CN111362998B - 氮杂20(r)-人参二醇衍生物及其抗肿瘤应用 - Google Patents

氮杂20(r)-人参二醇衍生物及其抗肿瘤应用 Download PDF

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CN111362998B
CN111362998B CN202010330822.1A CN202010330822A CN111362998B CN 111362998 B CN111362998 B CN 111362998B CN 202010330822 A CN202010330822 A CN 202010330822A CN 111362998 B CN111362998 B CN 111362998B
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孟庆国
王洪波
赵风兰
邓建强
刘书琪
刘丽
王嘉珍
赵若琳
牟晓懂
张晓凡
栾明珠
王晓慧
孙可微
唐航军
马颖
贺秀婷
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Yantai University
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Abstract

本发明属于四环三萜类化合物及其应用技术领域，具体涉及氮杂20(R)‑人参二醇衍生物及其抗肿瘤应用。本发明包含A系列、B系列和C系列20(R)‑人参二醇及其新衍生物。氮杂20(R)‑人参二醇衍生物或者它们药学上可接受的盐、水合物和溶剂合物在抗肿瘤方面的用途。经体外细胞实验，该类化合物具有良好的抗肿瘤活性，因此可用于制备抗肿瘤药物。

Description

氮杂20(R)-人参二醇衍生物及其抗肿瘤应用
技术领域
本发明属于四环三萜类化合物及其应用技术领域，具体涉及20(R)-人参二醇及其衍生物，或者它们药学上可接受的盐、水合物和溶剂合物在抗肿瘤方面的用途。
背景技术
癌症是一大类恶性肿瘤的统称，是目前严重危害人类健康的一大顽症，近年来抗癌药物的研究取得了较大的进展。治疗恶性肿瘤多采用综合手段，有手术治疗、放射治疗、免疫治疗，以及及中药治疗和化学治疗。癌症的治疗中，药物治疗是一个很重要的环节，有效的抗癌药物的使用，可以帮助患者获得更长的生存时间，拥有活下来的希望，目前最为常见的抗癌药物有化疗药物、中药、生物制药、靶向药物，等。
人参在我国已有千余年用药史，具有“益智、安神、抗衰老”等多重功效，人参皂苷是其主要活性物质，具有拮抗吗啡依赖、预防老年痴呆、保护心脑血管等功效，天然人参皂苷20位碳原子多为S构型，R构型主要在存在于红参中，但含量极少，获取困难，有关20(R)-人参皂苷的放量制备鲜有报道。调研文献发现，20(R)-人参二醇具有保护肝肾功能、抗乙肝病毒等作用。现有已知的是20(R)-人参二醇不具有抗肿瘤活性，但是与抗肿瘤药物合用具有提效效果。
发明内容
本发明的目的在于，提供氮杂20(R)-人参二醇新衍生物或者它们药学上可接受的盐、水合物和溶剂合物以及其在制备抗肿瘤药物方面的用途。
本发明的目的之一是通过以下的技术方案来实现的：
本发明涉及氮杂20(R)-人参二醇及其衍生物，所述化合物的结构如下所示：
Figure GDA0003776225900000011
其中，R3如表3所示的限定。
表3 C系列化合物
Figure GDA0003776225900000021
Figure GDA0003776225900000031
本发明C系列20(R)-人参二醇新衍生物可用下列方法制备得到:
a)酸降解人参茎叶总皂苷，制备20(R)-人参二醇；
b)C系列衍生物：将20(R)-人参二醇的C-3羟基氧化为羰基，再进一步修饰为氨基，再与氨基酸缩合，得到衍生物5、C1～C11。
c)C系列衍生物盐酸盐：将C系列衍生物溶解于无水乙醇，加入含氯化氢的无水乙醇溶液，搅拌后生成相应的盐酸盐，其中，所述的C系列化合物与所述的氯化氢的摩尔比为1:1.01～1.02，得到C系列化合物盐酸盐。合成路线如下所示：
C系列化合物的合成路线：
Figure GDA0003776225900000032
本发明的目的之二是通过以下的技术方案来实现的：
本发明涉及上述氮杂20(R)-人参二醇的衍生物在制备抗肿瘤药物中的应用。
所述C系列衍生物用于制备盐酸盐的应用。
MTT法测试了氮杂20(R)-人参二醇的衍生物对癌细胞Ls180、Lncap和Mkn45的抑制作用。结果表明，氮杂20(R)-人参二醇的新衍生物具有良好的抗肿瘤的作用。
有益效果
本发明提供了一类新的氮杂20(R)-人参二醇的衍生物，本发明制备的氮杂20(R)-人参二醇的新衍生物具有良好的抗肿瘤的作用，而且表现出很好的水溶性，能够作为药物有效利用。本发明提供氮杂20(R)-人参二醇新衍生物或者它们药学上可接受的盐、水合物和溶剂合物以及其在制备抗肿瘤药物方面的用途。
具体实施方式
以下结合具体实施例，对本发明作进一步说明。应理解，以下实施例仅用于说明本发明而非用于限定本发明的范围。
下列实施例中未注明具体条件的实验方法，通常按照常规条件，或厂商提供的条件进行。
其中20(R)-人参二醇参照文献方法制备(马佳慧.人参二醇制备新型人参皂苷元的化学研究[D],长春，吉林大学)。
具体制备方法如下：
1L反应瓶，加入50％乙醇500mL，降温至0℃，搅拌条件下滴加50mL浓盐酸，滴加完毕，转移至60℃油浴，搅拌下分批加入50g人参茎叶总皂苷，升温至100℃，反应4h，降至接近室温，减压浓缩，回收乙醇，加入氢氧化钠调节至中性，加入氯仿萃取，有机相经水洗、饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩回收氯仿，硅胶柱层析，得到5g白色固体，与对照品比较，为20(R)-人参二醇。m.p.:257～259℃,1H NMR(400MHz,CDCl3)δ6.27(s,1H),3.50(td,J＝10.3,5.2Hz,1H),3.17(dd,J＝11.2,5.1Hz,1H),1.25(s,3H),1.20(s,3H),1.16(s,3H),0.95(d,J＝2.0Hz,6H),0.86(s,6H),0.76(s,3H).13C NMR(101MHz,CDCl3)δ16.85,17.09,17.6,17.75,18.53,19.78,20.88,26.64,28.58,28.94,29.52,31.99,32.61,34.5,36.33,37.21,37.91,38.58,40.35,40.39,41.23,50.59,51.38,52.69,56.18,57.33,71.42,74.57,78.13,80.34.HRMS calcd for C30H55O3[M+H]+461.39892；found 461.39830.
