CN103613602B - 藤黄酸衍生物及其制备方法和应用 - Google Patents

藤黄酸衍生物及其制备方法和应用 Download PDF

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CN103613602B
CN103613602B CN201310682918.4A CN201310682918A CN103613602B CN 103613602 B CN103613602 B CN 103613602B CN 201310682918 A CN201310682918 A CN 201310682918A CN 103613602 B CN103613602 B CN 103613602B
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陈莉
冯俊俊
马国贞
张春霞
李鹏飞
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Nankai University
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Abstract

本发明涉及一种藤黄酸衍生物及其制备方法和应用。该结构的衍生物以对藤黄酸C-12、C-29位和C-30位进行改造为主,首次得到多个C-30位羧基还原及胺化的化合物。这些化合物经生物试验证明具有抗肿瘤活性,可用于制备抗肿瘤药物,并可以将该类衍生物作为先导化合物,为寻找新的抗肿瘤药物开辟途径。式中,R1为氢、烷基或者苄基;R2为无取代、氢或者烷基,此时C-12与氧可形成单键或者双键;R3、R4分别为甲基、酯基、亚甲基醇、醛基、取代氨基。

Description

藤黄酸衍生物及其制备方法和应用
技术领域
本发明涉及一种新型抗肿瘤活性的藤黄酸衍生物及其制备方法和应用。
背景技术
藤黄酸(gambogicacid,GA)是一种从中药藤黄中分离得到的具有较强抗肿瘤活性的天然产物。对藤黄酸的抗肿瘤作用的研究表明,它能选择性地杀死癌细胞,而对正常的造血系统和白细胞没有影响,这将提供寻找新颖抗癌药的途径。藤黄酸作为一种高效低毒的抗肿瘤药物,通过不同机制发挥抗肿瘤作用,包括诱导细胞周期阻滞和细胞凋亡,抑制端粒酶和拓扑异构酶活性,抗肿瘤血管生成和肿瘤转移,逆转多药耐药等。但藤黄酸水溶性差,生物利用度低,为寻找生物活性更优的化合物,科学家们对藤黄酸的相关结构部位的化学修饰表现了浓厚的兴趣,Cai(US2003078292、WO0044216)和郭青龙(CN1927861、CN102503951)等进行了深入研究,研究结果表明C-30的结构改造不会引起化合物生物活性的下降,但可以改善水溶性和生物利用度,而其改造仅限于羧基的酯化、酰化反应。本发明在充分认识藤黄酸化学反应活性的基础上,避免多位点化学反应的同时发生,绕开前述思路,设计合成了多个C-12、C-30位还原及胺化的衍生物,并对其进行抗肿瘤生物活性研究,希望得到结构更优化、疗效更好的抗肿瘤化合物。
发明内容
本发明的目的在于设计、提供新颖的具有抗肿瘤活性的藤黄酸衍生物。
本发明的另一目的是提供上述衍生物的制备方法。
本发明还有一个目的是提供上述藤黄酸衍生物在制备抗肿瘤药物中的应用。
本发明提供的光学纯的藤黄酸衍生物的结构通式如(1)所示:
式中,R1为氢、烷基或者苄基;R2为无取代、氢或者烷基,此时C-12与氧可形成单键或者双键;R3、R4分别为甲基、酯基、亚甲基醇、醛基、取代氨基。
可选地,R1为氢、甲基或者苄基;R2为无取代、氢或者甲基,此时C-12与氧可形成单键或者双键;R3、R4分别为甲基、甲酯基、亚甲基醇、甲醛基、或者为C1-C6烷基取代、五元、六元环烷基取代、杂环烷基取代、芳基取代的氨基。
本发明提供的藤黄酸衍生物通过酯化、还原、氧化、醚化和还原氨化等反应制备得到。制备方法包括如下的步骤:
合成步骤一:在-30℃~30℃条件下,在有机溶剂中,氮气保护下,在催化剂的作用下,藤黄酸与甲醇缩合得到相应的酯化合物。有机溶剂优选二氯甲烷,催化剂优选1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)和4-二甲氨基吡啶(DMAP)。
合成步骤二:在-78℃~-40℃条件下,在有机溶剂中藤黄酸酯与还原剂反应得到相应的还原产物。有机溶剂优选为二氯甲烷,还原剂优选为二异丁基氢化铝(Dibal-H)。
合成步骤三:在-30℃~30℃的温度范围内,在有机溶剂中,藤黄酸的醇衍生物在氧化剂的作用下,得到相应的醛的化合物。有机溶剂优选为二氯甲烷;氧化剂优选为四甲基哌啶氧化物(TEMPO)和二乙酸碘苯(BAIB)。
合成步骤四:在0℃~60℃条件下,各种藤黄酸的醛类衍生物在有机溶剂中,在碱的作用下,与卤代烃反应,得到相应的醚类化合物。有机溶剂优选为二甲基甲酰胺(DMF);所述的碱可以是有机碱和无机碱,优选为碳酸钾、氢氧化钠、氢化钠;所述卤代烃优选为碘甲烷(CH3I)、苄溴。
合成步骤五:在0℃~60℃条件下,藤黄酸的醛类衍生物在碘的催化作用下,与原甲酸酯反应,在无溶剂条件下,得到相应的缩醛化合物。原甲酸酯优选为原甲酸三甲酯。
