CN116217582A - 一种鹤氏唐松草碱衍生物及应用 - Google Patents
一种鹤氏唐松草碱衍生物及应用 Download PDFInfo
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- CN116217582A CN116217582A CN202211725266.3A CN202211725266A CN116217582A CN 116217582 A CN116217582 A CN 116217582A CN 202211725266 A CN202211725266 A CN 202211725266A CN 116217582 A CN116217582 A CN 116217582A
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Abstract
本发明公开了一种鹤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，涉及一种鹤氏唐松草碱衍生物及应用。
背景技术
尽管癌症药物治疗已经取得了一定进展，但大多数患者最终的治疗失败的主要原因之一是药物的耐药。目前活性最好的肿瘤耐药逆转剂是以tariquidar为代表的第三代合成药物，但在临床研究中未有良好的表现。例如，由于在临床研究中发现了较高比例的不良事件，活性最高的tariquidar在III期临床被停止。肿瘤耐药的复杂过程涉及宿主和肿瘤遗传改变，表观遗传变化和肿瘤环境等因素，抗肿瘤耐药的药物，对基于靶标设计的合成类药物是巨大的挑战。而天然产物往往具有多种作用机制，表现多种药理活性，因此，研究人员一直致力于从天然产物中寻找高效低毒的抗肿瘤药物。
鹤氏唐松草碱是一种双苄基异喹啉生物碱，主要存在于毛莨科唐松草属植物中。鹤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位取代的甲氧基(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。鹤氏唐松草碱天然来源受限，在先前的研究中，已经开发了鹤氏唐松草碱的大量制备方法(公开号为CN109280057A)。
式1鹤氏唐松草碱的分子结构
早年的药理研究表明，鹤氏唐松草碱具有多种生物活性。鹤氏唐松草碱对P388白血病小鼠、腹水型S180及C 26结肠癌小鼠有一定的治疗作用。在体外，鹤氏唐松草碱明显地抑制小鼠白血病L1210细胞及人口腔癌KB细胞的生长，对小鼠正常造血细胞(CFU-GM)的抑制作用较弱(药学学报Pharmaceutica Sinica 1990；25(5)：330～335)。马丽娟等人报道了鹤氏唐松草碱具有良好的抗血小板聚集作用(马丽绢，尹钟沫，刘干中；鹤氏唐松草碱对血小板聚集的影响及机理探讨，中国药理学与毒理学杂志，1991；5(1):41)。郭景珍等人发现鹤氏唐松草碱具有和维拉帕米相似的钙离子通道阻滞作用(中药临床与药理1995(5))。
近年研究发现鹤氏唐松草碱作为一种有效的AMPK激动剂，可以诱导耐药的肿瘤细胞凋亡(Oncotarget，Vol.7，No.7)。Chung-Pu Wu等人报道了鹤氏唐松草碱是一种有效的肿瘤多药耐药逆转剂，能够与临床上的多种抗肿瘤药物，如阿霉素、长春碱以及秋水仙碱等联用，在纳摩尔极浓度下，能够有效的逆转多药耐药。该研究表明鹤氏唐松草碱选择性作用于ABCB1耐药基因，毒性很低，有望开发为高效低毒的肿瘤化疗药物增敏剂(J.Nat.Prod.2016，79，2135-2142)。
近期，柏静等人发现鹤氏唐松草碱能有效降低2型糖尿病小鼠模型的体重和血糖，同时调节糖脂代谢，并研究了鹤氏唐松草碱激活AMPK的机制。鹤氏唐松草碱不会诱导心脏肥大，毒副作用很小，疗效明显优于2型糖尿病临床1线药物二甲双胍(Phytomedicine，2022，vol.105，art.no.154366)。宋长丰等人发现鹤氏唐松草碱呈现剂量和时间依赖性地抑制胰腺癌细胞增殖，通过AMPK-mTOR途径诱导自噬，并诱导自噬性死亡，为鹤氏唐松草碱治疗胰腺癌提供了有利的依据(Acta Pharmacologica Sinica(2022)0:1–12)。Wang等人发现鹤氏唐松草碱能够调节黑色素瘤细胞的增殖和自噬诱导的细胞凋亡(Journal ofNatural Products，2022，vol.85，#5，p.1351-1362)。
以上研究表明，鹤氏唐松草碱药理活性广泛，且活性高，具有很高的药用价值。因此关于鹤氏唐松草碱衍生物的研究具有重要价值。经过文献检索，目前尚未发现关于鹤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鹤氏唐松草碱衍生物。
本发明的另一个目的是提供一种所述鹤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鹤氏唐松草碱衍生物或其药用盐，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、C3～C6的烯基、
R2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；
R3选自-CF3、-CH3、
R4选自C1～C8烷基、
R5选自C1～C4烷基、C1～C4烷氧基C1～C4烷基；
R6、R7各自独立的选自C1～C6烷基，或与N、O一起形成3元～6元环；
R8选自单取代或多取代的F、Cl、Br、三氟甲基、氨基、氰基、酯基、硝基、氢、甲氧基、羟基；
R9选自
R10选自C1～C6烷基；
R11选自C1～C6烷基；
R12选自C1～C6烷基；
R13选自C1～C6烷基；
R14选自C1～C6烷基。
所述鹤氏唐松草碱衍生物中，R1选自以下结构的一种：
R9选自
本发明的第二方面提供了一种所述鹤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鹤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鹤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：
本发明提供的鹤氏唐松草碱衍生物，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。
本发明提供的鹤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，本发明提供的鹤氏唐松草碱衍生物与鹤氏唐松草碱相比，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，增加疗效。
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5-溴防己诺林碱和鹤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
5-甲氧基防己诺林碱合成
5-溴防己诺林碱(5g，1倍量)加入DMF 50ml，30％甲醇钠的甲醇溶液5ml，溴化亚铜200mg，与氮气保护下，回流反应6小时，减压浓缩，加入二氯甲烷50ml，过滤。母液减压浓缩，粗品经二氯甲烷和甲醇结晶，得浅黄色产物，收率82％。1H NMR(400MHz,CDCl3)δ7.33(dd,J＝8.2,2.1Hz,1H),7.13(dd,J＝8.2,2.5Hz,1H),6.85(d,J＝0.7Hz,2H),6.80(dd,J＝8.3,2.5Hz,1H),6.56(s,1H),6.52(s,1H),6.32(dd,J＝8.3,2.1Hz,1H),6.03(s,1H),3.93(s,3H),3.88(dd,J＝10.9,5.5Hz,1H),3.78(d,J＝5.9Hz,6H),3.76(d,J＝4.7Hz,1H),3.52–3.41(m,1H),3.38(dd,J＝8.3,4.1Hz,1H),3.34(s,3H),3.23(dd,J＝12.5,5.5Hz,1H),3.00–2.81(m,3H),2.80–2.67(m,4H),2.61(s,3H),2.57–2.44(m,2H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ153.72(s),149.40(s),148.61(s),147.07(s),144.80(s),143.25(s),138.51(s),138.29(s),138.21(s),135.15(s),134.83(s),132.57(s),130.14(s),128.88(s),128.10(s),125.90(s),122.77(s),121.96(s),121.93(s),120.41(s),117.28(s),116.14(s),113.03(s),111.49(s),63.69(s),61.37(s),60.83(s),60.22(s),56.14(s),56.00(s),45.25(s),43.68(s),42.61(s),42.36(s),41.69(s),37.66(s),25.53(s),16.15(s).ESI-MS m/z calcd for C38H42N2O7(M+H):639.3；found 639.32.
HD-01的制备
5-甲氧基防己诺林碱(200mg，1倍量)溶于5mL二氯甲烷中，加入三乙胺(1.5倍量)，滴加乙酰氯(1.2倍量)的1mL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20mL，溶液分层，分出二氯甲烷层，水相用20mL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HD-01，收率89％，收率92％。1H NMR(400MHz,CDCl3)δ7.36(dd,J＝8.1,1.8Hz,1H),7.14(dd,J＝8.1,2.4Hz,1H),7.04(s,1H),6.88(d,J＝8.1Hz,1H),6.80(dd,J＝8.2,2.3Hz,1H),6.55(s,1H),6.46(s,1H),6.27(d,J＝8.2Hz,1H),5.97(s,1H),3.99(dd,J＝10.4,5.3Hz,1H),3.96-3.89(m,4H),3.81(s,3H),3.73(s,3H),3.64–3.48(m,3H),3.41(s,3H),3.07–2.76(m,8H),2.71(s,3H),2.61(d,J＝14.0Hz,1H),2.40(s,3H),1.64(s,3H).13C NMR(100MHz,CDCl3):δ167.49,154.07,149.38,149.06,147.43,145.41,143.47,142.80,142.63,133.62,132.51,130.39,127.76,125.88,124.26,123.25,122.20,122.11,120.43,115.87,112.48,111.69,64.00,61.76,60.67,60.38,56.11,55.51,45.28,42.61,42.19,41.25,39.27,24.25,20.81,19.77,17.18ppm；HRMS(ESI)m/z:[M+H]+Calcdfor C40H45N2O8:681.3176；Found 681.3172.