化合物1的制备
将20(R)-人参二醇(5.0g,10.85mmol)溶于二氯甲烷(500mL)，搅拌下加入PCC(4.7g,43.5mmol)，室温反应4h，加饱和碳酸钠溶液搅拌30min，萃取，有机相经水洗、饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(石油醚/乙酸乙酯，4:1，v/v)，得到4.5g化合物1，收率为90.0％。m.p.:235～237℃,1H NMR(400MHz,CDCl3)δ6.35–6.27(m,1H),3.53(td,J＝10.2,4.7Hz,1H),1.26(s,3H),1.21(s,3H),1.18(s,3H),1.07(d,J＝1.4Hz,3H),1.03(d,J＝1.4Hz,3H),1.01(d,J＝1.4Hz,3H),0.97(d,J＝1.6Hz,3H),0.88(d,J＝1.2Hz,3H).HRMS calcd for C30H51O3[M+H]+459.38327；found 459.38278.
化合物2的制备
将化合物1(500mg,1.09mmol)溶于无水乙醇(20mL)，搅拌下加入盐酸羟胺(227mg,3.2mmol)和乙酸钠(268mg,3.2mmol)，室温反应4h。减压浓缩，回收乙醇，剩余物加入二氯甲烷溶解，有机相经水洗、饱和食盐水洗，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析(石油醚/乙酸乙酯，3:1，v/v)，得到400mg化合物2，白色固体，收率为78.0％。1H NMR(400MHz,CDCl3)δ6.30(s,1H),5.30(s,2H),3.52(td,J＝10.3,5.0Hz,1H),2.97(dt,J＝15.4,5.3Hz,1H),1.26(s,3H),1.21(s,3H),1.18(s,3H),1.13(s,3H),1.05(s,3H),1.00(s,3H),0.97(s,3H),0.86(s,3H).
化合物A1的制备
取50ml单口瓶，加入10mL THF，置于冰盐浴中，依次加入化合物2(100mg,0.211mmol)、氢化钠(50mg,2.11mmol)和1-溴-3-氟-丙烷(30.0mg,0.211mmol)，低温反应30mim，再转移至40℃油浴，反应3h，TLC(石油醚:乙酸乙酯＝3:1)监测反应，直到原料反应完毕。减压浓缩，回收THF，剩余物用二氯甲烷(3×20mL)溶解，经饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析，得到100mg化合物A1，白色固体，收率为90.1％，m.p.128.0～130.9℃。1H NMR(400MHz,CDCl3)δ6.24(s,1H),4.59(t,J＝6.2Hz,1H),4.47(t,J＝6.2Hz,1H),4.10(t,J＝6.2Hz,2H),3.50(td,J＝10.3,5.1Hz,1H),2.85(ddd,J＝15.6,6.0,3.9Hz,1H),2.23(ddd,J＝15.6,11.5,6.4Hz,1H),2.03(dq,J＝24.7,6.2Hz,2H),1.24(d,J＝5.1Hz,9H),1.20(s,3H),1.17(s,3H),1.11(s,3H),1.02(s,3H),0.99(s,3H),0.94(s,3H),0.85(s,3H).13C NMR(100MHz,CDCl3)δ166.20,82.43,80.80,77.41,77.30,77.09,76.78,76.73,73.19,69.94,68.80,68.75,56.05,54.77,49.55,49.31,40.21,39.88,38.95,37.14,36.53,35.82,34.55,33.10,32.00,31.51,31.18,30.85,30.69,30.49,29.77,29.74,29.44,27.63,27.21,25.23,23.11,19.49,19.18,17.89,17.05,16.35,15.82,15.58,14.19.HR-MS(ESI):calcd for C33H57NO3F,[M+H]+543.43170；found:543.43121.
化合物A2的制备
采用与目标物A1相同的合成方法，制备化合物A2。白色固体，收率为83.3％，m.p.152.5～155.5℃。1H NMR(400MHz,CDCl3)δ6.23(s,1H),5.99(ddt,J＝16.1,11.0,5.6Hz,1H),5.25(dd,J＝17.3,1.6Hz,1H),5.15(dd,J＝10.4,1.5Hz,1H),4.50(d,J＝5.6Hz,2H),3.50(td,J＝10.3,5.1Hz,1H),2.89(ddd,J＝15.6,6.0,3.9Hz,1H),2.26(ddd,J＝15.6,11.5,6.3Hz,1H),1.24(d,J＝4.7Hz,6H),1.17(s,3H),1.12(s,3H),1.02(s,3H),0.99(s,3H),0.94(s,3H),0.85(s,3H).13C NMR(100MHz,CDCl3)δ166.21,134.92,116.84,77.41,77.30,77.09,76.78,73.18,69.95,56.05,54.77,49.55,49.31,40.22,39.88,38.95,37.13,36.53,35.83,34.56,33.10,32.00,31.51,31.18,30.85,30.28,29.77,29.44,27.64,27.22,25.24,23.11,22.77,19.49,19.18,18.01,17.05,16.35,15.85,15.58,14.20.HR-MS(ESI):calcd for C33H56NO3,[M+H]+514.42574；found:514.42508.