合成步骤六:在-30℃~30℃的温度范围内,在有机溶剂中,藤黄酸的醛类衍生物与各种有机的一级胺和二级胺反应,然后加入还原剂得到还原氨化的产物。所述的有机溶剂优选为二氯甲烷;所述的胺优选为甲胺、二甲胺、吗啉、N-甲基哌嗪及其它二级胺;所述还原剂优选为醋酸硼氢化钠。
对通式(1)所示的化合物的体外抑制肿瘤细胞的实验表明,其对人白血病、肝癌和肺癌肿瘤细胞株的抑制效果与天然藤黄酸相当。因为常规抗肿瘤化合物的筛选是以化合物的细胞毒活性来体现的,所以本发明化合物具有抗肿瘤活性,可以与药用载体混合,制备抗肿瘤药物。
具体实施方式
以下再通过实施例形式的具体实施方式对本发明的上述内容作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实施例,凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1藤黄酸甲酯和异藤黄酸甲酯的制备
在室温条件下,氮气保护,将3g藤黄酸GA(4.78mmol)溶于二氯甲烷(50mL)中,分别加入EDCI(1.83g,9.55mmol,2eq),DMAP(1.17g,9.55mmol,2eq),最后加入甲醇1.93mL(47.8mmol,10eq),室温反应2h。加水淬灭反应,二氯甲烷萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化得到黄色固体(甲酯化产物1和异构化甲酯产物2)。
化合物1:橘黄色固体,熔点,98℃;1HNMR(400MHz,CDCl3)δ12.85(s,1H),7.54(d,J=6.9Hz,1H),6.68(d,J=10.1Hz,1H),5.93(td,J=7.4,1.3Hz,1H),5.44(d,J=10.2Hz,1H),5.10-5.00(m,2H),3.48(dd,J=6.8,4.6Hz,1H),3.43(s,3H),3.31(dd,J=14.6,8.0Hz,1H),3.15(dd,J=14.6,5.3Hz,1H),3.07-2.92(m,2H),2.52(d,J=9.3Hz,1H),2.31(dd,J=13.4,4.7Hz,1H),2.03(dd,J=16.2,7.3Hz,2H),1.83-1.76(m,1H),1.74(s,3H),1.69(s,3H),1.67(d,J=1.2Hz,3H),1.65(s,3H),1.65(s,3H),1.62-1.58(m,1H),1.55(s,3H),1.44(s,3H),1.38(dd,J=13.4,9.6Hz,1H),1.29(s,3H)ppm;uCNMR(101MHz,CDCl3)δ203.5,179.0,167.3,161.3,157.5,136.1,135.1,133.5,131.8,131.5,127.8,124.5,123.8,122.2,115.9,107.5,102.4,100.4,90.9,83.9,83.7,81.3,51.1,49.0,46.8,42.0,29.9,29.1,28.8,28.0,25.8,25.7,25.1,22.7,21.6,20.8,18.1,17.6ppm.IR(KBr)v3291,2969,1736,1711,1631,1593,1437,1135,823cm-1HRMS(EI)m/zcalcdforC39H46O8Na665.3091,foundfor[M+Na]+665.3089.
化合物2:橘黄色无定形固体;1HNMR(400MHz,CDCl3)δ12.78(s,1H),7.51(d,J=6.9Hz,1H),6.67(d,J=10.1Hz,1H),6.37(t,J=7.6,1H),5.45(d,J=10.1Hz,1H),5.13(t,J=6.8Hz,1H),5.06(t,J=7.1Hz,1H),3.65(s,3H),3.50(dd,J=6.8,4.5Hz,1H),3.25(d,J=6.9Hz,2H),2.62(d,J=7.7Hz,2H),2.52(d,J=9.4Hz,1H),2.34(dd,J=13.5,4.7Hz,1H),2.10-1.97(m,2H),1.82-1.75(m,1H),1.74(s,3H),1.71(s,3H),1.65(s,6H),1.64-1.58(m,1H),1.55(s,3H),1.42(s,3H),1.39-1.32(m,1H),1.37(s,3H),1.29(s,3H)ppm;CNMR(101MHz,CDCl3)δ203.0,179.0,167.7,161.3,157.6,157.4,135.2,134.3,133.4,131.9,131.8,129.5,124.8,123.8,122.2,115.9,107.9,102.8,100.4,90.7,83.8,83.7,81.3,51.7,49.1,46.9,41.9,30.0,29.0,28.9,27.5,25.7,25.6,25.4,22.7,21.6,18.1,17.6,11.8ppm.HRMS(EI)m/zcalcdforC39H46O8Na665.3091,foundfor[M+Na]665.3084.