实施例2，参考HD-01所述合成方法，以丙烯酰氯和5-甲氧基防己诺林碱为原料，合成HD-02，白色粉末，收率85％.1H NMR(400MHz,CDCl3):δ7.33(d,J＝8.0Hz,1H),7.12(dd,J1＝8.0Hz,J2＝2.0Hz,1H),6.94(d,J＝7.6Hz,1H),6.85(d,J＝8.0Hz,1H),6.78(dd,J1＝8.0Hz,J2＝2.0Hz,1H),6.49(d,J＝11.2Hz,2H),6.23(d,J＝8.0Hz,1H),6.14-6.09(m,1H),5.88(s,1H),5.72-5.69(m,2H),3.92(s,3H),3.85 -3.81(m,5H),3.71(s,3H),3.59-3.49(m,2H),3.40(m,4H),3.00-2.74(m,7H),2.63-2.54(m,5H),2.36(s,3H)ppm.13C NMR(100MHz,CDCl3)：δ162.25,154.39,149.63,149.31,147.74,145.61,143.80,143.20,142.44,132.62,132.55,132.44,132.07,130.58,126.73,126.17,123.96,123.62,122.67,122.33,122.20,120.73,115.70,112.36,111.80,64.09,61.96,60.71,60.48,56.10,55.60,45.38,44.84,42.81,41.33,41.06,39.48,22.88,17.70ppm；HRMS(ESI)m/z:[M+H]+Calcd for C41H45N2O8:693.3176；Found 693.3179.
实施例3，参考HD-01所述制备方法，以环丙基甲酰氯和5-甲氧基防己诺林碱为原料，合成HD-03，经二氯甲烷和正己烷重结晶纯化得到HD-03，白色粉末，收率83％。1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.0,2.5Hz,1H),7.07(dd,J＝8.2,2.5Hz,1H),6.98(s,1H),6.81(d,J＝8.2Hz,1H),6.74(dd,J＝8.3,2.5Hz,1H),6.49(d,J＝9.7Hz,1H),6.41(d,J＝1.7Hz,1H),6.20(dd,J＝8.3,2.0Hz,1H),5.91(s,1H),3.97(dd,J＝10.9,5.4Hz,1H),3.93–3.80(m,4H),3.74(d,J＝4.8Hz,3H),3.65(s,3H),3.61–3.41(m,3H),3.35(d,J＝11.2Hz,3H),2.98(t,J＝13.1Hz,3H),2.91–2.77(m,3H),2.73(d,J＝11.7Hz,1H),2.69(s,3H),2.56(d,J＝14.8Hz,1H),2.35(s,3H),1.23–1.13(m,2H),0.89–0.80(m,1H),0.76-0.67(m,2H),0.61-0.57(m,1H).13C NMR(100MHz,CDCl3)δ170.42,153.12,148.29,148.15,146.50,144.49,142.63,142.17,141.84,132.05,131.96,131.54,129.41,125.95,123.75,122.82,122.38,121.19,121.11,119.44,114.75,111.40,110.66,62.89,60.89,59.61,59.41,55.08,55.05,54.54,44.11,41.69,40.75,40.17,37.64,23.17,16.41,11.06,7.91,7.74.MS(ESI+)m/e[M+H]+：707.48，C42H46N2O8。
实施例4，参考HD-01制备方法，以2-呋喃甲酰氯和5-甲氧基防己诺林碱为原料，合成HD-04，经硅胶柱层析纯化得到产物，收率89％。1H NMR(400MHz,CDCl3)δ7.50(s,1H),7.32–7.24(m,1H),7.11(dd,J＝8.1,2.3Hz,1H),6.93-6.80(m,3H),6.75(dd,J＝8.1,2.0Hz,1H),6.51(s,1H),6.49(s,1H),6.40(dd,J＝3.0,1.3Hz,1H),6.21(d,J＝7.5Hz,1H),5.84(s,1H),3.92(s,3H),3.82(s,2H),3.78(s,1H),3.74(s,3H),3.57–3.44(m,2H),3.42(s,3H),3.38–3.30(m,1H),3.15(dd,J＝12.6,5.7Hz,1H),2.98(dd,J＝13.8,6.2Hz,1H),2.89–2.66(m,4H),2.66-2.50(m,4H),2.34(s,3H),2.26(s,3H).13C NMR(101MHz,CDCl3)δ153.77(s),149.35(s),148.20(s),147.10(s),146.79(s),145.33(s),143.50(s),143.27,143.19,142.75(s),134.99(s),134.79(s),132.52(s),131.70(s),130.16(s),129.00(s),128.04(s),125.03(s),122.80(s),121.88,121.82,120.88(s),118.71(s),116.28(s),112.53(s),111.88(s),111.51(s),63.96(s),61.33(s),60.63(s),60.25(s),56.14(s),55.59(s),45.79(s),43.38(s),42.52,42.25,41.63,40.81(s),24.80(s),16.41(s).MS(ESI+)m/e[M+H]+：733.22，C43H44N2O9。
实施例5，参考HD-01制备方法，以四氢吡喃-4-甲酰氯和5-甲氧基防己诺林碱为原料，合成HD-05，经硅胶柱层析纯化得到产物，浅黄色粉末，收率82％。1H NMR(400MHz,CDCl3)δ7.32(dd,J＝8.1,1.6Hz,1H),7.13(dd,J＝8.1,2.3Hz,1H),6.86(s,2H),6.78(dd,J＝8.2,2.1Hz,1H),6.50(s,2H),6.26(d,J＝7.6Hz,1H),5.91(s,1H),4.03(dd,J＝10.9,3.1Hz,1H),3.93(s,3H),3.89–3.83(m,2H),3.81(s,3H),3.75(d,J＝9.9Hz,1H),3.71(s,3H),3.53–3.42(m,2H),3.37(d,J＝6.7Hz,3H),3.35–3.28(m,3H),3.23(dd,J＝12.6,5.4Hz,1H),3.00–2.80(m,3H),2.80–2.69(m,4H),2.61(s,3H),2.58-2.48(m,2H),2.31(s,3H),1.64–1.48(m,4H).13C NMR(101MHz,CDCl3)δ173.65(s),153.75(s),149.35(s),148.46(s),147.06(s),145.35(s),143.04(s),143.04,142.85,142.65,135.06(s),134.66(s),132.56(s),132.31(s),130.12(s),128.97,128.65,125.64(s),124.65(s),122.80(s),121.99(s),120.36,120.32,116.14(s),112.54(s),111.51(s),66.87(s),64.14(s),61.27(s),60.53(s),60.26(s),56.13(s),55.52(s),45.74(s),43.37(s),42.90(s),42.27(s),41.45(s),39.10(s),38.48(s),28.32(s),25.86(s),16.45(s).MS(ESI+)m/e[M+H]+：751.36，C44H50N2O9。
实施例6，参考HD-01制备方法，以肉桂酰氯和5-甲氧基防己诺林碱为原料，合成HD-06，经硅胶柱层析纯化得到产物，浅黄色粉末，收率86％。1H NMR(400MHz,CDCl3)δ7.53–7.41(m,3H),7.41-7.33(m,3H),7.28(s,1H),7.11(dd,J＝7.9,1.6Hz,1H),6.92-6.82(m,2H),6.76(d,J＝6.6Hz,1H),6.51(s,2H),6.21(d,J＝7.8Hz,1H),5.98(d,J＝16.0Hz,1H),5.89(s,1H),3.92(s,3H),3.83(s,3H),3.79(d,J＝9.9Hz,1H),3.75(s,3H),3.59–3.47(m,2H),3.43(s,3H),3.35-3.23(m,1H),3.13(dd,J＝12.5,5.3Hz,1H),2.98(dd,J＝13.8,6.0Hz,1H),2.86–2.47(m,8H),2.34(s,3H),2.06(s,3H).13C NMR(101MHz,CDCl3)δ163.56(s),153.74(s),149.35(s),148.40(s),147.07(s),145.90,145.85,145.30(s),143.30,143.22,142.73(s),135.01(s),134.80(s),134.13(s),132.51(s),132.24(s),130.57(s),130.19(s),128.82(s),128.28,128.10,125.60(s),124.71(s),122.81(s),121.95,121.88,120.87(s),116.23,116.10,112.54(s),111.50(s),63.85(s),61.35(s),60.73(s),60.31(s),56.14(s),55.65(s),45.38(s),43.42(s),42.27,42.16,41.56(s),39.97(s),24.80(s),16.46(s).MS(ESI+)m/e[M+H]+：769.36，C47H48N2O8。
实施例7：HD-07的制备