化合物A3的制备
取25mL反应瓶，加入10mL二氯甲烷，搅拌条件下加入化合物2(200mg,0.42mmol)，完全溶解后，依次加入乙酸酐(43mg,0.42mmol)、DMAP(66.2mg,0.42mmol)和EDCI(87.6mg,0.42mmol)，室温搅拌反应3h，TLC(石油醚/乙酸乙酯＝3/1,v/v)显示原料反应完全。减压浓缩，回收二氯甲烷，用15mL乙酸乙酯溶解剩余物，并依次用蒸馏水(5mL×2)、饱和氯化钠溶液洗涤有机相，然后用无水硫酸钠干燥，过滤，减压浓缩，硅胶薄层层析，得到205mg化合物A3，类白色粉末，总收率为94.1％，m.p.235.5～238.2℃。1H NMR(400MHz,CDCl3)δ6.26(s,1H),3.50(td,J＝10.3,5.1Hz,1H),2.96(ddd,J＝15.3,5.6,4.0Hz,1H),2.26(ddd,J＝15.5,11.7,6.2Hz,1H),1.24(s,3H),1.20(s,3H),1.16(s,3H),1.12(s,3H),1.04(s,3H),0.98(s,3H),0.96(s,3H),0.84(s,3H).13C NMR(100MHz,CDCl3)δ167.06,77.42,77.10,76.78,76.73,73.19,69.95,56.11,54.76,51.28,49.60,49.27,40.47,39.88,39.06,37.25,36.52,35.81,34.56,33.09,31.17,30.81,27.40,27.20,25.22,22.85,19.48,19.14,17.19,17.03,16.34,15.92,15.60.HR-MS(ESI):calcd for C32H53NO4,[M+H]+516.42279；found:516.42480.
采用与化合物A3相同的合成方法，合成化合物A4-A7。
化合物A4：类白色粉末，总收率为81.8％，m.p.222.5～225.3℃。1H NMR(400MHz,CDCl3)δ7.81–7.78(m,1H),7.45(d,J＝2.0Hz,1H),6.96(d,J＝11.2Hz,2H),6.27(s,1H),3.86(s,3H),3.51(td,J＝10.4,5.1Hz,1H),2.99(ddd,J＝15.0,5.8,4.5Hz,1H),2.49(ddd,J＝15.1,11.1,6.3Hz,1H),1.30(s,3H),1.24(d,J＝4.8Hz,9H),1.20(s,3H),1.17(d,J＝2.1Hz,6H),0.99(d,J＝3.3Hz,6H),0.86(s,3H).13C NMR(100MHz,CDCl3)δ176.17,164.75,158.87,133.43,131.79,120.36,119.96,112.00,77.43,77.11,76.79,76.75,73.21,69.91,56.13,55.98,54.75,51.29,49.59,49.31,49.14,41.66,39.88,39.45,37.23,36.52,35.81,34.50,34.03,33.09,32.00,31.19,30.94,29.77,29.43,27.41,27.22,25.72,25.22,25.02,22.72,20.17,19.50,19.09,17.05,16.34,16.19,15.57,14.19.HR-MS(ESI):calcd for C38H58NO5,[M+H]+608.43095；found:608.42987.
化合物A5：类白色粉末，总收率为82.0％，m.p.206.3～209.2℃。1H NMR(400MHz,CDCl3)δ7.86(dd,J＝8.1,1.4Hz,1H),7.39(td,J＝7.5,1.4Hz,1H),7.27–7.23(m,2H),6.26(s,1H),3.51(td,J＝10.3,5.0Hz,1H),2.93(m,1H),2.61(s,3H),2.49(m,1H),1.32(s,3H),1.25(s,3H),1.19(d,J＝2.8Hz,6H),1.17(s,3H),1.00(d,J＝3.7Hz,6H),0.86(s,3H).13CNMR(100MHz,CDCl3)δ175.95,140.32,132.00,131.78,77.42,77.31,77.10,76.79,76.73,69.87,56.07,54.75,51.28,49.55,49.30,49.17,41.72,39.31,37.21,36.51,35.81,34.47,34.04,33.10,31.19,30.92,27.50,27.22,25.72,25.22,25.02,22.89,20.22,19.50,19.12,17.05,16.34,16.10.HR-MS(ESI):calcd for C38H58NO4,[M+H]+592.43604；found:592.43572.
化合物A6：类白色粉末，总收率为86.0％，m.p.225.5～227.2℃。1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.2Hz,2H),7.24(d,J＝7.7Hz,2H),6.25(s,1H),3.51(td,J＝10.3,5.1Hz,1H),3.00–2.92(m,1H),2.52(ddd,J＝15.4,11.1,6.4Hz,1H),2.40(s,3H),1.31(s,3H),1.25(s,3H),1.19(d,J＝4.4Hz,6H),1.17(s,3H),0.99(d,J＝3.5Hz,6H),0.86(s,3H).13C NMR(100MHz,CDCl3)δ164.41,129.63,129.26,126.99,77.43,77.31,77.11,76.79,76.74,69.87,55.98,54.75,51.28,49.53,49.30,41.66,39.87,39.22,36.52,35.81,34.46,33.10,31.19,30.92,27.57,27.22,25.72,25.23,25.03,22.94,20.05,19.50,19.13,17.04,16.34,16.08.HR-MS(ESI):calcd for C33H57NO4,[M+H]+592.43604；found:592.43530.