实施例2还原化合物3和还原二醇化合物5的制备
氮气保护,将1.313g化合物1(2.05mmol,leq)溶于二氯甲烷中,在-78℃条件下,向该溶液中滴加5.1mL(6.14mmol,3eq)Dibal-H,3小时后补加1.7mL(1eq)Dibal-H,继续反应1小时。饱和的酒石酸钾钠溶液淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化得化合物3和5。
化合物3:橘黄色无定形固体;1HNMR(400MHz,CDCl3)δ13.02(s,1H),7.65(d,J=7.2Hz,1H),6.68(d,J=10.1Hz,1H),5.96(t,J=6.8Hz,1H),5.43(d,J=10.1Hz,1H),5.12-5.00(m,2H),3.54(s,3H),3.33(dd,J=14.8,7.8Hz,1H),3.29-3.26(m,1H),3.23(dd,J=15.4,4.4Hz,1H),3.04(d,J=5.6Hz,1H),2.93-2.88(m,1H),2.84(dd,J=16.4,6.4Hz,1H),2.61(dd,J=15.7,7.8Hz,1H),2.33(dd,J=14.2,4.1Hz,1H),2.17(d,J=10.0Hz,1H),2.04(dd,J=15.9,7.8Hz,2H),1.84-1.76(m,7H),1.74(s,3H),1.65(s,3H),1.63(s,3H),1.62-1.58(m,1H),1.55(s,3H),1.54(s,3H),1.43(s,3H),1.40-1.36(m,1H)ppm;13CNMR(101MHz,CDCl3)δ180.0,167.8,161.0,158.2,157.6,142.4,136.0,131.8,131.3,131.0,129.1,124.4,123.8,122.6,116.0,107.4,102.4,100.2,92.7,84.5,84.1,81.1,71.1,51.1,49.0,42.0,36.9,34.3,30.2,28.4,27.8,25.7,24.8,22.7,21.9,20.9,18.1,17.6.HRMS(EI)m/zcalcdforC39H48O8Na667.3247,foundfor[M+Na]+667.3236.
化合物5:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ12.99(s,1H),7.66(d,J=7.2Hz,1H),6.68(d,J=10.1Hz,1H),5.44(d,J=10.1Hz,1H),5.20(t,J=7.9Hz,1H),5.12-5.02(m,2H),4.15(d,J=11.9Hz,1H),3.72(d,J=11.5Hz,1H),3.42-3.27(m,3H),2.97-2.89(m,1H),2.77(d,J=4.1Hz,1H),2.62(dd,J=14.0,9.0Hz,1H),2.43-2.30(m,2H),2.20(d,J=10.0Hz,1H),2.10-1.99(m,2H),1.90-1.70(m,11H),1.65(s,3H),1.64(s,3H),1.63-1.58(m,1H),1.56(s,3H),1.52(s,3H),1.43(s,3H),1.30(dd,J=14.0,10.4Hz,1H)ppm;13CNMR(101MHz,CDCl3)δ180.0,161.3,158.3,157.6,142.4,140.2,131.9,131.8,131.0,124.6,123.8,122.3,120.2,115.9,107.5,102.5,100.3,92.4,84.5,84.3,81.2,70.8,61.2,49.1,42.1,36.7,32.2,30.2,28.4,27.8,25.7,25.7,24.9,22.7,22.5,21.9,18.2,17.6ppm.IR(KBr)v3305,2964,2925,1645,1595,1456,1434,913,744cm-1.HRMS(EI)m/zcalcdforC38H48O7Na639.3298,foundfor[M+Na]+639.3296.
实施例3过还原化合物4a和4b的制备
同实施例2,不同在于Dibal-H的加入量为6eq,得到化合物4a、4b和5.
化合物4a:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ12.14(s,1H),6.63(d,J=10.1Hz,1H),5.42(d,J=10.1Hz,1H),5.31-5.22(m,1H),5.17(t,J=6.6Hz,1H),5.06(t,J=7.0Hz,1H),4.08(d,J=11.7Hz,1H),3.64-3.60(m,2H),3.34(dd,J=11.7,7.2Hz,1H),3.28(d,J=6.7Hz,2H),2.64(br,2H)2.43(d,J=9.6Hz,1H),2.36(dd,J=13.6,10.0Hz,1H),2.29(d,J=14.4Hz,1H),2.13(dd,J=13.5,7.0Hz,1H),2.05(dd,J=15.7,7.8Hz,2H),1.97(dd,J=12.5,4.5Hz,1H),1.90(d,J=10.2Hz,1H),1.84-1.73(m,12H),1.69(s,3H),1.65(s,3H),1.63-1.58(m,1H),1.56(s,3H),1.46(s,3H),1.42(s,3H)ppm;13CNMR(101MHz,CDCl3)δ196.2,160.5,158.2,155.6,140.4,131.9,131.8,124.7,123.8,121.8,120.2,115.9,107.4,102.2,101.8,90.0,86.5,82.5,81.0,76.5,61.1,51.3,41.9,40.1,34.1,30.3,29.8,27.4,27.0,26.3,25.9,25.7,25.6,22.8,22.7,21.8,18.2,17.6ppm.HRMS(EI)m/zcalcdforC38H50O7Na641.3455,foundfor[M+Na]641.3449
化合物4b:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ12.02(s,1H),6.66(d,J=10.1Hz,1H),5.54(t,J=7.8Hz,1H),5.44(d,J=10.1Hz,1H),5.14(t,J=7.3Hz,1H),5.09(t,J=6.7Hz,1H),4.31(d,J=11.7Hz,1H),3.90(d,J=11.7Hz,1H),3.76(s,1H),3.34-3.21(m,2H),3.05-2.92(m,2H),2.76(br,2H),2.54(d,J=13.6Hz,1H),2.39-2.27(m,2H),2.16-2.02(m,3H),1.88(s,3H),1.77(s,5H),1.70-1.54(m,11H),1.49(dd,J=14.6,9.9Hz,1H),1.39(s,3H),1.38(s,3H),1.36(s,3H)ppm;13CNMR(101MHz,CDCl3)δ196.3,160.6,155.9,155.7,140.5,131.8,131.2,124.9,123.8,122.6,120.7,116.0,108.3,102.5,102.2,89.4,85.5,83.0,80.8,75.8,61.3,43.6,41.8,39.9,31.6,29.7,29.5,27.1,26.4,25.7,25.7,25.3,24.4,22.8,22.7,21.7,18.1,17.6ppm.HRMS(EI)m/zcalcdforC38H50O7Na641.3455,foundfor[M+Na]+641.3442
实施例4异构化二醇化合物6的制备
同实施例2,不同在于以化合物2代替化合物1作为反应物,得到化合物6.