5-甲氧基防己诺林碱(200mg，1倍量)溶于10mL二氯甲烷中，加入三乙胺(1.5倍量)，滴加三氟甲基磺酰氯(1.2倍量)的5mL二氯甲烷溶液，室温反应10小时，经薄层色谱和LC-MS检测，反应结束。加入水50mL，溶液分层，水相用20mL二氯甲烷萃取，合并有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到油状物，经二氯甲烷-甲醇重结晶纯化得到HD-07，白色粉末，收率76％。1H NMR(400MHz,CDCl3)δ7.45(dd,J＝8.2,1.7Hz,1H),7.20(dd,J＝8.2,2.4Hz,1H),6.87(d,J＝8.2Hz,2H),6.83(dd,J＝8.2,2.4Hz,1H),6.58(s,1H),6.46(s,1H),6.35(dd,J＝8.3,1.9Hz,1H),5.99(s,1H),3.99(dd,J＝11.5,4.8Hz,1H),3.94(s,3H),3.84(s,3H),3.81(s,3H),3.76-3.70(m,2H),3.62(d,J＝7.7Hz,1H),3.52–3.43(m,1H),3.40(s,3H),3.14–2.89(m,4H),2.87-2.74(m,3H),2.70(s,3H),2.57-2.49(m,2H),2.27(s,3H).13C NMR(100MHz,CDCl3)δ154.12,149.36,148.26,147.23,145.72,143.09,142.95,141.87,133.82,133.49,133.37,,132.50,132.18,132.08,130.99,130.54,130.04,127.89,127.38,126.55,123.03,122.44,122.08,121.49,115.64,112.38,111.57,100.00,64.57,61.40,61.11,56.13,55.58,44.75,43.10,42.32,41.63,41.23,40.26,23.07,16.66.MS(ESI+)m/e[M+H]+：771.52，C39H41F3N2O9S。
实施例8：HD-08的制备
5-甲氧基防己诺林碱(200mg，1倍量)溶于10mL二氯甲烷中，加入三乙胺(1.5倍量)，滴加入对甲基苯磺酰氯(1.2倍量)的5mL二氯甲烷溶液，自然升温反应10小时，经薄层色谱和LC-MS检测，反应结束。加入水50mL，溶液分层，水相用20mL二氯甲烷萃取，合并有机相，用20mL饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到油状物，经硅胶柱层析分离得到产物，浅黄色粉末，收率82％。1H NMR(400MHz,CDCl3)：δ7.49(d,J＝8.0Hz,2H),7.41(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.23(d,J＝8.0Hz,2H),7.15(dd,J1＝8.0Hz,J2＝2.0Hz,2H),6.94(d,J＝7.6Hz,1H),6.85(d,J＝8.0Hz,1H),6.77(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.54(s,1H),6.37(d,J＝1.2Hz,1H),6.26(dd,J1＝8.4Hz,J2＝2.0Hz,1H),5.46(s,1H),4.09-4.05(m,1H),3.90-3.80(m,5H),3.72(d,J＝10.0Hz,1H),3.67(s,3H),3.45(m,4H),3.35(s,3H),3.26-3.22(m,1H),3.08-3.04(m,2H),2.95(dd,J1＝14.0Hz,J2＝5.6Hz,1H),2.86-2.79(m,6H),2.59-2.52(m,2H),2.43(s,3H),2.28(s,3H)ppm.13C NMR(100MHz,CDCl3)：δ153.45,148.21,148.19,146.44,144.55,144.09,143.45,142.96,141.80,132.71,132.58,131.60,131.23,131.05,129.46,128.29,127.47,125.23,124.38,122.32,121.62,121.13,121.00,120.59,114.72,111.19,110.70,63.60,60.55,59.60,59.36,55.12,54.53,43.45,42.92,41.44,40.30,40.07,38.58,21.37,20.79,15.98ppm；HRMS(ESI)m/z:[M+H]+Calcd forC45H49N2O9S:793.3159；Found 793.3159。
实施例9：HD-09的制备
5-甲氧基防己诺林碱(200mg，1倍量)溶于10mL二氯甲烷中，加入三乙胺(1.5倍量)，加入正丁基异氰酸酯(1.2倍量)，室温反应4小时，经薄层色谱检测反应结束。反应液水洗2次，饱和食盐水洗1次，无水硫酸铵干燥，减压蒸除溶剂得粗产物，粗品经氧化铝柱层析分离，得到产物HD-09。
白色固体，收率63％。1H NMR(400MHz,CDCl3):δ7.28(d,J＝8.0Hz,1H),7.11(dd,J1＝8.0Hz,J2＝2.0Hz,1H),6.87-6.82(m,2H),6.76(dd,J1＝8.0Hz,J2＝2.0Hz,1H),6.49(d,J＝8.4Hz,2H),6.23(d,J＝7.2Hz,1H),5.92(s,1H),4.44(s,1H),3.90(s,3H),3.79-3.74(m,8H),3.47-3.44(m,1H),3.34(m,4H),3.20(dd,J1＝12.4Hz,J2＝5.6Hz,1H),3.01-2.69(m,9H),2.61-2.49(m,5H),2.30(s,3H),1.41 -1.36(m,2H),1.31-1.24(m,2H),0.91(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3):δ153.87,153.27,149.28,148.66,147.07,145.29,144.06,143.98,143.19,134.89,134.75,132.76,132.59,130.14,128.15,128.00,125.32,124.22,122.88,122.06,122.01,120.35,116.31,112.43,111.49,63.73,61.43,60.77,60.31,56.15,55.63,45.36,43.50,42.66,42.27,41.56,41.10,36.90,32.00,25.88,19.92,16.46,13.88ppm；HRMS(ESI)m/z:[M+H]+Calcd for C43H52N3O8:738.3754；Found738.3759。
实施例10：HD-10的制备
合成步骤：在25mL反应瓶中加入5-甲氧基防己诺林碱(150mg,1倍量)，加入3mL二氯甲烷，加入1.2当量Et3N作碱，再加入1.1当量4-甲氧基苯基异氰酸酯，室温下反应2小时，反应结束后加甲醇淬灭，通过氧化铝柱色谱层析纯化得HD-10，白色固体，收率86％。1H NMR(400MHz,CDCl3)：δ7.50(s,1H),7.28(d,J＝6.8Hz,2H),7.19(d,J＝8.0Hz,1H),7.03-6.97(m,2H),6.80(d,J＝8.4Hz,1H),6.72-6.66(m,3H),6.45(s,1H),6.41(s,1H),6.09(d,J＝9.6Hz,1H),5.96(s,1H),4.07-4.01(m,1H),3.90-3.84(m,4H),3.72(s,3H),3.68(m,5H),3.51-3.44(m,3H),3.37(s,3H),3.00-2.61(m,9H),2.53-2.47(m,4H),2.36(s,3H)ppm.13CNMR(100MHz,CDCl3):δ155.83,154.63,150.15,149.83,149.17,147.67,145.50,144.58,143.57,133.63,133.05,132.64,132.53,131.97,131.18,130.37,126.30,124.06,123.54,122.22,122.10,121.32,120.26,116.31,114.06,112.35,111.83,63.74,61.85,60.83,60.40,56.19,55.61,55.54,45.17,44.63,42.50,41.36,41.11,37.35,23.85,17.06ppm；HRMS(ESI)m/z:[M+H]+Calcd for C46H50N3O9:788.3547；Found 788.3549。
实施例11：HD-11的合成
冰盐浴下，25mL反应瓶中加入5-甲氧基防己诺林碱(200mg，1当量)和5mL DMSO作溶剂，加入1.2当量叔丁醇钾作碱，磁力搅拌反应10分钟，再分批加入1.1当量溴乙烷，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78％。1H NMR(400MHz,CDCl3)δ7.36(dd,J＝8.2,2.0Hz,1H),7.14(dd,J＝8.1,2.5Hz,1H),6.86(s,2H),6.81(dd,J＝8.3,2.5Hz,1H),6.54(s,1H),6.51(s,1H),6.33(dd,J＝8.3,2.0Hz,1H),5.97(s,1H),3.93(s,3H),3.85-3.81(m,1H),3.82–3.79(m,3H),3.78(s,3H),3.76–3.67(m,2H),3.55–3.42(m,2H),3.36(s,3H),3.33-3.27(m,1H),3.04–2.64(m,8H),2.60(s 3H),2.55–2.44(m,2H),2.30(s,3H),0.79(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ162.98(s),162.47(s),161.09(s),155.81(s),148.48(s),142.89,142.65,137.06(s),136.06(s),131.84(s),130.79,130.47,128.80(s),125.60(s),124.98,124.94,124.91,124.13,122.90,122.75,122.72,111.94(s),104.32(s),99.11(s),68.76(s),55.32,55.20,46.75,46.64,45.80,45.69,37.42,37.30,33.20,33.08,30.39,30.27,29.78(s),25.69(s),15.28(s).MS(ESI+)m/e[M+H]+：667.36，C40H46N2O7。
实施例12：HD-12的合成