化合物A7：类白色粉末，总收率为83.7％，m.p.217.5～219.2℃。1H NMR(400MHz,CDCl3)δ8.32(s,1H),8.29(d,J＝3.6Hz,1H),8.22(s,1H),8.20(s,1H),6.29(s,1H),3.51(s,1H),2.93(d,J＝14.6Hz,1H),2.61–2.51(m,1H),1.32(s,3H),1.25(s,3H),1.20(s,6H),1.17(s,3H),1.00(s,6H),0.86(s,3H).13C NMR(100MHz,CDCl3)δ150.62,135.29,130.71,127.76,123.88,77.42,77.30,77.10,76.78,73.25,69.85,55.93,54.75,49.54,49.29,41.85,39.87,39.21,37.20,36.51,35.81,34.42,33.86,33.10,31.19,30.94,29.77,27.60,27.21,25.22,24.94,22.90,20.27,19.13,17.04,16.33,15.56.HR-MS(ESI):calcdfor C37H55N2O6,[M+H]+623.40546；found:623.40399.
化合物3的制备
取50mL单口反应瓶，加入100mL冰乙酸，再加入中间体1(4.0g,8.46mmol)，加入吡啶氢溴酸盐高溴化物(2.71g,8.46mmol)，室温搅拌，逐渐溶解，为浅黄色透明溶液，室温搅拌5h，TLC(石油醚:乙酸乙酯＝3:1)监测反应，直到原料反应完毕。减压浓缩，去除乙酸，用饱和碳酸钠溶液将反应体系调节至中性，用乙酸乙酯(3×20mL)进行萃取，去离子水洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析(石油醚:乙酸乙酯＝10:1)，得到3.8g棕色固体3，收率为81.3％。
化合物4的制备
取100mL单口反应瓶，加入50mL无水乙醇，将中间体3(3.5g,6.52mmol)和硫脲(0.497g,6.52mmol)，回流反应5h，TLC(石油醚:乙酸乙酯＝1:1)监测反应，直到原料反应完毕。减压浓缩，回收乙醇，用乙酸乙酯(3×20mL)进行萃取，去离子水洗涤有机相，无水硫酸钠干燥，减压浓缩，经硅胶柱层析(石油醚:乙酸乙酯＝3:1-1:1)，得到1.5g化合物4，浅黄色固体，收率为44.7％。
化合物B1的制备
25mL反应瓶，加入10mL二氯甲烷，加入化合物4(100mg,0.195mmol)，完全溶解后，依次加入Boc-Gly-OH(41mg,0.234mmol)、DMAP(24mg,0.20mmol)和EDCI(112mg,0.59mmol)，室温反应3h，TLC(石油醚/乙酸乙酯＝3/1,v/v)显示原料反应完全。加入适量的蒸馏水萃取，用饱和氯化钠溶液洗涤有机相，过滤，减压浓缩，回收二氯甲烷。再加入10mL(20％TFA/DCM)溶液，0℃反应1h，TLC(二氯甲烷/甲醇＝10/1,v/v)检测反应，反应结束后，用饱和碳酸钠溶液调节pH＝9～10左右，加入适量的蒸馏水，用饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩，回收二氯甲烷，硅胶柱层析，得到90mg化合物B1，白色粉末，总收率为81.0％，m.p.145.0～147.9℃。1H NMR(400MHz,CDCl3)δ6.29(s,1H),5.30(s,1H),3.63–3.58(m,2H),3.57(dd,J＝10.2,5.0Hz,1H),2.76(d,J＝15.5Hz,1H),2.27(d,J＝15.5Hz,1H),1.28(s,3H),1.23(s,6H),1.20(s,3H),1.04(s,3H),0.91(s,6H).13C NMR(100MHz,CDCl3)δ170.49,154.52,151.10,120.51,77.50,77.38,77.18,76.86,73.18,69.84,54.68,53.52,53.28,49.31,48.59,44.43,38.95,36.81,36.50,35.79,34.17,33.07,31.23,31.00,30.58,27.21,25.20,22.44,19.64,19.49,17.05,16.33,16.14,15.26.HR-MS(ESI):calcd for C33H54N3O3S,[M+H]+572.38804；found:572.38763.
采用与化合物B1相同的合成方法，合成化合物B2～B6。
化合物B2：类白色粉末，总收率为83.5％，m.p.237.9～240.9℃。1H NMR(400MHz,CDCl3)δ6.26(s,1H),3.68(q,J＝7.0Hz,1H),3.53(ddd,J＝10.2,7.7,3.1Hz,1H),2.71(d,J＝15.6Hz,1H),2.23(d,J＝15.5Hz,1H),1.39(d,J＝7.0Hz,3H),1.23(s,3H),1.19(s,9H),1.15(s,3H),1.11(s,3H),0.99(s,3H),0.87(s,6H).13C NMR(100MHz,CDCl3)δ173.43,154.65,151.18,120.51,77.46,77.37,77.14,77.10,76.82,76.71,76.66,73.20,73.18,69.84,54.69,53.32,52.32,51.33,50.57,49.34,48.61,39.83,38.99,38.37,36.84,36.80,36.51,35.80,34.19,34.01,33.07,31.24,31.04,30.60,29.35,27.21,25.90,25.71,25.21,25.01,22.45,21.47,19.66,19.50,17.89,17.05,16.34,16.29,16.11,15.27.HR-MS(ESI):calcd for C34H56N3O3S,[M+H]+586.40217；found:586.40192.