化合物6:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ12.99(s,1H),7.62(d,J=7.2Hz,1H),6.68(d,J=10.1Hz,1H),5.44(d,J=10.1Hz,1H),5.24(t,J=6.8Hz,1H),5.11(t,J=6.7Hz,1H),5.06(t,J=7.1Hz,1H),3.83(m,2H),3.32(d,J=7.7Hz,3H),2.95-2.86(m,1H),2.42(dd,J=14.6,5.8Hz,1H),2.34(dd,J=14.1,4.1Hz,1H),2.21-2.12(m,2H),2.05(dd,J=15.6,7.8Hz,2H),1.82-1.77(m,4H),1.75(s,3H),1.65(s,6H),1.63-1.57(m,1H),1.56(s,3H),1.53(s,3H),1.42(s,3H),1.40(s,3H),1.30-1.23(m,1H)ppm.13CNMR(101MHz,CDCl3)δ180.3,161.1,158.4,157.5,142.0,138.3,131.9,131.5,131.3,124.6,123.8,122.5,118.3,116.0,107.6,102.4,100.3,92.6,84.9,83.9,81.1,70.4,68.4,49.1,42.0,36.9,32.2,30.3,28.5,27.6,25.7,25.7,25.0,22.7,21.9,18.2,17.6,13.7ppm;IR(KBr)v3274,2925,1645,1592,1460,1276,1261,1136,750cm-1.HRMS(EI)m/zcalcdforC38H48O7Na639.3298,foundfor[M+Na]+639.3296
实施例5氧化物醛7的制备
室温条件下,向0.159g(0.26mmol,leq)的二醇化合物5中依次加入0.004gTEMPO(0.1eq),0.091g二乙酸碘苯(1.1eq),置换氮气,加入15mL二氯甲烷。室温搅拌5h后,用饱和的硫代硫酸钠溶液淬灭反应,二氯甲烷萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化得到氧化产物7.
化合物7:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ12.96(s,1H),9.89(s,1H),7.68(d,J=7.2Hz,1H),6.67(d,J=10.1Hz,1H),6.41(t,J=7.8Hz,1H),5.44(d,J=10.1Hz,1H),5.10-5.02(m,2H),3.41-3.28(m,2H),3.24(dd,J=14.7,5.1Hz,1H),3.02(d,J=5.8Hz,1H),3.01-2.92(m,2H),2.48(dd,J=14.6,8.4Hz,1H),2.35(dd,J=14.2,4.0Hz,1H),2.21(d,J=10.0Hz,1H),2.05(dd,J=15.6,7.8Hz,2H),1.83-1.77(m,4H),1.76(s,3H),1.69(s,3H),1.65(s,6H),1.62-1.57(m,1H),1.56(s,3H),1.53(s,3H),1.44(s,3H),1.31(dd,J=14.0,10.5Hz,1H)ppm.13CNMR(101MHz,CDCl3)δ190.4,179.7,161.3,157.9,157.6,142.5,140.8,138.5,131.9,131.8,130.8,124.7,123.8,122.3,115.8,107.4,102.7,100.1,92.5,84.4,84.1,81.3,70.8,49.1,42.0,36.9,31.2,30.1,28.5,27.7,25.7,25.7,24.9,22.7,21.9,18.2,17.6,16.7ppm.HRMS(EI)m/zcalcdforC38H46O7Na637.3142,foundfor[M+Na]+637.3136.
实施例6异构化醛8的制备
同实施例5,用化合物6代替化合物5作原料,得到异构化醛化合物8.
化合物8:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ12.99(s,1H),9.34(s,1H),7.69(d,J=7.1Hz,1H),6.67(d,J=10.1Hz,1H),6.50(t,J=7.1Hz,1H),5.45(d,J=10.1Hz,1H),5.10-5.01(m,2H),3.32(dd,J=14.4,7.6Hz,1H),3.24(dd,J=14.1,5.2Hz,2H),3.05(d,J=5.8Hz,1H),2.98-2.91(m,1H),2.76(dd,J=15.4,7.3Hz,1H),2.35(dd,J=14.3,3.8Hz,1H),2.26(dd,J=15.6,7.2Hz,1H).,2.21(d,J=10.1Hz,1H),2.04(dd,J=15.4,7.4Hz,2H),1.81(s,3H),1.79-1.75(m,1H),1.74(s,3H),1.65(s,3H),1.66-1.62(m,1H),1.62(s,3H),1.55(s,9H),1.42(s,3H),1.35-1.25(m,1H)ppm.13CNMR(101MHz,CDCl3)δ194.8,179.7,161.3,157.9,157.7,147.2,142.7,141.2,131.9,131.8,130.8,124.8,123.8,122.3,115.9,107.5,102.7,100.2,92.6,84.5,84.2,81.3,71.5,49.0,42.0,37.0,34.0,30.2,28.6,27.7,25.7,25.7,24.9,22.7,21.9,18.2,17.7,9.3ppm.HRMS(EI)m/zcalcdforC38H46O7Na637.3142,foundfor[M+Na]+637.3141
实施例7单甲醚化合物9和双甲醚化合物10的制备
在室温条件下,氮气保护,将847mg醛7(1.38mmol)溶于DMF(25mL)中,分别加入CH3I(12.5mL,201.3mmol,146eq),K2CO3(6.3g,45.5mmol,33eq)室温反应过夜,原料基本反应完。水淬灭反应,无水乙醚萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化得到化合物9和10.