参考HD-11方法，以5-甲氧基防己诺林碱和溴代异丙烷反应合成HD-12，收率85％。1H NMR(400MHz,CDCl3)δ7.38(dd,J＝8.2,1.7Hz,1H),7.15(dd,J＝8.1,2.4Hz,1H),6.85(s,2H),6.83(d,J＝2.4Hz,1H),6.51(s,1H),6.51(s,1H),6.38(dd,J＝8.3,1.8Hz,1H),5.86(s,1H),4.02(dt,J＝12.2,6.1Hz,1H),3.93(s,3H),3.80(s,3H),3.78(s,3H),3.76–3.70(m,1H),3.55–3.42(m,2H),3.35(s,3H),3.29(dd,J＝13.0,4.4Hz,1H),3.05–2.63(m,8H),2.58(s,3H),2.56-2.45(m,2H),2.27(s,3H),0.90(d,J＝6.1Hz,3H),0.75(d,J＝6.1Hz,3H).13C NMR(101MHz,CDCl3)δ153.64(s),149.44(s),148.65(s),146.96(s),145.37(s),144.94(s),144.72(s),143.31(s),139.40(s),135.21(s),134.55(s),132.65(s),130.25(s),127.56,127.37,125.00(s),122.81(s),122.09,122.02,121.49(s),120.14(s),115.68(s),112.63(s),111.49(s),74.15(s),64.53(s),61.44(s),60.57,60.47,56.10(s),55.72(s),45.31(s),43.69(s),42.53,42.41,41.62(s),40.76(s),24.03(s),21.80,21.67,16.66(s).MS(ESI+)m/e[M+H]+：681.38，C41H48N2O7。
实施例13：HD-13的合成
参考HD-11方法，以5-甲氧基防己诺林碱和环氧溴丙烷为原料，合成HD-13，收率72％。1H NMR(400MHz,CDCl3)δ7.36(dd,J＝8.1,1.7Hz,1H),7.15(dd,J＝8.1,2.4Hz,1H),6.91-6.80(m,3H),6.54(s,1H),6.52(s,1H),6.34(dd,J＝8.3,1.9Hz,1H),5.97(s,1H),3.93(s,3H),3.81(s,3H),3.79(s,3H),3.73(dd,J＝10.5,3.9Hz,2H),3.51–3.41(m,2H),3.37(s,3H),3.35–3.32(m,1H),3.27(dd,J＝12.5,5.6Hz,1H),3.00–2.66(m,8H),2.61(t,J＝4.5Hz,2H),2.58(s,3H),2.53–2.44(m,2H),2.33(dd,J＝4.8,2.8Hz,1H),2.28(s,3H).13CNMR(101MHz,CDCl3)δ153.72(s),149.41(s),148.42(s),147.04(s),145.55(s),144.26,144.12,143.57(s),140.85(s),135.17(s),134.61(s),132.63(s),130.18(s),128.20,128.18,125.53(s),122.78(s),122.31(s),122.02,121.96,119.99(s),115.96(s),112.74(s),111.52(s),74.07(s),64.21(s),61.38(s),61.00(s),60.56(s),56.13(s),55.69(s),49.85(s),45.45(s),44.56(s),43.52(s),42.62(s),42.35(s),41.67(s),39.75(s),24.73(s),16.49(s).MS(ESI+)m/e[M+H]+：695.36，C41H46N2O8。
实施例14：HD-14的合成
冰盐浴，25mL反应瓶中加入5-甲氧基防己诺林碱(200mg，1当量)和5mL 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2-氟乙醇对甲苯磺酸酯，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％。1H NMR(400MHz,CDCl3)δ7.35(dd,J＝8.1,2.0Hz,1H),7.14(dd,J＝8.1,2.5Hz,1H),6.86(s,2H),6.80(dd,J＝8.2,2.5Hz,1H),6.53(s,1H),6.51(s,1H),6.32(dd,J＝8.3,2.0Hz,1H),5.97(s,1H),4.15–4.07(m,1H),4.03–3.96(m,1H),3.93(s,3H),3.89–3.83(m,1H),3.81(s,3H),3.79(s,3H),3.75(d,J＝9.8Hz,1H),3.57-3.42(m,3H),3.37(s,3H),3.27(dd,J＝13.4,6.4Hz,1H),2.99–2.67(m,8H),2.61(s,3H),2.55-2.45(m,2H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ153.76(s),149.39(s),148.43(s),147.07(s),145.57(s),144.29,144.19,143.68(s),140.67(s),135.09(s),134.64(s),132.61(s),130.19(s),128.12,128.07,125.62(s),122.81(s),122.28(s),121.97,121.95,120.27(s),116.06(s),112.62(s),111.52(s),83.01(d,J＝168.70),71.59(d,J＝20.30),64.12(s),61.39(s),60.96(s),60.58(s),56.13(s),55.70(s),45.37(s),43.55(s),42.58(s),42.34(s),41.68(s),39.80(s),24.57(s),16.47(s).[M+H]+：685.34，C40H45FN2O7。
实施例15：HD-15的合成
参考HD-14方法，以甲基乙二醇对甲苯磺酸酯和5-甲氧基防己诺林碱为原料，合成HD-15，收率82％。1H NMR(400MHz,CDCl3)δ7.35(d,J＝7.9Hz,1H),7.14(d,J＝8.1Hz,1H),6.86(s,2H),6.80(d,J＝8.1Hz,1H),6.53(s,1H),6.51(s,1H),6.32(d,J＝8.3Hz,1H),5.99(s,1H),3.92(s,3H),3.87-3.77(m,8H),3.75(d,J＝10.1Hz,1H),3.52–3.42(m,2H),3.35(s,3H),3.29(d,J＝8.8Hz,1H),3.23(s,3H),3.06(s,2H),2.96–2.69(m,8H),2.63(s,3H),2.56–2.46(m,2H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ153.77(s),149.38(s),148.46(s),147.08(s),145.55(s),144.40,144.28,143.79(s),141.07(s),135.01(s),134.62(s),132.61(s),130.18(s),127.99,127.91,125.45(s),122.83(s),121.95,121.93,121.87,120.31(s),116.06(s),112.65(s),111.53(s),71.56(s),71.09(s),64.19(s),61.44(s),60.94(s),60.54(s),58.77(s),56.13(s),55.68(s),45.50(s),43.66(s),42.65(s),42.36(s),41.69(s),39.93(s),24.63(s),16.50(s).[M+H]+：697.36，C41H48N2O8。
实施例16：HD-16的合成
参考HD-11所述方法，以苄基溴和5-甲氧基防己诺林碱为原料，合成HD-16，浅黄色粉末，收率78％。1H NMR(400MHz,CDCl3)：δ7.38(d,J＝8.0Hz,1H),7.19-7.18(m,3H),7.12(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.06(d,J＝6.8Hz,1H),6.96(d,J＝6.0Hz,2H),6.86(d,J＝8.4Hz,1H),6.78(dd,J1＝8.0Hz,J2＝1.6Hz,1H),6.53(s,1H),6.42(s,1H),6.27(d,J＝8.0Hz,1H),5.80(s,1H),4.63(d,J＝11.6Hz,1H),4.35(d,J＝11.2Hz,1H),3.94-3.89(m,5H),3.80-3.72(m,8H),3.54-3.52(m,1H),3.42(s,3H),3.08-2.72(m,8H),2.59(d,J＝14.0Hz,1H),2.39(s,3H),2.37(s,3H)ppm.13C NMR(100MHz,CDCl3)：δ154.28,149.58,149.32,147.56,145.90,145.03,144.17,143.93,141.19,137.38,132.60,132.38,130.47,128.13,127.62,126.94,125.30,123.49,122.70,122.26,122.19,121.72,120.20,115.63,112.33,111.72,74.27,64.43,62.05,61.11,60.79,56.09,55.73,45.27,44.70,42.81,41.34,40.85,39.83,22.65,17.43ppm；HRMS(ESI)m/z:[M+H]+Calcd for C45H49N2O7:729.3540；Found 729.3544。
实施例17：HD-17的合成
参考HD-14方法，以5-甲氧基防己诺林碱和三氟乙醇三氟甲磺酸酯为原料合成HD-17，收率85％。1H NMR(400MHz,CDCl3)δ7.31(dd,J＝8.2,1.9Hz,1H),7.09(dd,J＝8.1,2.5Hz,1H),6.89–6.83(m,1H),6.82–6.76(m,1H),6.71(dd,J＝8.3,2.5Hz,1H),6.48(s,1H),6.42(d,J＝1.6Hz,1H),6.19(dd,J＝8.3,2.0Hz,1H),5.86(s,1H),3.91(dd,J＝11.2,5.6Hz,1H),3.86(s,3H),3.75(s,3H),3.68(s,3H),3.49(dd,J＝12.6,5.3Hz,1H),3.42(dd,J＝12.9,4.3Hz,1H),3.37(d,J＝6.1Hz,3H),3.04–2.85(m,4H),2.83–2.69(m,4H),2.65(s,3H),2.55(s,3H),2.48(dd,J＝17.6,4.2Hz,1H),2.36(d,J＝13.9Hz,1H),2.27(s,3H).13CNMR(101MHz,CDCl3)δ156.65,154.25,149.30,148.97,147.40,145.66,143.09,142.56,142.47,134.27,133.70,132.58,130.30,127.80,126.13,125.71,123.02,122.15,121.98,121.35,116.38,111.98,111.68,64.35,61.21,60.50,56.16,55.44,44.86,43.39,42.31,41.89,41.58,40.99,40.22,23.27,22.14,16.46.MS(ESI+)m/e[M+H]+：721.38，C40H43F3N2O7。