化合物B3：白色粉末，总收率为80.6％，m.p.237.9～240.9℃。1H NMR(400MHz,CDCl3)δ6.26–6.21(m,1H),3.51(dt,J＝10.3,5.2Hz,1H),3.43–3.39(m,1H),2.70(d,J＝15.3Hz,1H),2.36(dq,J＝6.8,3.7Hz,1H),2.21(d,J＝15.6Hz,1H),1.21(s,3H),1.16(s,6H),1.13(s,3H),1.09(d,J＝2.9Hz,3H),0.98(d,J＝4.0Hz,6H),0.85(s,6H),0.81(dd,J＝6.8,2.5Hz,3H).13C NMR(100MHz,CDCl3)δ172.36,154.53,151.15,120.33,77.49,77.38,77.17,76.85,76.70,76.67,73.17,69.82,60.43,59.93,54.68,53.34,51.33,49.33,48.60,39.83,39.00,38.34,36.82,36.50,35.79,34.18,34.00,33.05,31.23,31.04,30.94,30.62,29.74,27.20,25.71,25.20,25.01,22.42,21.09,19.67,19.49,17.05,16.33,16.28,16.11,15.26,14.26.HR-MS(ESI):calcd for C36H60N3O3S,[M+H]+614.43499；found:614.43512.
化合物B4：白色粉末，总收率为80.6％，m.p.209.0～210.9℃。1H NMR(400MHz,CDCl3)δ6.25(s,1H),3.56(td,J＝11.3,10.4,4.6Hz,2H),2.73(d,J＝15.6Hz,1H),2.25(d,J＝15.7Hz,1H),1.25(s,3H),1.21(d,J＝2.1Hz,6H),1.17(s,3H),1.13(s,3H),1.01(s,3H),0.95(d,J＝6.0Hz,3H),0.92(d,J＝6.0Hz,3H),0.89(m,6H).13C NMR(100MHz,CDCl3)δ173.34,151.25,120.49,77.43,77.32,77.11,76.80,69.84,54.71,53.49,53.38,53.31,51.36,49.37,48.63,43.96,39.86,39.03,36.85,36.53,35.83,34.21,33.08,31.25,31.07,30.60,27.22,25.22,24.95,23.35,22.43,21.51,19.68,19.51,16.36,16.12,15.28.HR-MS(ESI):calcd for C37H62N3O3S,[M+H]+628.45064；found:628.45026.
化合物B5：白色粉末，总收率为80.6％，m.p.172.2～174.9℃。1H NMR(400MHz,CDCl3)δ7.25(d,J＝1.6Hz,1H),7.23–7.06(m,5H),6.26(s,1H),3.77(dd,J＝9.1,4.0Hz,1H),3.54(td,J＝10.4,5.1Hz,1H),3.27(dd,J＝13.8,4.0Hz,1H),2.82–2.67(m,2H),2.24(d,J＝15.6Hz,1H),1.23(s,3H),1.19(s,3H),1.16(d,J＝3.8Hz,6H),1.08(s,3H),1.00(s,3H),0.87(d,J＝3.8Hz,6H).13C NMR(100MHz,CDCl3)δ172.11,154.43,151.32,137.46,137.26,136.24,129.42,129.38,129.34,129.32,128.90,128.86,128.76,128.71,128.62,128.47,127.07,126.90,120.60,77.52,77.40,77.20,76.89,73.19,69.85,60.45,56.13,54.70,53.87,53.32,53.30,52.04,49.35,48.62,40.53,39.85,39.02,38.38,38.36,36.52,35.81,34.19,34.01,33.08,31.25,31.05,30.60,30.57,27.23,25.22,22.44,19.67,19.51,17.07,16.35,16.15,15.28,14.27.HR-MS(ESI):calcd for C40H60N3O3S,[M+H]+662.43499；found:662.43500.
化合物B6：白色粉末，总收率为80.6％，m.p.205.0～208.2℃。1H NMR(400MHz,CDCl3)δ8.50(s,1H),7.62(d,J＝7.9Hz,1H),7.35(d,J＝8.1Hz,1H),7.20–7.15(m,1H),7.12–7.07(m,1H),7.03(d,J＝2.2Hz,1H),6.32(s,1H),5.28(s,1H),3.88(dd,J＝8.7,4.1Hz,1H),3.58(td,J＝10.8,10.4,5.5Hz,1H),3.42(dd,J＝14.7,3.8Hz,1H),3.06–2.97(m,1H),2.76(d,J＝15.6Hz,1H),2.27(d,J＝15.6Hz,1H),1.26(s,3H),1.22(d,J＝4.5Hz,6H),1.19(s,3H),1.12(s,3H),1.03(s,3H),0.91(d,J＝5.1Hz,6H).13C NMR(100MHz,CDCl3)δ172.70,154.50,151.34,136.51,127.58,123.39,122.37,120.57,119.79,118.80,111.44,111.04,77.44,77.33,77.13,76.81,73.24,69.91,55.36,54.73,53.51,53.36,51.38,49.38,48.65,39.87,39.06,36.87,36.54,35.84,34.22,34.03,33.10,31.27,31.09,30.61,30.35,27.24,25.24,25.02,22.44,19.68,19.54,17.09,16.37,16.18,15.30.HR-MS(ESI):calcd for C42H61N3O4S,[M+H]+701.44589；found:701.44531.
