37 | 8.30 | 1.84 |
| TD-62 | 8.62 | 9.65 | 6.38 | 4.22 | 5.33 |
| TD-63 | 1.94 | 2.34 | 2.08 | 2.22 | 0.98 |
| TD-64 | 9.01 | 6.97 | 8.01 | 9.65 | 6.41 |
| TD-81 | 8.73 | 6.96 | 2.38 | 3.67 | 1.21 |
| TD-82 | 7.90 | 2.65 | 5.58 | 2.95 | 4.26 |
| TD-83 | 9.22 | 7.50 | 4.38 | 9.76 | 3.48 |
| TD-84 | 6.50 | 2.54 | 10.85 | 8.28 | 6.47 |
| TD-85 | 1.38 | 2.45 | 5.46 | 5.36 | 1.84 |
| TD-86 | 15.3 | 18.34 | 22.54 | 38.01 | 32.84 |
| TD-87 | 4.51 | 6.24 | 8.24 | 4.24 | 6.45 |
| TD-88 | 1.84 | 2.54 | 9.65 | 14.32 | 7.45 |
| TD-89 | 7.24 | 12.54 | 2.34 | 5.34 | 1.74 |
| TD-90 | 1.72 | 3.14 | 2.54 | 3.45 | 1.87 |
| TD-91 | 9.73 | 12.37 | 18.87 | 9.98 | 6.45 |
| TD-93 | 17.96 | 15.64 | 17.34 | 22.39 | 18.64 |
| 芬氏唐松草碱 | 15.45 | 17.54 | 18.64 | 12.45 | 9.85 |
表2 芬氏唐松草碱衍生物抗肿瘤细胞和耐药细胞增殖活性IC50
| Capan-1 | Hela | K562/ADR | MCF-7/ADR | A549/Taxol | |
| TD-01 | 8.98 | 6.34 | 5.12 | 9.15 | 7.47 |
| TD-02 | 11.62 | 8.15 | 7.34 | 10.05 | 12.98 |
| TD-03 | 11.51 | 12.03 | 8.26 | 9.78 | 9.56 |
| TD-04 | 13.53 | 8.24 | 5.42 | 6.82 | 4.35 |
| TD-06 | 11.69 | 6.04 | 18.20 | 12.31 | 17.56 |
| TD-07 | 18.86 | 16.35 | 20.74 | 21.02 | 23.84 |
| TD-08 | 11.46 | 8.63 | 6.46 | 8.34 | 10.24 |
| TD-09 | 11.54 | 6.45 | 7.17 | 10.85 | 15.34 |
| TD-10 | 9.16 | 6.24 | 7.42 | 12.45 | 10.78 |
| TD-11 | 11.8 | 10.34 | 7.38 | 12.56 | 15.14 |
| TD-12 | ＞50 | 22.07 | 27.48 | 30.05 | 35.32 |
| TD-21 | 5.52 | 2.05 | 1.64 | 1.34 | 3.18 |
| TD-22 | 10.32 | 5.83 | 4.89 | 3.96 | 3.54 |
| TD-23 | 11.68 | 6.27 | 5.28 | 14.28 | 12.72 |
| TD-24 | 7.86 | 2.47 | 1.38 | 8.63 | 5.08 |
| TD-25 | 15.99 | 13.17 | 13.48 | 14.35 | 17.65 |
| TD-26 | ＞50 | 26.89 | 24.87 | 35.38 | 27.49 |
| TD-27 | 7.64 | 2.22 | 3.32 | 13.19 | 14.45 |
| TD-28 | ＞50 | 35.24 | 22.54 | 38.45 | ＞50 |
| TD-29 | 5.97 | 1.32 | 1.54 | 2.58 | 3.46 |