实施例18：HD-18的合成
5-甲氧基防己诺林碱(200mg，1.0当量)溶于5mL二甲基亚砜中，加入叔丁醇钠(2当量)，滴加入4-三氟甲基苄溴(2当量)的1mL二甲基亚砜溶液，在0℃反应1.5小时，经薄层色谱和LC-MS检测，反应结束。加入水20mL，溶液分层，水相用二氯甲烷萃取2次，合并二氯甲烷，用20mL饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到油状物，经二氯甲烷-甲醇柱层析纯化得到HD-18，收率68％。1H NMR(400MHz,CDCl3)δ7.46(d,J＝8.1Hz,2H),7.36(d,J＝8.1Hz,1H),7.12-7.05(m,4H),6.85(d,J＝8.2Hz,1H),6.78(dd,J＝8.2,2.3Hz,1H),6.54(s,1H),6.41(d,J＝1.3Hz,1H),6.27(dd,J＝8.2,1.7Hz,1H),5.81(s,1H),4.69(d,J＝12.0Hz,1H),4.39(d,J＝12.0Hz,1H),4.00–3.84(m,5H),3.78(s,3H),3.70(s,3H),3.68–3.49(m,3H),3.42(s,3H),3.04–2.70(m,8H),2.59(d,J＝14.3Hz,1H),2.39(s,3H),2.35(s,3H).13C NMR(101MHz,CDCl3)δ152.60,148.37,147.24,146.01,144.69,143.41,143.37,142.60,140.40,139.74,134.21,133.49,131.58,129.09,128.58,128.25,127.70,127.29,126.34,124.79,124.52,123.98,123.94,121.76,121.41,120.92,120.86,119.07,114.93,111.68,110.45,72.40,62.92,60.39,59.97,59.55,55.06,54.72,44.49,42.54,41.40,41.34,40.67,37.53,24.49,15.47.MS(ESI+)m/e[M+H]+：797.35，C46H47F3N2O7。
实施例19：HD-19的合成
参考HD-18方法，以5-甲氧基防己诺林碱和4-三氟甲基溴代苯乙酮为原料合成HD-19，经二氯甲烷-甲醇硅胶柱层析纯化，收率71％。1H NMR(400MHz,CDCl3)δ7.79(d,J＝8.2Hz,2H),7.66(d,J＝8.3Hz,2H),7.31(dd,J＝8.2,1.8Hz,1H),7.06(dd,J＝8.2,2.3Hz,2H),6.82(d,J＝8.2Hz,1H),6.75(dd,J＝8.2,2.3Hz,1H),6.45(s,1H),6.40(s,1H),6.22(dd,J＝8.3,1.7Hz,1H),5.94(s,1H),4.89(d,J＝16.0Hz,1H),4.45(d,J＝16.0Hz,1H),4.07(dd,J＝11.3,5.0Hz,1H),4.02–3.90(m,1H),3.85(s,3H),3.80–3.68(m,5H),3.66(d,J＝11.4Hz,3H),3.50(dd,J＝24.2,10.1Hz,1H),3.42(s,3H),3.13–2.65(m,11H),2.63–2.48(m,1H),2.39(s,3H).13C NMR(101MHz,CDCl3)δ192.39,154.28,149.33,149.28,147.67,145.88,144.64,144.20,143.08,140.38,136.82,135.07,134.74,132.55,132.32,132.29,130.46,128.23,127.42,125.90,125.86,124.71,124.71,122.26,121.99,120.90,115.66,112.36,111.72,74.56,64.16,61.91,61.07,60.65,56.07,55.96,53.52,44.63,42.81,41.01,39.10,22.82,17.51.MS(ESI+)m/e[M+H]+：825.35，C47H47F3N2O8。
实施例20：HD-20的合成
参考HD-18方法，以5-甲氧基防己诺林碱和溴甲基丙烯酸乙酯为原料合成HD-20，浅黄色粉末，收率66％.1H NMR(400MHz,CDCl3)：δ7.42(d,J＝7.2Hz,1H),7.11(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.04(d,J＝7.6Hz,1H),6.85(d,J＝8.0Hz,1H),6.81(dd,J1＝8.0Hz,J2＝2.0Hz,1H),6.58(s,1H),6.50(td,J1＝16.0Hz,J2＝4.0Hz,1H),6.41(s,1H),6.31(dd,J1＝8.0Hz,J2＝0.8Hz,1H),5.94(s,1H),5.59(d,J＝15.6Hz,1H),4.23-4.07(m,4H),3.93-3.83(m,5H),3.78(s,3H),3.72(s,3H),3.55-3.49(m,1H),3.42(s,3H),3.19-3.16(m,1H),3.05-2.96(m,3H),2.89-2.81(m,3H),2.75(s,3H),2.59-2.56(m,1H),2.37(s,3H),1.22(t,J＝7.2Hz,3H)ppm.13C NMR(100MHz,CDCl3):δ165.94,154.25,149.60,149.39,147.56,145.85,144.78,144.04,143.32,143.04,140.59,132.55,132.37,130.56,125.75,123.45,122.83,122.35,122.26,122.07,120.69,119.94,115.43,112.30,111.76,70.91,64.63,61.98,61.11,60.76,60.62,56.09,55.72,53.49,45.26,45.03,42.83,41.19,40.07,22.67,17.53,14.27ppm；HRMS(ESI)m/z:[M+H]+Calcd for C44H51N2O9:751.3595；Found751.3590。
实施例21：HD-21的合成
参考参考HD-01制备方法，以苯甲酰氯和5-甲氧基防己诺林碱为原料，合成HD-21，经硅胶柱层析纯化得到白色粉末，收率91％。1H NMR(400MHz,CDCl3)δ8.20(d,J＝7.0Hz,2H),7.62(t,J＝7.0Hz,1H),7.49(t,J＝7.6Hz,2H),7.33(dd,J＝8.0,2.0Hz,1H),7.14(dd,J＝8.2,2.4Hz,1H),6.82(s,2H),6.78(dd,J＝8.2,2.4Hz,1H),6.56(s,1H),6.52(s,1H),6.30(dd,J＝8.2,2.0Hz,1H),6.02(s,1H),3.91(s,3H),3.87(d,J＝5.6Hz,1H),3.78(d,J＝9.6Hz,1H),3.70(s,3H),3.60–3.40(m,2H),3.38(s,3H),3.25(s,3H),3.21(d,J＝5.6Hz,1H),3.05–2.86(m,3H),2.83–2.64(m,4H),2.62(s,3H),2.54(d,J＝13.6Hz,1H),2.34-2.32(m,1H),2.30(s,3H).13C NMR(101MHz,CDCl3)δ164.71,153.79,149.38,148.32,147.13,146.52,143.64,143.46,142.44,136.68,135.18,134.67,133.58,132.66,130.18,130.13,129.29,128.62,128.51,128.05,125.76,122.81,121.94,121.90,121.51,120.15,116.23,112.75,111.54,63.80,61.34,60.90,60.40,56.14,55.73,45.24,42.93,42.70,42.12,41.63,37.72,25.46,16.17.MS(ESI+)m/e[M+H]+：743.34，C45H46N2O8。
实施例22：HD-22的合成
参考参考HD-01制备方法，以烟酰氯和5-甲氧基防己诺林碱为原料，合成HD-22，经硅胶柱层析纯化得到淡黄色粉末，收率82％。1H NMR(400MHz,CDCl3)δ8.88(d,J＝6.0Hz,2H),8.02(d,J＝6.0Hz,2H),7.37(dd,J＝8.2,2.4Hz,1H),7.17(dd,J＝8.2,2.4Hz,1H),6.87(s,2H),6.81(dd,J＝8.4,2.4Hz,1H),6.58(s,1H),6.55(s,1H),6.34(dd,J＝8.2,2.0Hz,1H),6.04(s,1H),3.94(s,3H),3.90(d,J＝5.8Hz,1H),3.82(d,J＝10.0Hz,1H),3.72(s,3H),3.58–3.37(m,5H),3.29(s,3H),3.26(d,J＝5.6Hz,1H),3.03-2.86(m,3H),2.82-2.72(m,4H),2.65(s,3H),2.56(d,J＝13.6Hz,1H),2.33(s,3H),2.34-2.30(m,1H).13C NMR(101MHz,CDCl3)δ163.39,153.79,150.86,149.37,148.26,147.14,146.82,143.47,143.17,142.50,136.52,136.16,135.15,134.52,132.65,130.12,128.53,128.12,125.91,123.21,122.80,121.93,121.16,120.12,116.18,112.64,111.53,63.78,61.29,60.89,60.39,56.13,55.66,53.44,45.19,42.80,42.66,42.11,41.54,37.60,25.48,16.17.MS(ESI+)m/e[M+H]+：744.35，C44H45N3O8。
实施例23：HD-23的合成