化合物5的制备
250mL反应瓶，加入100mL甲醇，室温搅拌下缓慢加入化合物1(6g,12.69mmol)，溶液澄清透明，依次加入醋酸铵(4.89g,63.45mmol)、氰基硼氢化钠(1.99g,31.73mmol)和10mL三氯化钛，氮气保护下反应24h，溶液由透明逐渐变为混浊状态，TLC(二氯甲烷:甲醇＝10:1)监测反应，直到原料反应完毕。抽滤，滤液减压浓缩，剩余物用二氯甲烷(3×20mL)和水萃取，饱和食盐水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析(二氯甲烷:甲醇＝20:1-10:1)，得到3.2g化合物5，白色固体，收率为53.5％。
化合物C1的制备
取25mL反应瓶，加入10mL二氯甲烷，搅拌条件下加入化合物4(100mg,0.218mmol)，完全溶解后，依次加入Boc-Gly-OH(45.7mg,0.261mmol)、DMAP(26.6mg,0.22mmol)和EDCI(135.2mg,0.66mmol)，室温搅拌反应3h，TLC(二氯甲烷/甲醇＝10/1,v/v)显示原料反应完全。依次用蒸馏水(5mL×2)、饱和氯化钠溶液洗涤有机相，有机相减压浓缩，剩余物加入10ml(20％TFA/DCM)溶液，低温反应1h，TLC(二氯甲烷/甲醇＝10/1,v/v)检测反应，反应结束后，用饱和碳酸钠溶液调节pH 9～10左右，依次用蒸馏水(5mL×2)、饱和氯化钠溶液洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱层析，得到95mg化合物C1，类白色粉末，总收率为84.8％,m.p.249.0～251.8℃。1H NMR(400MHz,CDCl3)δ6.29(s,1H),3.62(q,J＝9.6Hz,1H),3.51(td,J＝10.4,5.2Hz,1H),3.36(s,1H),2.63(s,4H),1.23(d,J＝4.0Hz,6H),1.19(s,3H),1.15(s,3H),0.95(s,3H),0.85(s,6H),0.83(s,3H),0.77(s,3H).13C NMR(100MHz,CDCl3)δ77.43,77.32,77.11,76.80,76.74,73.19,70.02,56.64,56.24,54.76,51.28,49.94,49.20,39.41,37.98,36.52,35.80,34.88,33.08,32.00,31.58,31.18,30.48,29.77,29.73,29.43,28.55,27.21,26.95,25.67,25.23,22.76,19.49,18.65,17.09,16.46,16.34,16.13,15.69,14.20.HR-MS(ESI):calcd for C32H57N2O3,[M+H]+517.43637；found:517.43567.
采用与化合物C1相同的制备方法，制备化合物C2-C11。
化合物C2：白色粉末，总收率为84.8％,m.p.242.0～245.1℃。1H NMR(400MHz,CDCl3)δ6.89(d,J＝9.0Hz,1H),6.25(s,1H),3.62(dd,J＝17.4,8.1Hz,6H),3.50(td,J＝10.3,5.2Hz,1H),3.09(s,2H),2.47(s,2H),1.23(s,3H),1.19(s,3H),1.15(s,3H),0.95(s,3H),0.86–0.82(m,9H),0.75(s,3H).13C NMR(100MHz,CDCl3)δ171.37,130.96,77.43,77.43,77.31,77.11,76.79,70.00,68.23,56.82,56.63,54.75,51.29,49.92,49.22,39.48,36.52,35.80,34.88,33.09,31.19,30.52,30.43,29.77,28.61,27.23,25.59,25.25,23.05,19.50,18.65,17.14,16.60,16.35,16.14,15.69.HR-MS(ESI):calcd forC33H59N2O3,[M+H]+531.45202；found:531.45135.
化合物C3：类白色粉末，总收率为84.8％，m.p.104.2～106.8℃。1H NMR(400MHz,CDCl3)δ7.23(d,J＝9.6Hz,1H),6.23(s,1H),3.56(dtd,J＝32.6,10.7,5.3Hz,2H),3.25(d,J＝3.7Hz,1H),2.28(ddp,J＝10.6,6.9,3.7Hz,1H),1.24(s,3H),1.23(s,1H),1.19(s,3H),1.16(s,3H),0.97(d,J＝7.4Hz,7H),0.86(s,6H),0.81(s,1H),0.79(s,1H),0.78(s,3H).13CNMR(100MHz,CDCl3)δ173.57,77.42,77.36,77.10,76.79,76.76,76.72,76.70,73.15,69.96,60.17,56.66,56.24,54.77,51.29,49.94,49.25,39.40,37.86,37.12,36.52,35.81,34.88,33.09,31.18,30.99,30.55,29.77,28.61,27.40,27.22,25.95,25.23,19.82,19.50,18.66,17.13,16.54,16.35,16.10,16.01,15.69.HR-MS(ESI):calcd forC35H63N2O3,[M+H]+559.48332；found:559.48260.
化合物C4：白色粉末，总收率为84.8％，m.p.109.0～112.0℃。1H NMR(400MHz,CDCl3)δ7.19(d,J＝10.0Hz,1H),6.26(s,1H),3.53(dtd,J＝21.4,10.4,5.4Hz,2H),3.38(dd,J＝9.4,2.8Hz,1H),1.23(s,3H),1.19(s,3H),1.15(s,3H),0.95(s,3H),0.93(d,J＝6.3Hz,3H),0.90(d,J＝6.1Hz,3H),0.85(d,J＝2.9Hz,6H),0.82(s,3H),0.76(s,3H).13CNMR(100MHz,CDCl3)δ174.88,77.45,77.33,77.13,76.81,76.71,69.97,56.60,56.11,54.76,53.68,51.28,49.91,49.21,44.14,39.81,39.38,37.10,36.50,35.79,34.85,33.10,31.18,30.52,29.78,28.59,27.20,25.69,25.22,24.96,23.51,21.49,19.49,18.65,17.12,16.52,16.35,16.12,15.68.HR-MS(ESI):calcd for C36H65N2O3,[M+H]+573.49897；found:573.49805.