化合物9:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ9.86(s,1H),7.56(d,J=7.1Hz,1H),6.66(d,J=10.2Hz,1H),6.44(t,J=8.1Hz,1H),5.55(d,J=10.2Hz,1H),5.14-5.01(m,2H),3.83(s,3H),3.44(dd,J=14.5,7.9Hz,1H),3.36-3.25(d,J=5.3Hz,2H),3.00(dd,J=13.9,7.0Hz,2H),2.90(s,1H),2.44(dd,J=14.7,8.1Hz,1H),2.32(dd,J=14.1,3.7Hz,1H),2.22(d,J=10.1Hz,1H),2.04(t,J=4.1Hz,2H),1.80(s,3H),1.77(s,3H),1.76-1.72(m,1H),1.69(s,3H),1.65(s,6H),1.63-1.58(m,1H),1.55(s,3H),1.53(s,3H),1.45(s,3H),1.38-1.30(m,1H)PPm.13CNMR(101MHz,CDCl3)δ190.2,175.3,159.8,158.7,155.2,141.2,140.8,138.1,133.2,132.0,131.6,127.4,123.7,121.8,116.5,112.4,110.0,107.3,92.4,84.1,84.1,80.5,70.9,62.1,48.9,41.9,36.7,31.2,30.0,28.4,27.5,25.6,25.6,25.0,22.6,22.3,18.1,17.5,16.6ppm;HRMS(EI)m/zcalcdforC39H48O7Na651.3298,foundfor[M+Na]+651.3296.
化合物10:橘黄色无定形固体;1HNMR(400MHz,CDCl3)δ9.75(s,1H),7.49(d,J=7.2Hz,1H),6.65(d,J=10.1Hz,1H),6.36(t,J=8.0Hz,1H),5.55(d,J=10.2Hz,1H),5.11(t,J=6.8Hz,1H),5.06(t,J=7.0Hz,1H),4.36(s,1H),3.81(s,3H),3.80(s,3H),3.40(dd,J=14.4,7.9Hz,1H),3.30(dd,J=14.1,4.8Hz,1H),3.03(dd,J=15.0,7.7Hz,1H),2.95(dd,J=15.2,8.5Hz,2H),2.43(dd,J=14.0,4.0Hz,1H),2.22(d,J=10.0Hz,1H),2.04(dd,J=15.4,7.9Hz,2H),1.83-1.80(m,1H),1.76(s,3H),1.75(s,3H),1.65(s,6H),1.63-1.59(m,1H),1.57(s,3H),1.55(s,6H),1.45(s,3H),1.41-1.37(m,1H)ppm.13CNMR(101MHz,CDCl3)δ190.3,175.0,159.8,159.0,155.2,155.2,141.7,137.9,137.3,134.4,132.0,131.8,127.5,123.8,121.9,116.5,112.6,110.1,107.2,92.3,83.7,83.5,80.7,75.7,62.1,55.1,48.7,41.9,34.2,31.4,30.4,27.9,27.6,25.9,25.6,25.6,22.7,22.2,18.2,17.6,16.6ppm.
实施例8二甲缩醛化合物11的制备
分别称取原料300mg醛7(0.488mm0l),单质I2(12.36mg,0.049mmol,0.1eq)和原甲酸三甲酯CH(OCH3)3(0.11mL,0.977mmol,2eq),三者在室温搅拌过夜,饱和的Na2S2O3淬灭反应,无水乙醚萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化得到化合物11.
化合物11:橘黄色无定形固体;1HNMR(400MHz,CDCl3)δ13.05(s,1H),7.62(d,J=7.2Hz,1H),6.68(d,J=10.1Hz,1H),5.44(d,J=10.1Hz,1H),5.38(t,J=7.3Hz,1H),5.12-5.03(m,2H),4.30(s,1H),3.32(d,J=6.5Hz,2H),3.28-3.24(m,1H),3.20(s,3H),3.17(s,3H),3.05(d,J=5.4Hz,1H),2.92-2.88(m,1H),2.50(dd,J=14.6,6.7Hz,1H),2.34(dd,J=14.1,4.1Hz,1H),2.16(d,J=10.0Hz,1H),2.10(dd,J=14.4,8.0Hz,1H),2.05(dd,J=15.8,7.9Hz,2H),1.83-1.80(m,1H),1.79(s,3H),1.75(s,3H),1.65(s,3H),1.64(s,3H),1.63-1.59(m,1H),1.56(s,3H),1.52(s,3H),1.43(s,3H),1.42(s,3H),1.31-1.24(m,1H)PPm;13CNMR(101MHz,CDCl3)δ180.2,161.1,158.3,157.6,142.0,135.4,131.9,131.5,131.2,124.6,123.8,122.6,122.2,116.0,107.5,107.2,102.5,100.3,92.5,84.7,83.7,81.1,70.3,53.6,53.2,49.2,42.0,37.0,32.1,30.3,28.6,27.6,25.7,25.7,25.1,22.7,21.9,18.2,17.6,11.3PPm;HRMS(EI)m/zcalcdforC40H52O8Na683.3560,foundfor[M+Na]683.3556.