参考HD-11所述方法，合成HD-23，浅黄色粉末，收率78％。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.2Hz,1H),7.12(d,J＝7.2Hz,1H),6.84(s,2H),6.78(d,J＝7.6Hz,1H),6.54(s,1H),6.50(s,1H),6.30(d,J＝8.0Hz,1H),6.00(s,1H),4.02(dt,J＝21.2,7.6Hz,2H),3.90(s,3H),3.90–3.85(m,1H),3.75(s,3H),3.73(s,1H),3.50–3.39(m,2H),3.30(s,3H),3.26-3.16(m,4H),3.01–2.84(m,3H),2.82–2.65(m,6H),2.62(s,3H),2.55-2.46(m,2H),2.33(s,6H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ153.70,149.34,148.30,147.06,144.71,144.40,144.32,143.71,142.42,135.16,134.78,132.62,130.11,128.37,127.73,125.62,122.75,121.93,121.90,121.86,120.16,116.14,112.66,111.50,70.62,63.80,61.45,60.92,60.50,59.42,56.12,55.59,45.80,45.22,43.63,42.65,42.27,41.78,37.81,25.38,16.67.MS(ESI+)m/e[M+H]+：710.39，C42H51N3O7。
实施例24：HD-24的合成
参考HD-11所述方法，合成HD-24，黄色粉末，收率78％。1H NMR(400MHz,CDCl3)δ7.35(dd,J＝8.2,1.9Hz,1H),7.15(dd,J＝8.2,2.5Hz,1H),6.87(s,2H),6.81(dd,J＝8.2,2.5Hz,1H),6.56(s,1H),6.52(s,1H),6.32(dd,J＝8.2,2.1Hz,1H),5.98(s,1H),4.12-4.02(m,2H),3.94(s,3H),3.91–3.87(m,1H),3.78(t,J＝4.6Hz,8H),3.53-3.37(m,2H),3.36(s,3H),3.28(d,J＝5.6Hz,1H),3.25(s,3H),3.08–2.86(m,4H),2.85–2.66(m,6H),2.62(s,3H),2.60–2.46(m,5H),2.29(s,3H).13C NMR(101MHz,CDCl3)δ153.75,149.38,148.36,147.10,144.56,144.49,144.36,143.68,142.45,135.12,134.66,132.64,130.14,128.29,127.75,125.63,122.79,121.96,121.90,120.17,116.13,114.09,112.63,111.53,69.76,66.97,63.83,61.49,60.96,60.53,58.87,56.15,55.62,53.99,45.22,43.75,42.63,42.36,41.82,37.81,25.36,16.74.MS(ESI+)m/e[M+H]+：752.40，C44H53N3O8。
实施例25：HD-25的合成
在100mL反应瓶中加入鹤氏唐松草碱(2g，1当量)，加入3当量多聚甲醛，加入20mL浓盐酸搅拌溶解，室温下搅拌反应10小时。反应结束后，将反应液浓缩，用饱和碳酸钾溶液调节pH至9-10，搅拌1小时，过滤并减压干燥得粗品，经氧化铝柱层析纯化，得产物，收率65％，白色固体。1H NMR(400MHz,CDCl3):δ7.28(dd,J1＝8.4Hz,J2＝2.0Hz),7.12(dd,J1＝8.4Hz,J2＝2.4Hz),6.90(s,1H),6.70(s,1H),6.69(dd,J1＝8.0Hz,J2＝2.4Hz),6.48(s,1H),6.16(dd,J1＝8.4Hz,J2＝2.0Hz),5.94(s,1H),4.61(d,J＝11.6Hz),4.23(d,J＝12.0Hz),3.92-3.82(m,5H),3.78(s,3H),3.74(s,3H),3.49-3.35(m,2H),3.30(s,3H),3.21(dd,J1＝12.0Hz,J2＝6.0Hz),3.12(s,3H),2.97-2.83(m,4H),2.78-2.67(m,4H),2.62(s,3H),2.58-2.51(m,2H),2.29(s,3H)ppm.13C NMR(100MHz,CDCl3):δ152.84,147.59,147.41,146.51,144.61,144.17,143.93,143.10,141.80,133.91,133.83,131.75,131.26,129.01,127.22,127.11,123.70,120.38,120.28,120.05,120.02,117.64,112.71,111.54,62.59,62.04,59.69,59.56,59.35,59.27,54.99,54.51,44.09,42.48,41.53,40.13,38.58,36.54,24.40,14.85ppm；HRMS(ESI)m/z:[M+H]+Calcd for C40H47N2O8:683.3332；Found683.3338。
实施例26：HD-26的合成
方法1：将HD-25(500mg，1倍量)溶于二氯甲烷20ml，加入Dessmartin试剂(1.2倍量)，室温反应2小时，过滤，浓缩得产物醛，粗品可直接用于下一步反应，也可以经过硅胶柱层析纯化，纯化收率92％。
方法2：鹤氏唐松草碱(500mg)溶于三氟乙酸10ml，加入乌洛托品(2倍量)，80摄氏度封管反应10小时，浓缩，加饱和碳酸氢钠中和，二氯甲烷萃取，粗品经硅胶柱层析得产物，白色固体，53.1mg(78％yield).1H NMR(400MHz,CDCl3):δ9.95(s,1H),7.45-7.43(m,2H),7.16(dd,J1＝8.0Hz,J2＝2.4Hz,1H),6.75(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.56(s,1H),6.52(s,1H),6.24(d,J＝8.4Hz,1H),6.02(s,1H),4.32(dd,J1＝10.4Hz,J2＝4.4Hz,1H),3.95(s,3H),3.78-3.74(m,7H),3.67-3.60(m,1H),3.45-3.32(m,5H),3.22(s,3H),3.09(s,1H),2.98-2.87(m,4H),2.76(s,1H),2.58(s,1H),2.55(s,1H),2.23(s,3H)ppm.13C NMR(150MHz,CDCl3):δ191.35,153.58,153.56,149.58,147.90,144.83,144.51,144.36,142.35,133.79,133.06,130.55,129.68,126.14,124.21,124.07,122.43,122.04,121.77,120.61,117.36,112.47,64.00,60.90,60.65,60.60,56.17,55.67,44.99,44.15,41.89,41.73,41.04,38.35,36.77,23.77,16.39ppm；HRMS(ESI)m/z:[M+H]+Calcd for C40H45N2O8:681.3176；Found 681.3177。
实施例27：HD-27、HD-28、HD-29、HD-30、HD-31和HD-32的合成
将HD-25与取代的酰氯室温反应，以三乙胺为碱，以二氯甲烷或四氢呋喃为溶剂，反应0.5-1小时，浓缩溶剂，粗品经硅胶或氧化铝纯化，制备酯类化合物。
HD-27：白色固体，收率84％.1H NMR(400MHz,CDCl3):δ7.37(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.09(dd,J1＝8.0Hz,J2＝2.4Hz,1H),6.90(s,1H),6.76(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.53(s,2H),6.23(dd,J1＝8.0Hz,J2＝1.6Hz,1H),5.98(s,1H),5.40(d,J＝12.0Hz,1H),5.04(d,J＝12.0Hz,1H),4.22(dd,J1＝7.2Hz,J2＝5.6Hz,1H),3.89(s,3H),3.81-3.66(m,9H),3.39(td,J1＝12.4Hz,J2＝4.8Hz,1H),3.33(s,3H),3.23-3.18(m,4H),3.09-2.81(m,8H),2.75-2.67(m,1H),2.49(dd,J1＝17.6Hz,J2＝4.0Hz,1H),2.40(d,J＝14.0Hz,1H),2.23(s,3H),2.02(s,3H)ppm.13C NMR(100MHz,CDCl3):δ170.06,152.97,148.59,148.04,146.05,144.79,143.63,143.50,143.26,141.23,132.95,131.65,129.45,127.28,124.37,123.91,122.34,121.08,120.84,119.55,116.04,112.65,111.45,64.31,63.03,60.86,59.83,59.53,59.49,55.14,54.58,43.87,42.73,41.06,40.44,37.49,37.39,22.31,20.21,15.09ppm；HRMS(ESI)m/z:[M+H]+Calcd for C42H49N2O9:725.3438；Found 725.3435。