化合物C5：类白色粉末，总收率为84.8％，m.p.123.2～125.0℃。1H NMR(400MHz,CDCl3)δ8.24(d,J＝5.4Hz,1H),6.67(d,J＝7.4Hz,1H),6.25(s,1H),3.76(d,J＝46.8Hz,2H),3.64–3.48(m,3H),3.19(s,4H),1.24(s,6H),1.20(s,3H),1.17(s,3H),1.09(s,2H),0.96(s,3H),0.87(s,6H),0.84(s,3H),0.79(s,3H).13C NMR(100MHz,CDCl3)δ77.43,77.31,77.11,76.79,73.17,69.99,56.58,54.76,49.91,49.22,39.73,39.36,37.98,37.09,36.51,35.80,34.85,33.09,31.19,30.53,30.21,29.76,29.43,28.54,27.23,25.54,25.24,22.76,19.50,18.63,17.12,16.42,16.34,16.10,15.68,14.19.HR-MS(ESI):calcdfor C33H59N2O4,[M+H]+547.44693；found:547.44629.
化合物C6：类白色粉末，总收率为84.8％，m.p.105.2～108.0℃。1H NMR(400MHz,CDCl3)δ6.25(s,1H),4.11(s,1H),3.56(d,J＝29.5Hz,3H),3.14(d,J＝4.5Hz,2H),2.25(s,1H),1.24(s,3H),1.19(s,3H),1.15(s,3H),0.95(s,3H),0.85(d,J＝8.2Hz,6H),0.77(d,J＝12.1Hz,6H).13C NMR(100MHz,CDCl3)δ127.09,113.84,77.41,77.30,77.10,76.78,76.73,73.17,70.61,69.96,61.83,57.21,56.64,54.76,51.29,49.92,49.23,39.83,36.52,35.81,34.85,33.09,31.75,31.19,30.54,29.78,28.55,28.47,27.58,27.29,27.22,25.46,25.23,22.77,19.50,18.63,17.15,16.35,16.06,15.69.HR-MS(ESI):calcdfor C35H61N2O3,[M+H]+557.46767；found:557.46667.
化合物C7：类白色粉末，总收率为84.8％，m.p.219.2～221.8℃。1H NMR(400MHz,CDCl3)δ7.36(d,J＝9.9Hz,1H),6.24(s,1H),4.24–4.15(m,1H),3.64–3.46(m,2H),3.23(d,J＝3.1Hz,1H),2.07(s,3H),1.23(s,3H),1.19(s,3H),1.17(s,2H),1.15(s,4H),0.95(s,3H),0.86(s,6H),0.83(s,3H),0.77(s,3H).13C NMR(100MHz,CDCl3)δ173.12,77.43,77.31,77.11,76.79,76.66,69.96,68.24,59.38,56.64,56.56,54.89,54.76,49.93,49.23,39.83,39.38,37.93,36.51,35.88,35.80,34.86,33.09,31.18,30.54,28.61,27.23,25.90,25.23,19.50,18.79,18.64,16.48,16.34,16.11,15.69.HR-MS(ESI):calcd forC34H61N2O4,[M+H]+561.45990；found:561.46014.
化合物C8：白色粉末，总收率为84.8％，m.p.107.0～109.9℃。1H NMR(400MHz,CDCl3)δ6.24(s,1H),3.58–3.50(m,2H),3.47(dd,J＝9.2,3.8Hz,1H),3.10(dd,J＝12.6,3.8Hz,1H),2.60(dd,J＝12.6,9.3Hz,1H),1.31(s,12H),1.24(s,3H),1.19(s,3H),1.15(s,3H),0.95(s,3H),0.86(s,6H),0.83(s,3H),0.77(s,3H).13C NMR(100MHz,CDCl3)δ172.77,78.10,77.43,77.32,77.11,76.79,73.16,69.97,56.64,56.46,55.02,54.77,51.29,49.93,49.23,42.71,39.83,39.40,37.95,37.12,36.51,35.80,34.87,34.25,33.08,31.18,30.98,30.53,28.60,27.22,27.11,25.71,25.23,19.49,18.65,17.13,16.50,16.35,16.11,15.69.HR-MS(ESI):calcd for C37H67N2O4S,[M+H]+619.48669；found:619.48633.
化合物C9：白色粉末，总收率为84.8％，m.p.216.0～219.0℃。1H NMR(400MHz,CDCl3)δ7.32–7.27(m,2H),7.24–7.18(m,4H),6.25(s,1H),3.63–3.58(m,2H),3.57–3.48(m,1H),3.24(dd,J＝13.8,4.1Hz,1H),2.69(dd,J＝13.8,9.1Hz,1H),1.24(s,3H),1.20(s,3H),1.16(s,3H),0.95(s,3H),0.87(s,3H),0.85(s,3H),0.82(s,3H),0.72(s,3H).13C NMR(100MHz,CDCl3)δ173.60,138.04,129.40,128.76,126.84,77.43,77.32,77.12,76.80,76.73,69.98,56.63,56.52,56.30,54.77,49.94,49.23,41.10,39.83,39.41,37.13,37.11,36.52,35.81,34.87,33.10,31.18,30.53,28.57,27.23,25.66,25.24,19.50,18.65,16.45,16.35,16.11.HR-MS(ESI):calcd for C39H63N2O3,[M+H]+607.48332；found:607.48267.
化合物C10：白色粉末，总收率为84.8％，m.p.130.5～133.2℃。1H NMR(400MHz,CDCl3)δ7.64(d,J＝7.9Hz,1H),7.35(d,J＝8.1Hz,1H),7.24(d,J＝10.1Hz,1H),7.18–7.12(m,1H),7.09–7.01(m,2H),6.33(s,1H),3.75–3.69(m,2H),3.59(d,J＝2.5Hz,2H),3.53–3.51(td,1H),3.51(s,1H),3.34(dd,J＝14.4,4.0Hz,1H),2.91(dd,J＝14.5,8.7Hz,1H),1.23(s,6H),1.20(d,J＝2.4Hz,3H),1.16(s,3H),0.94(s,3H),0.86(s,3H),0.80(d,J＝2.8Hz,6H),0.68(s,3H).13C NMR(100MHz,CDCl3)δ172.69,154.46,151.33,136.46,127.55,123.38,122.42,120.59,119.83,118.82,111.44,111.08,77.45,77.34,77.13,76.81,76.74,69.90,55.36,54.73,53.31,49.36,48.63,39.86,39.04,38.39,36.87,36.53,35.83,34.20,34.05,33.12,31.27,31.08,30.61,30.33,27.22,25.70,25.24,25.03,22.45,19.69,19.53,17.08,16.38,16.20,15.30.HR-MS(ESI):calcd for C41H64N3O3,[M+H]+646.49422；found:646.49329.