实施例9异构化单甲醚化合物12的制备
在室温条件下,氮气保护,将65mg缩醛11(0.098mmol)溶于DMF(8mL)中,分别加入CH3I(0.89mL,14.37mmol,146eq),K2CO3(448.9mg,3.25mmol,33eq)室温反应过夜,原料基本反应完。水淬灭反应,无水乙醚萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化异构化单甲醚化合物12.
化合物12:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ9.32(s,1H),7.57(d,J=7.0Hz,1H),6.66(d,J=10.2Hz,1H),6.48(t,J=7.0Hz,1H),5.56(d,J=10.1Hz,1H),5.09(t,J=6.7Hz,1H),5.06(t,J=6.7Hz,1H),3.83(s,3H),3.42(dd,J=14.3,7.7Hz,1H),3.32(dd,J=14.3,4.4Hz,1H),3.23(d,J=5.1Hz,1H),3.05(d,J=5.8Hz,1H),2.93-2.86(m,1H),2.74(dd,J=15.4,7.2Hz,1H),2.38-2.27(m,2H),2.24(dd,J=16.4,9.0Hz,1H),2.04(dd,J=15.4,7.5Hz,2H),1.81(s,3H),1.80-1.74(m,4H),1.69-1.59(m,7H),1.55(s,6H),1.53(s,3H),1.43(s,3H),1.37-1.30(m,1H);13CNMR(101MHz,CDCl3)δ194.8,175.5,159.9,158.9,155.3,147.3,141.1,140.9,133.3,132.1,131.9,127.6,123.7,121.9,116.6,112.7,110.1,107.5,92.6,84.4,84.3,80.6,71.6,62.3,48.9,41.9,36.8,34.1,30.1,28.6,27.5,25.7,25.6,25.2,22.7,22.4,18.2,17.6,9.2ppm,HRMS(EI)m/zcalcdforC39H48O7Na651.3298,foundfor[M+Na]+651.3295。
实施例10二甲胺13和异构化二甲胺iso-13的制备
室温条件下,氮气保护,搅拌下向化合物7(0.161g,0.262mmol,1eq)的2mL二氯甲烷溶液中,加入二甲胺的(1.05mmol,4eq)的二氯甲烷15mL的低温溶液(0℃),继续搅拌0.5h,加入NaBH(OAc)30.078g(0.37mmol,1.4eq),反应过夜后,用饱和的碳酸氢钠溶液淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化得到二甲胺13和异构化二甲胺iso-13。
化合物13:橘黄色粘稠液体,1HNMR(400MHz,CDCl3)δ13.04(s,1H),7.63(d,J=7.2Hz,1H),6.68(d,J=10.1Hz,1H),5.44(d,J=10.1Hz,1H),5.17(t,J=6.6Hz,1H),5.10(t,J=6.4Hz,1H),5.07(t,J=7.2Hz,1H),3.33(d,J=6.4Hz,2H),3.29(s,1H),2.94-2.89(m,1H),2.66(d,J=12.3Hz,1H),2.53(d,J=12.4Hz,1H),2.47(dd,J=14.4,6.5Hz,1H),2.34(dd,J=14.0,4.0Hz,1H),2.19-2.14(m,2H),2.10-2.02(m,8H),1.83-1.77(m,4H),1.76(s,3H),1.65(s,6H),1.63(s,3H),1.62-1.59(m,1H),1.56(s,3H),1.52(s,3H),1.42(s,3H),1.34-1.28(m,1H)ppm;13CNMR(101MHz,CDCl3)δ180.1,161.0,158.4,157.6,142.0,136.2,131.9,131.4,131.2,124.5,123.8,122.6,121.8,116.0,107.4,102.4,100.3,100.0,92.6,84.7,83.7,81.1,70.5,59.7,49.2,45.2,42.0,36.9,32.2,30.28,28.5,27.7,25.8,25.6,25.0,23.0,22.7,22.0,18.2,17.6ppm;HRMS(EI)m/zcalcdforC40H54NO6644.3951,foundfor[M+H]644.3949.