HD-28：白色固体，收率86％。1H NMR(400MHz,CDCl3):δ8.05(dd,J1＝8.4Hz,J2＝5.6Hz,2H),7.32(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.12(dd,J1＝8.4Hz,J2＝2.4Hz,1H),7.08(t,J＝8.6Hz,2H),7.02(s,1H),6.78(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.65(s,1H),6.50(s,1H),6.26(dd,J1＝8.4Hz,J2＝2.0Hz,1H),5.99(s,1H),5.69(d,J＝12.0Hz,1H),5.34(d,J＝12.0Hz,1H),3.95-3.90(m,4H),3.82(s,1H),3.79(s,3H),3.76(s,3H),3.48-3.38(m,2H),3.33(m,3H),3.27-3.20(m,4H),3.09-2.86(m,4H),2.83-2.70(m,3H),2.64(s,3H),2.49(d,J＝14.4Hz,2H),2.27(s,3H)ppm.13C NMR(150MHz,CDCl3):δ166.61,165.68,164.93,154.34,150.12,149.18,147.35,145.98,144.92,144.73,144.11,142.36,132.71,132.25,132.19,131.76,130.62,128.50,126.65,124.61,122.28,122.03,121.72,120.64,117.08,115.62,115.47,113.99,112.44,77.16,65.93,64.29,61.98,60.91,60.60,56.26,55.67,44.87,43.87,42.09,41.14,38.87,38.34,22.68,16.27,14.24ppm；HRMS(ESI)m/z:[M+H]+Calcd for C47H50FN2O9:805.3500；Found 805.3507。
HD-29白色固体，收率82％。1H NMR(400MHz,CDCl3):δ7.96(d,J＝8.8Hz,2H),7.40(dd,J1＝8.4Hz,J2＝1.6Hz,1H),7.13(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.01(s,1H),6.86(d,J＝8.8Hz,2H),6.80(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.56(d,J＝4.8Hz,2H),6.25(dd,J1＝8.4Hz,J2＝1.6Hz,1H),6.01(s,1H),5.62(d,J＝12.2Hz,1H),5.30(d,J＝12.3Hz,1H),4.27(dd,J1＝10.8Hz,J2＝5.6Hz,1H),3.91(s,3H),3.80-3.74(m,12H),3.45(td,J1＝12.4Hz,J2＝4.8Hz,1H),3.36(s,3H),3.28-3.25(m,1H),3.20(s,3H),3.12-3.01(m,3H),2.96-2.84(m,6H),2.53-2.44(m,2H),2.27(s,3H)ppm.13C NMR(100MHz,CDCl3):δ165.34,162.30,153.13,148.78,147.95,146.10,144.82,143.72,143.53,143.17,141.21,132.79,131.64,131.23,130.63,129.47,127.66,124.00,121.73,121.66,121.15,120.91,119.52,116.02,112.64,112.57,111.40,64.43,63.12,60.89,59.86,59.54,59.51,55.17,54.59,54.42,43.82,42.72,41.04,40.28,37.62,37.32,22.02,15.15ppm；HRMS(ESI)m/z:[M+H]+Calcdfor C48H53N2O10:817.3700；Found 817.3703。
HD-30：白色固体，收率89％。1H NMR(400MHz,CDCl3):δ7.48(dd,J1＝1.6Hz,J2＝0.4Hz,1H),7.31(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.09-7.06(m,2H),6.96(s,1H),6.73(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.54(s,1H),6.48(s,1H),6.41(dd,J1＝3.2Hz,J2＝1.6Hz,1H),6.19(dd,J1＝8.4Hz,J2＝2.0Hz,1H),5.94(s,1H),5.63(d,J＝12.0Hz,1H),5.25(d,J＝12.0Hz,1H),4.07(dd,J1＝11.2Hz,J2＝5.2Hz,1H),3.88(s,3H),3.86(s,1H),3.73(s,4H),3.70(s,3H),3.38(s,2H),3.29(s,3H),3.14(s,3H),3.08-2.75(m,7H),2.72(s,3H),2.48-2.39(m,2H),2.21(s,3H)ppm.13C NMR(150MHz,CDCl3):δ158.82,154.11,149.75,149.22,147.20,146.34,145.86,144.79,144.73,144.60,144.27,142.28,134.09,132.69,132.52,130.51,128.05,125.26,124.79,123.10,122.13,121.89,120.62,117.98,117.16,113.96,112.49,111.85,77.16,65.71,64.03,61.90,60.89,60.58,60.53,56.21,55.64,44.76,43.82,42.07,41.31,38.55,38.44,23.18,16.21ppm；HRMS(ESI)m/z:[M+H]+Calcd forC45H49N2O10:777.3387；Found 777.3382。
HD-31：浅黄色固体，收率86％。1H NMR(400MHz,CDCl3):δ7.33(d,J＝7.6Hz,1H),7.08(dd,J1＝8.0Hz,J2＝1.9Hz,1H),6.90(s,1H),6.74(dd,J＝8.0Hz,J2＝1.9Hz,1H),6.51(d,J＝10.8Hz,2H),6.35(d,J＝17.6Hz,1H),6.20(d,J＝8.4Hz,1H),6.08(dd,J1＝17.6Hz,J2＝10.4Hz,1H),5.95(s,1H),5.75(d,J＝10.4Hz,1H),5.47(d,J＝12.0Hz,1H),5.12(d,J＝12.4Hz,1H),4.13(dd,J1＝10.4Hz,J2＝5.2Hz,1H),3.87(s,3H),3.74-3.60(m,9H),3.41-3.30(m,4H),3.15-3.11(m,4H),3.07-2.65(m,9H),2.46(dd,J1＝17.6Hz,J2＝2.8Hz,1H),2.38(d,J＝14.4Hz,1H),2.21(s,3H)ppm.13C NMR(150MHz,CDCl3):δ165.22,153.10,148.75,148.05,146.12,144.83,143.73,143.53,143.22,141.24,132.90,131.66,131.37,129.78,129.47,127.56,127.28,124.15,123.83,121.90,121.12,120.86,119.58,116.09,112.66,111.45,64.35,63.10,60.88,59.84,59.54,59.49,55.16,54.60,43.84,42.76,41.05,40.32,37.60,37.42,22.12,15.12ppm；HRMS(ESI)m/z:[M+H]+Calcd for C43H49N2O9:737.3438；Found 737.3440。
HD-32：浅黄色固体，收率82％。1H NMR(400MHz,CDCl3):δ7.70(d,J＝16.0Hz,1H),7.49(dd,J1＝6.5Hz,J2＝2.7Hz,2H),7.42-7.29(m,4H),7.12(dd,J1＝8.1Hz,J2＝2.4Hz,1H),7.00(s,1H),6.78(dd,J1＝8.3Hz,J2＝2.4Hz,1H),6.65(s,1H),6.50(s,1H),6.47(d,J＝16.0Hz,1H),6.26(dd,J1＝8.3Hz,J2＝1.9Hz,1H),5.99(s,1H),5.60(d,J＝12.1Hz,1H),5.23(d,J＝12.1Hz,1H),4.00-3.89(m,4H),3.82(s,1H),3.79(s,3H),3.76(s,3H),3.50-3.37(m,2H),3.32(s,3H),3.29-3.17(m,4H),3.10-2.68(m,8H),2.63(s,3H),2.56-2.44(m,2H),2.28(s,3H)ppm.13C NMR(100MHz,CDCl3):δ166.00,152.28,148.26,147.42,145.93,144.57,143.79,143.72,143.47,143.05,141.36,134.26,133.52,133.42,131.64,129.21,127.84,127.17,127.08,127.02,126.86,124.48,121.09,120.69,120.56,119.60,117.27,116.20,112.56,111.70,64.53,62.58,60.95,59.78,59.51,59.39,55.15,54.63,44.21,42.85,41.58,41.14,37.67,36.69,24.40,15.02ppm；HRMS(ESI)m/z:[M+H]+Calcd forC49H53N2O9:813.3751；Found 813.3756。
实施例28：HD-33、HD-34、HD-35、HD-36、HD-37和HD-38的合成
将HD-26(200mg，1倍量)溶于甲醇和二氯甲混合溶剂(3:1)10ml，加入相应的胺(1.5倍量)，室温搅拌5分钟，加入三乙酰氧基硼氢化钠(3倍量)，室温搅拌反应2小时。浓缩，加碳酸钾溶液和二氯甲烷分层，二氯甲烷层干燥浓缩得粗品，经氧化铝柱层析分离得到产物。
HD-33：白色固体，收率72％。1H NMR(400MHz,CDCl3):δ7.31(d,J＝7.2Hz,1H),7.09-7.07(m,2H),6.69(s,2H),6.50(s,1H),6.15(d,J＝7.2Hz,1H),5.89(s,1H),4.20(d,J＝12.0Hz,1H),4.11(s,1H),3.98-3.83(m,7H),3.73(s,3H),3.68(s,3H),3.57-3.51(m,4H),3.28(s,3H),3.11-3.02(m,7H),2.90-2.76(m,11H),2.60(m,4H)ppm.13C NMR(100MHz,CDCl3):δ153.90,149.85,149.13,148.25,145.94,145.77,144.79,144.31,143.27,133.45,132.96,132.23,130.37,127.29,124.93,124.83,121.96,121.80,121.38,120.91,119.50,118.97,116.79,112.37,63.55,61.08,60.64,60.59,60.24,59.96,57.96,56.63,55.96,55.60,44.82,43.65,41.70,41.59,39.11,37.77,24.11,15.72ppm；HRMS(ESI)m/z:[M+H]+Calcd for C43H54N3O8:740.3911；Found 740.3918。