| TD-51 | 8.25 | 3.17 | 8.56 | 2.30 | 8.97 |
| TD-52 | 11.26 | 5.32 | 2.05 | 8.89 | 8.45 |
| TD-53 | 9.76 | 6.39 | 7.36 | 2.45 | 7.98 |
| TD-54 | 18.91 | 11.08 | 9.37 | 18.34 | 12.87 |
| TD-55 | 9.55 | 4.80 | 9.26 | 12.06 | 11.54 |
| TD-56 | 7.49 | 6.28 | 3.54 | 13.34 | 8.41 |
| TD-57 | 15.74 | 12.25 | 10.13 | 10.44 | 15.87 |
| TD-58 | 39.13 | 22.53 | 28.51 | 43.76 | 25.37 |
| TD-59 | 9.06 | 3.76 | 2.02 | 8.68 | 14.75 |
| TD-60 | 11.35 | 6.28 | 9.76 | 7.38 | 15.34 |
| TD-61 | 13.06 | 10.67 | 9.37 | 8.30 | 9.32 |
| TD-62 | 12.62 | 7.65 | 9.38 | 12.22 | 18.65 |
| TD-63 | 4.94 | 1.34 | 2.08 | 4.20 | 5.84 |
| TD-64 | 19.01 | 6.97 | 11.01 | 22.65 | 24.35 |
| TD-81 | 11.73 | 5.96 | 10.38 | 9.67 | 14.21 |
| TD-82 | 11.9 | 4.25 | 5.51 | 2.92 | 14.56 |
| TD-83 | 12.22 | 18.5 | 23.38 | 34.76 | 38.61 |
| TD-84 | 11.50 | 7.56 | 10.88 | 15.28 | 7.84 |
| TD-85 | 6.38 | 2.45 | 5.34 | 8.65 | 12.45 |
| TD-86 | 23.3 | 14.56 | 18.45 | 22.42 | 28.31 |
| TD-87 | 10.51 | 6.21 | 6.01 | 12.49 | 8.77 |
| TD-88 | 5.84 | 2.01 | 3.64 | 6.44 | 9.32 |
| TD-89 | 17.24 | 10.45 | 9.10 | 14.77 | 17.36 |
| TD-90 | 5.72 | 2.41 | 1.87 | 3.89 | 5.42 |
| TD-91 | 11.73 | 6.21 | 9.17 | 13.58 | 18.95 |
| TD-93 | 12.96 | 9.24 | 9.43 | 13.34 | 18.73 |
| 芬氏唐松草碱 | 25.38 | 15.46 | 93.66 | 22.75 | 28.64 |
实验结论：芬氏唐松草碱衍生物具有广谱的抗肿瘤活性，活性较好，并且具有抗耐药细胞增殖活性，大部分衍生物活性强于芬氏唐松草碱。
实施例39：芬氏唐松草碱衍生物逆转肿瘤耐药活性
实验材料和试剂： K562/ADR（人白血病细胞阿霉素耐药株）、MCF-7/ADR（人乳腺癌细胞阿霉素耐药株）和A549/Taxol（人非小细胞肺癌细胞紫杉醇耐药株）来源于华东理工大学药学院。对照药物Tarquidar来源于禹捷生物科技（上海）有限公司，紫杉醇和阿霉素购自上海阿拉丁生化科技股份有限公司，其它常规试剂购买自各大生物医药试剂公司。
实验方法：分别对K562/ADR、MCF-7/ADR和A549/Taxol耐药细胞进行培养基停药处理，以排除培养基中所含微量药物对细胞实验的影响。停药1周后，对耐药细胞及各自的亲本细胞进行耐药性检测。首先，实验测得阿霉素对K562耐药株IC50为16.18，对敏感株IC50为0.31，耐药52倍；阿霉素对MCF-7耐药株IC50为14.07，对敏感株IC50为1.04，耐药13.5倍；紫杉醇对A549耐药株IC50为26.84，对敏感株IC50为2.18，耐药12倍。