化合物iso-13:橘黄色粘稠液体;1HNMR(400MHz,CDCl3)δ13.04(s,1H),7.61(d,J=7.1Hz,1H),6.67(d,J=10.1Hz,1H),5.43(d,J=10.1Hz,1H),5.15-5.03(m,3H),3.32(d,J=6.1Hz,2H),3.25(s,1H),3.01(br,1H),2.90-2.86(m,1H),2.62(q,J=12.2Hz,2H),2.46(dd,J=14.4,6.4Hz,1H),2.33(dd,J=14.0,3.7Hz,1H),2.21-1.99(m,10H),1.83-1.70(m,7H),1.69-1.59(m,7H),1.55(s,3H),1.51(s,3H),1.47(s,3H),1.42(s,3H),1.35-1.25(m,1H)ppm.13CNMR(101MHz,CDCl3)δ179.1,160.0,157.4,156.6,140.9,135.8,130.8,130.4,130.2,123.5,122.8,121.6,119.6,115.0,106.5,101.4,99.3,91.5,83.9,82.6,80.0,69.3,67.9,48.2,44.1,41.0,35.9,31.4,29.3,28.7,27.5,26.6,24.7,24.6,24.1,21.7,20.9,17.2,16.6,14.0ppm;HRMS(EI)m/zcalcdforC40H54NO6644.3952,foundfor[M+H]644.3951.
实施例11吗啉化合物14和异构化吗啉化合物iso-14的制备
室温条件下,氮气保护,将化合物7(0.089g,0.145mmol,leq)溶于8mL二氯甲烷中,随后加入0.013mL(0.145mmol,1eq)吗啉,反应0.5h后,再加入0.043g(0.203mmol,1.4eq)NaBH(OAc)3,反应过夜。用饱和的碳酸氢钠溶液淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化化合物14和iso-14.
化合物14:橘黄色粘稠物,1HNMR(400MHz,CDCl3)δ13.03(s,1H),7.63(d,J=6.9Hz,1H),6.68(d,J=10.1Hz,1H),5.43(d,J=10.1Hz,1H),5.20(t,J=6.9Hz,1H),5.14-5.03(m,2H),3.65-3.53(m,4H),3.33(d,J=5.6Hz,2H),3.30(s,1H),3.09(br,1H),2.95-2.88(m,1H),2.69(d,J=12.4Hz,1H),2.56(d,J=12.4Hz,1H),2.45(dd,J=14.1,5.9Hz,1H),2.38-2.30(m,1H),2.27-2.13(m,6H),2.11-2.01(m,2H),1.80-1.73(m,1H),1.78(s,3H),1.76(s,3H),1.65(s,6H),1.62(s,3H),1.62-1.56(m,1H),1.56(s,3H),1.52(s,3H),1.42(s,3H),1.37-1.28(m,1H)ppm.13CNMR(101MHz,CDCl3)δ180.1,161.0,158.4,157.6,141.9,135.4,131.8,131.4,131.3,124.5,123.8,122.5,122.0,116.0,107.4,102.4,100.3,92.6,84.7,83.8,81.1,70.5,67.0,58.9,53.4,49.2,42.0,36.9,32.3,30.3,28.5,27.7,25.8,25.6,25.0,23.3,22.7,22.0,18.2,17.6ppm;HRMS(EI)mzcalcdforC42H56NO7686.4058,foundfor[M+H]+686.4056.
化合物iso-14:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ13.04(s,1H),7.61(d,J=7.2Hz,1H),6.68(d,J=10.1Hz,1H),5.44(d,J=10.1Hz,1H),5.17-5.08(m,2H),5.06(t,J=7.8Hz,1H),3.68-3.58(m,4H),3.32(d,J=6.3Hz,2H),3.25(s,1H),3.01(d,J=4.8Hz,1H),2.94-2.87(m,1H),2.68(s,2H),2.44(dd,J=14.5,6.2Hz,1H),2.33(dd,J=14.1,3.8Hz,1H),2.26-2.17(m,4H),2.14(dd,J=13.4,8.5Hz,2H),2.09-2.02(m,2H),1.82-1.76(m,4H),1.75(s,3H),1.65(s,3H),1.64(s,3H),1.62-1.59(m,1H),1.56(s,3H),1.52(s,3H),1.45(s,3H),1.42(s,3H),1.31-1.25(m,1H)ppm.13CNMR(101MHz,CDCl3)δ180.0,161.0,158.4,157.5,141.9,135.6,131.8,131.4,131.2,124.5,123.8,122.6,120.9,116.0,107.5,102.4,100.3,92.5,84.9,83.7,81.1,70.3,67.6,67.0,53.4,49.2,42.0,36.9,32.4,30.3,28.5,27.6,25.7,25.7,25.1,22.7,21.9,18.2,17.6,15.1ppm.HRMS(EI)m/zcalcdforC42H56NO7686.4057,foundfor[M+H]+686.4053.
实施例12甲基哌嗪化合物15的制备
室温条件下,氮气保护,将化合物7(0.283g,0.461mmol,leq)溶于25mL二氯甲烷中,随后加入0.051mL(0.461mmol,1eq)N-甲基哌嗪,反应0.5h后,再加入0.137g(0.65mmol,1.4eq)NaBH(OAc)3,反应过夜。用饱和的碳酸氢钠溶液淬灭,乙酸乙酯萃取,合并有机相,饱和食盐水溶液洗涤,无水硫酸钠干燥,旋干,柱层析纯化得到甲基哌嗪化合物15.