HD-34：浅黄色粉末，收率78％。1H NMR(400MHz,MeOD)δ7.37(dd,J＝8.2,1.9Hz,1H),7.06(d,J＝7.9Hz,1H),6.93(s,1H),6.69(s,1H),6.60(s,1H),6.50(d,J＝8.3Hz,1H),6.15(d,J＝7.7Hz,1H),5.88(s,1H),4.11(s,1H),3.97(dd,J＝10.6,6.0Hz,1H),3.82(s,3H),3.73(s,3H),3.65(s,3H),3.56–3.45(m,1H),3.43–3.35(m,1H),3.30(s,3H),3.23–3.19(m,5H),3.18–3.11(m,2H),3.07(s,3H),2.99–2.82(m,4H),2.80–2.70(m,4H),2.62-2.31(m,11H),2.29(s,3H).[M+H]+：765.41，C45H56N4O7。
HD-35：浅黄色粉末，收率75％。1H NMR(400MHz,CDCl3)δ7.30(dd,J＝8.2,1.8Hz,1H),7.07(d,J＝6.3Hz,1H),7.00(s,1H),6.80–6.70(m,1H),6.53(s,1H),6.49(s,1H),6.18(d,J＝9.8Hz,1H),5.93(s,1H),4.09(dd,J＝10.8,5.7Hz,1H),3.95–3.79(m,5H),3.76(s,3H),3.74–3.64(m,7H),3.63–3.42(m,4H),3.31(s,3H),3.22–3.06(m,5H),3.05–2.88(m,3H),2.87–2.76(m,2H),2.74(s,3H),2.65–2.43(m,5H),2.37(d,J＝14.7Hz,1H),2.30(s,3H).[M+H]+：752.40，C44H53N3O8。
HD-36：浅黄色粉末，收率63％。1H NMR(400MHz,MeOD)δ7.36(dd,J＝8.2,2.1Hz,1H),7.06(dd,J＝8.2,2.5Hz,1H),6.94(s,1H),6.70(s,1H),6.60(s,1H),6.49(dd,J＝8.2,1.7Hz,1H),6.14(dd,J＝8.4,1.7Hz,1H),5.87(s,1H),5.83–5.73(m,1H),5.22-5.12(m,2H),4.09(d,J＝9.2Hz,1H),3.96(dd,J＝10.7,6.1Hz,1H),3.82(s,3H),3.73(s,3H),3.65(s,3H),3.53(d,J＝11.2Hz,1H),3.42–3.36(m,1H),3.30(s,3H),3.23–3.16(m,4H),3.12(d,J＝9.7Hz,1H),3.06(s,3H),3.03(d,J＝6.2Hz,2H),2.95–2.71(m,10H),2.68-2.40(m,11H).[M+H]+：791.45，C47H58N4O7。
HD-37：浅黄色粉末，收率67％。1H NMR(400MHz,MeOD)δ7.38(dd,J＝8.2,2.1Hz,1H),7.09(dd,J＝8.2,2.6Hz,1H),6.98(s,1H),6.74(s,1H),6.62(s,1H),6.51(dd,J＝8.3,2.5Hz,1H),6.16(dd,J＝8.4,2.1Hz,1H),5.88(s,1H),4.40(d,J＝13.1Hz,1H),4.08(dd,J＝10.6,5.8Hz,1H),3.94(d,J＝8.7Hz,1H),3.83(s,3H),3.71(s,3H),3.64(s,3H),3.58-3.42(m,2H),3.33–3.26(m,4H),3.24–3.16(m,4H),3.09–3.01(m,5H),2.97(dd,J＝15.6,6.8Hz,2H),2.93–2.69(m,6H),2.66(s,3H),2.53(d,J＝15.3Hz,1H),2.46(s,3H),2.10–1.85(m,2H),1.83–1.50(m,2H).[M+H]+：766.42，C45H55N3O8。
HD-38：浅黄色粉末，收率69％。1H NMR(400MHz,MeOD)δ7.38(dd,J＝8.2,2.0Hz,1H),7.08(dd,J＝8.2,2.5Hz,1H),6.98(s,1H),6.75(s,1H),6.63(s,1H),6.54(dd,J＝8.3,2.5Hz,1H),6.18(dd,J＝8.3,2.0Hz,1H),5.89(s,1H),4.41(d,J＝12.9Hz,1H),4.11(dd,J＝10.7,5.3Hz,1H),3.90(d,J＝9.5Hz,1H),3.84(s,3H),3.71(s,3H),3.64(s,3H),3.53(dd,J＝31.7,16.4Hz,2H),3.32-3.26(m,4H),3.05(s,3H),3.04–2.91(m,4H),2.85–2.68(m,8H),2.67(s,3H),2.55(d,J＝15.2Hz,1H),2.44(s,3H).[M+H]+：696.38，C41H49N3O7。
实施例29：鹤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。对照药物鹤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鹤氏唐松草碱衍生物，浓度分别为50、25、12.5、6.25、3.125、1.56、0.78μM的衍生物。以鹤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450nm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鹤氏唐松草碱衍生物抗肿瘤细胞增殖活性IC50
表2鹤氏唐松草碱衍生物抗肿瘤细胞和耐药细胞增殖活性IC50
| Hela | Capan-1 | K562/ADR | MCF-7/ADR | A549/Taxol | |
| HD-01 | 11.36 | 10.16 | 8.64 | 9.34 | 6.68 |
| HD-02 | 8.28 | 12.76 | 7.63 | 12.89 | 7.26 |
| HD-03 | 6.68 | 10.82 | 12.34 | 8.09 | 9.08 |
| HD-04 | 6.96 | 8.35 | 6.23 | 7.89 | 5.28 |
| HD-05 | 25.78 | 28.96 | |||
| HD-06 | 28.10 | 39.68 | |||
| HD-07 | 37.18 | 36.38 | |||
| HD-11 | 12.34 | 22.46 | |||
| HD-12 | 7.39 | 18.3 | 8.56 | 8.79 | 9.23 |
| HD-13 | 5.20 | 18.38 | 15.12 | 14.98 | 17.07 |
| HD-14 | 7.37 | 12.83 | 5.38 | 6.56 | 11.43 |
| HD-15 | 10.63 | 28.37 | |||
| HD-16 | 13.63 | 32.27 | |||
| HD-17 | 4.2 | 4.67 | 2.65 | 3.58 | 4.28 |
| HD-18 | 5.47 | 8.37 | 11.15 | 9.38 | 10.28 |
| HD-19 | 9.23 | 28.88 | |||
| 鹤氏唐松草碱 | 14.98 | 18.89 | 19.44 | 11.68 | 10.23 |
实验结论：鹤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，部分衍生物活性强于鹤氏唐松草碱。化合物HD-17、化合物HD-18的活性最好。
实施例30：鹤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。
对鹤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1μM/L的鹤氏唐松草碱衍生物，30分钟后再加入浓度梯度为5、2.5、1.25、0.625、0.3125、0.156、0.078μM/L的阿霉素。以tarquidar为阳性药物对照。药物共作用48小时。通过cck8法测定1μM浓度的鹤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)。同法检测鹤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鹤氏唐松草碱衍生物逆转K562/ADR耐药活性
表4鹤氏唐松草碱衍生物逆转MCF-7/ADR耐药活性
表5鹤氏唐松草碱衍生物逆转A549/Taxol耐药活性
实验结论：鹤氏唐松草碱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)
1.一种鹤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、C3～C6的烯基、
R2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；
R3选自-CF3、-CH3、
R4选自C1～C8烷基、
R5选自C1～C4烷基、C1～C4烷氧基C1～C4烷基；
R6、R7各自独立的选自C1～C6烷基，或与N、O一起形成3元～6元环；
R8选自单取代或多取代的F、Cl、Br、三氟甲基、氨基、氰基、酯基、硝基、氢、甲氧基、羟基；
R9选自
R10选自C1～C6烷基；
R11选自C1～C6烷基；
R12选自C1～C6烷基；
R13选自C1～C6烷基；
R14选自C1～C6烷基。
2.根据权利要求1所述的鹤氏唐松草碱衍生物或其药用盐，其特征在于，所述鹤氏唐松草碱衍生物中，R1选自以下结构的一种：
R9选自
3.一种权利要求1或2所述的鹤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所述的鹤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所述的鹤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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