化合物C11：白色粉末，总收率为84.8％，m.p.265.0～267.9℃。1H NMR(400MHz,CDCl3)δ7.28(d,J＝10.1Hz,1H),6.99(d,J＝8.4Hz,2H),6.80(d,J＝8.5Hz,2H),6.56(s,1H),3.55(ddd,J＝21.5,11.7,7.0Hz,4H),3.04(td,J＝13.9,4.2Hz,1H),2.68(dd,J＝13.8,8.5Hz,1H),1.22(s,3H),1.18(s,3H),1.15(s,3H),0.93(s,3H),0.85(s,3H),0.79(d,J＝3.9Hz,6H),0.70(s,3H).13C NMR(100MHz,CDCl3)δ174.78,156.02,130.49,128.31,115.72,77.86,77.74,77.54,77.22,77.04,73.51,70.66,70.48,56.79,56.76,56.52,54.83,51.44,50.00,49.42,49.19,49.08,48.98,48.78,48.56,40.47,39.91,39.54,38.05,37.17,36.56,35.89,34.90,33.03,31.30,30.21,28.56,27.27,25.48,25.33,19.51,18.71,17.12,16.35,16.12,15.70.HR-MS(ESI):calcd for C39H63N2O4,[M+H]+623.47555；found:623.47601.
20(R)-人参二醇及其新衍生物的抗肿瘤活性筛选
采用MTT法评价20(R)-人参二醇衍生物对三种肿瘤细胞系Ls180、Lncap和Mkn45的体外抗肿瘤活性。取收集对数生长期的细胞，将细胞以8000/孔培养于96孔培养板，培养12h后，按化合物终浓度为10、5、2.5、1、0.5、0.1、0.05和0.01μg/mL处理细胞，过夜。每孔加入20μL MTT液，继续培养4h。去除培养液，添加150μL DMSO，振荡10min。用酶标仪测定OD值，检测波长为570nm。实验结果见表4。
表4 20(R)-人参二醇新衍生物的体外抗肿瘤活性(IC50,μM)
Figure GDA0003776225900000151
Figure GDA0003776225900000161
体外抗肿瘤活性试验结果表明，三个系列新衍生物中，A系列化合物对三种肿瘤细胞的活性与20(R)-人参二醇相比较，没有显著的提高，B系列化合物中仅有化合物B2的活性得到提高，化合物5以及C系列衍生物对三种肿瘤细胞显示出较强的有效活性。
与20(R)-人参二醇本身不具有抗肿瘤活性的特点相比，本发明制备的大部分新化合物改变了20(R)-人参二醇本身仅具有与抗肿瘤药物合用的增效效果，显示出20(R)-人参二醇本身不具有的抗肿瘤活性，其中，化合物C7、C9和C10对三种肿瘤细胞Ls180、Lncap、Mkn45的IC50值均小于5μM，具有显著的抗肿瘤有效活性。本发明化合物分子结构特征的改变决定了新化合物的抗肿瘤活性的获得，本发明将20(R)-人参二醇的3位羟基修饰为氨基，使得本发明修饰后的氮杂20(R)-人参二醇衍生物能够与肿瘤细胞DNA形成分子间氢键，进一步的，3位氨基再与氨基酸缩合形成酰胺键，进一步引入氨基和羧基，进而使得20(R)-人参二醇3位氨基酸衍生物与肿瘤细胞DNA形成分子间氢键，均抑制了肿瘤细胞DNA的复制，即本发明的氮杂20(R)-人参二醇衍生物通过与肿瘤细胞DNA形成分子间氢键破坏/杀死肿瘤细胞。
C系列化合物盐酸盐的制备
将C系列化合物溶解于无水乙醇中，控制温度在10℃以下，加入含氯化氢的无水乙醇溶液，搅拌后生成盐酸盐，其中，所述的C系列化合物与所述的氯化氢的摩尔比为1:1.01～1.02，减压浓缩，将生成的盐酸盐干燥，即得到C系列化合物盐酸盐，收率87.5％-95.3％。
选取C系列化合物盐酸盐测试水溶解度
取研成细粉的待测物质，加入到盛有蒸馏水的具塞瓶中，在室温下混合24h，取上清液稀释，然后采用高效液相色谱法以外标法计算溶液浓度。试验显示C系列化合物盐酸盐在水中的溶解度为0.005-0.033g/ml，说明本发明制备的氮杂20(R)-人参二醇衍生物具有成药性，尤其是化合物C7、C9、C10盐酸盐的水溶解度分别达到了0.022g/ml、0.019g/ml和0.032g/ml，能够有效在人体内溶解，已经符合制备抗肿瘤药物的潜力，而20(R)-人参二醇本身几乎不溶于水(小于1/10000，单位g/ml)很难有效使用。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (2)

1.氮杂20(R)-人参二醇衍生物，其特征是所述化合物的结构如通式(Ⅲ)所示：
Figure FDA0003776225890000011
其中：
R3选自
Figure FDA0003776225890000012
Figure FDA0003776225890000013
的任意一种。
2.权利要求1所述的氮杂20(R)-人参二醇衍生物制备抗肿瘤药物的用途。
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