化合物15:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ13.02(s,1H),7.60(d,J=7.1Hz,1H),6.65(d,J=10.1Hz,1H),5.40(d,J=10.1Hz,1H),5.14(t,J=6.9Hz,1H),5.11-4.97(m,2H),3.38-3.02(m,4H),2.87(s,1H),2.67(d,J=12.5Hz,1H),2.55(d,J=12.7Hz,1H),2.45-2.10(m,15H),2.07-1.97(m,2H),1.80-1.78(m,1H),1.75(s,3H),1.72(s,3H),1.62(s,6H),1.61-1.58(m,1H),1.57(s,3H),1.53(s,3H),1.49(s,3H),1.40(s,3H),1.38-1.31(m,1H)ppm.13CNMR(101MHz,CDCl3)δ180.2,161.1,158.5,157.7,142.1,136.0,132.0,131.5,131.3,124.5,124.0,122.7,121.9,116.2,107.6,102.5,100.4,92.8,84.9,83.9,81.2,70.6,58.7,55.2,52.9,49.3,46.1,42.2,37.0,32.4,30.4,28.6,27.9,25.9,25.8,25.2,23.6,22.8,22.1,18.3,17.8.HRMS(EI)m/zcalcdforC43H59N2O6699.4374,foundfor[M+H]+699.4374.
实施例13二甲醚化吗啉化合物16的制备
同实施例12,不同在于用化合物10代替化合物7,用吗啉代替甲基哌嗪作为反应物,得到化合物16.
化合物16:橘黄色无定形固体,1HNMR(400MHz,CDCl3)δ7.45(d,J=7.2Hz,1H),6.67(d,J=10.1Hz,1H),5.54(d,J=10.2Hz,1H),5.22-5.11(m,2H),5.05(t,J=6.7Hz,1H),4.36(s,1H),3.82(s,3H),3.78(s,3H),3.56(s,4H),3.39(d,J=6.3Hz,2H),2.98-2.91(m,1H),2.63-2.50(m,2H),2.49-2.36(m,3H),2.21-2.01(m,7H),1.80-1.70(m,7H),1.65(s,6H),1.63-1.58(m,1H),1.55(s,3H),1.53(s,6H),1.42(s,3H),1.37-1.29(m,1H)ppm;13CNMR(101MHz,CDCl3)δ175.5,160.4,158.6,155.2,137.4,134.8,131.9,131.8,127.3,123.7,122.7,122.1,116.7,112.8,109.7,107.4,92.3,83.8,82.9,80.4,75.7,67.0,62.2,58.7,54.9,53.4,48.9,41.9,34.2,32.7,30.5,28.1,27.6,26.0,25.8,25.6,23.1,22.6,22.4,18.2,17.6.
实施例14藤黄酸类似物抗肿瘤生物活性体外筛选试验
采用四氮唑盐(Methyl-Thiazol-Tetrozolium,MTT)还原法的筛选方法,作用细胞株为HL-60人白血病和BEL-7402人肝癌和A-549人肺癌MOLT-4,作用时间为72小时。
对肿瘤细胞生长的抑制率%

Claims (4)

1.一种藤黄酸衍生物,它为通式(1)的化合物:
其特征在于:R1为氢、甲基或者苄基;
R2为氢或者甲基,此时C-12与氧形成单键;R3、R4分别为甲基、亚甲基醇、或者为C1-C6烷基取代的氨基;R3、R4不同时为甲基;或者
R2为氢、甲基,此时C-12与氧形成单键;R3、R4分别为甲基、甲醛基;R3、R4不同时为甲基。
2.一种藤黄酸衍生物,其特征在于选自下列化合物:
3.权利要求2所述的藤黄酸衍生物的制备方法,其特征在于包括酯化、还原、氧化、醚化和还原氨化步骤:
合成步骤一:在-30℃~30℃条件下,在有机溶剂中,氮气保护下,在催化剂的作用下,藤黄酸与甲醇缩合得到相应的酯化合物1,2;有机溶剂为二氯甲烷,催化剂为1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和4-二甲氨基吡啶;
合成步骤二:在-78℃~-40℃条件下,在有机溶剂中藤黄酸酯1,2与还原剂作用得到相应的还原产物3,4a,4b,5和6;有机溶剂为二氯甲烷,还原剂为二异丁基氢化铝;
合成步骤三:在-30℃~30℃的温度范围内,在有机溶剂中,藤黄酸的醇衍生物5,6在氧化剂的作用下,得到相应的醛的化合物7,8,有机溶剂为二氯甲烷;氧化剂为四甲基哌啶氧化物和二乙酸碘苯;
合成步骤四:在0℃~60℃条件下,藤黄酸的醇类衍生物7在有机溶剂中,在碱的作用下,与卤代烃反应,得到相应的醚类化合物9,10,有机溶剂为二甲基甲酰胺;所述的碱是碳酸钾;所述卤代烃为碘甲烷;
合成步骤五:在0℃~60℃条件下,藤黄酸的醛类衍生物7在碘的催化作用下,与原甲酸酯反应,在无溶剂条件下,得到相应的缩醛化合物11,原甲酸酯为原甲酸三甲酯,然后在碘甲烷作用下得到醚类化合物12;
合成步骤六:在-30℃~30℃的温度范围内,在有机溶剂中,藤黄酸的醛类衍生物7或10与胺反应,然后加入还原剂得到还原氨化的产物14,15,16;所述的有机溶剂为二氯甲烷;所述的胺为吗啉、N-甲基哌嗪;所述还原剂为醋酸硼氢化钠。
4.权利要求1或2所述化合物用于制备抗肿瘤药物的用途。
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