耐药倍数=药物对耐药株IC50值/药物对敏感株的IC50值。
对芬氏唐松草碱衍生物进行抗耐药活性测试，将耐药细胞按每孔5000个细胞的浓度孵育在96孔板中并待细胞贴壁后，先向实验孔中加入终浓度为1 μM/L的芬氏唐松草碱衍生物，30分钟后再加入浓度梯度为5、2.5、1.25、0.625、0.3125、0.156、0.078 μM/L的阿霉素，每个浓度设3个复孔。以tarquidar为阳性药物对照，药物共作用48小时。通过cck8法测定1 μM浓度的芬氏唐松草碱衍生物与阿霉素联用后阿霉素对耐药细胞的IC50，最后计算各衍生物逆转MDR倍数(RF)。同法检测芬氏唐松草碱衍生物对MCF-7/ADR耐药细胞和A549/Taxol耐药细胞的抗耐药活性。
逆转倍数= (阿霉素单独作用耐药细胞的IC50) / (阿霉素与衍生物联用后阿霉素对耐药细胞的IC50)。利用GraphPad软件计算各衍生物的IC50值，实验结果见表3、表4和表5，单位：μM/L。
表3 芬氏唐松草碱衍生物逆转K562/ADR耐药活性
表4 芬氏唐松草碱衍生物逆转MCF-7/ADR耐药活性
表5 芬氏唐松草碱衍生物逆转A549/Taxol耐药活性
实验结论：芬氏唐松草碱衍生物具有优良的逆转肿瘤耐药的活性，能够增加化疗药物的疗效，部分化合物效果明显优于Tarquidar。
以上所述仅是本发明的较佳实施例而已，并非对本发明作任何形式上的限制，虽然本发明已以较佳实施例揭露如上，然而并非用以限定本发明，任何熟悉本专利的技术人员在不脱离本发明技术方案范围内，当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例，但凡是未脱离本发明技术方案的内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明方案的范围内。
Claims (7)
1.一种芬氏唐松草碱衍生物或其药用盐，其特征在于，结构选自以下结构的一种：
R1选自C2~C6烷基，或C1~C6烷基且烷基上的氢被F原子单取代或多取代，或C1~C6烷基且烷基上的氢被CF3取代，C1~C6烷氧基C1~C6烷基、 ；
R2选自苯环上的取代基，包括F、Cl、Br、三氟甲基、氨基、氰基、酯基、硝基、甲氧基、羟基，取代基数量为1-3；
R3选自C1~C6烷基、C2~C6的烯基、C3~C6的环烷基、吡喃环基、苯基、吡啶基、呋喃基、噻吩基，其中苯基、吡啶基、呋喃基、噻吩基上有1-3个取代基，取代基包括F、Cl、Br、三氟甲基、氨基、氰基、酯基、硝基、甲氧基、羟基；
R4、R5各自独立的选自C1~C6烷基，或与C、N、O一起形成3元~6元环，环上N可以与甲基、乙基和异丙基连接，环上C原子上的H可以被F、Cl原子单取代或多取代，当R4为H或甲基时，R5选自苯环或取代的苯环，取代基包括F、Cl、Br、三氟甲基、氨基、氰基、酯基、硝基、甲氧基、羟基，取代基数量为1-3；
R6、R7各自独立的选自H、C1~C4烷基，或与C、N、O一起形成3元~6元环；
R8选自H、甲基、乙基。R9选自C1~C5的烷基、、苯基、吡啶基、嘧啶基、呋喃基、噻吩基，其中苯基、吡啶基、嘧啶基、呋喃基、噻吩基上有1-3个取代基，取代基包括F、Cl、Br、三氟甲基、氨基、氰基、硝基、甲氧基、羟基。
2. 根据权利要求1所述的芬氏唐松草碱衍生物或其药用盐，其特征在于，所述芬氏唐松草碱衍生物中，R1选自以下结构的一种：
3.一种权利要求1或2所述的芬氏唐松草碱衍生物或其药用盐在制备抗肿瘤药物中的应用。
4.根据权利要求3所述的应用，其特征在于，所述肿瘤选自白血病、多发性骨髓瘤、淋巴瘤、肝癌、胃癌、乳腺癌、结肠癌、胆管细胞癌、胰腺癌、肺癌、大肠癌、骨肉瘤、黑色素瘤、人宫颈癌、神经胶质瘤、鼻咽癌、喉癌、食管癌、中耳肿瘤或前列腺癌。
5.一种权利要求1或2所述的芬氏唐松草碱衍生物或其药用盐与其他药物联用在制备抗肿瘤药物中的应用。
6.根据权利要求5所述的应用，其特征在于，所述其他药物选自阿霉素、紫杉醇。
7.一种权利要求1或2所述的芬氏唐松草碱衍生物或其药用盐在制备肿瘤耐药逆转剂中的应用。
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