CN111454274B - 倍半萜内酯—saha衍生物的制备方法及其在制备抗癌药物中的用途 - Google Patents

倍半萜内酯—saha衍生物的制备方法及其在制备抗癌药物中的用途 Download PDF

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CN111454274B
CN111454274B CN201910046728.0A CN201910046728A CN111454274B CN 111454274 B CN111454274 B CN 111454274B CN 201910046728 A CN201910046728 A CN 201910046728A CN 111454274 B CN111454274 B CN 111454274B
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CN111454274A (zh
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陈悦
张泉
丁亚辉
戈伟智
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Luoyang Shangde Pharmaceutical Margin Technology Co ltd
Nankai University
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Nankai University
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Abstract

本发明提供了式(I)的倍半萜内酯—SAHA衍生物的制备方法以及在治疗癌症的药物中的用途，其中癌症为白血病。

Description

倍半萜内酯—SAHA衍生物的制备方法及其在制备抗癌药物中 的用途
技术领域
本发明涉及倍半萜内酯—SAHA衍生物以其为有效成分的治疗癌症或辅助治疗癌症的药物组合物，以及该药物化合物和组合物在制备抗癌或辅助抗癌药物中的应用，属于药物化学领域。
背景技术
急性髓系白血病(AML)是一种恶性疾病，其特征是不成熟髓系造血细胞异常聚集。化疗是常见的治疗方法之一，大多数患者通过化疗可以获得较长的生存期。但大约20％的患者在化疗后会产生耐药性，其中一半以上会复发。[B.Lowenberg,Acute myeloidleukemia,N.Engl.J.Med.,341(1999)1051-1062；J.Kell,Treatment of relapsed acutemyeloid leukaemia,Rev.Recent Clin.Trials,1(2006)103-111]许多白血病细胞不仅会对特定药物产生耐药性，还会对其他类型的药物产生交叉耐药性，这种现象被定义为多药耐药。组蛋白去乙酰酶(Histone deacetylases,HDACs)可以去除组蛋白中的乙酰基团，维持核糖体组蛋白和非组蛋白乙酰化水平的动态平衡，在细胞增殖和分化中发挥重要的调节作用。[L.Catley,E.Weisberg,T.Kiziltepe,Y.-T.Tai,T.Hideshima,P.Neri,P.Tassone,P.Atadja,D.Chauhan,N.C.Munshi,K.C.Anderson,Aggresome induction by proteasomeinhibitor bortezomib and alpha-tubulin hyperacetylation by tubulindeacetylase(TDAC)inhibitor LBH589are synergistic in myeloma cells,Blood,108(2006)3441-3449.]SAHA是一种口服生物有效的HDACs抑制剂，具有广谱抗癌作用。小白菊内酯(PTL)是一类典型的吉马烷类倍半萜内酯，良好的抗癌特性。PTL可以通过泛素化/蛋白酶体降解HDAC1，在不影响其他I/II类HDACs的情况下，特异性地消耗HDAC1蛋白。[Y.N.V.Gopal,T.S.Arora,M.W.V.Dyke,Parthenolide specifically depletes histonedeacetylase 1protein and induces cell death through ataxia telangiectasiamutated,Chem.Biol.,14(2007)813-823.]
发明内容
本发明提供了一种倍半萜内酯—SAHA衍生物为主要成分的治疗癌症的药物组合物或与其他抗癌药物的组合物，其制备方法，以及式(I)的倍半萜内酯—SAHA衍生物及其药物组合物在制备治疗癌症药物中的应用。
其中，其中，P为以下结构：
R为羧基，对氨基苯甲酸基，对羟基苯甲酸基，对羟基肉桂酸基，苯环取代的对羟基肉桂酸基，邻羟基肉桂酸基，间羟基肉桂酸基；n为5-8。
根据权利要求1所述的化合物，化合物为5,8,14,17,20a-c,23a-c,26,29
本发明还提供了式5,8,14,17,20a-c,23a-c,26,29化合物的制备方法以及在治疗癌症的药物中的用途，其中癌症为白血病。
本发明还提供了一种用于治疗癌症的药物组合物，其中含有有效量的式5,8,14,17,20a-c,23a-c,26,29化合物和药学上可接受的载体或与其他抗癌药物的组合物。
附图说明
图1.化合物5，8的制备方法
图2.化合物14，17的制备方法
图3.化合物20a-20c，23a-23c的制备方法
图4.化合物26，29的制备方法
具体实施方式
为了理解本发明，下面以实施例进一步说明本发明，但不意于限制本发明的保护范围。
实施例1：5,8,14,17,20a-c,23a-c,26,29衍生物的合成
具体合成路线见图1-4，具体步骤如下：
化合物4的合成：
将MMB(80mg,0.3mmol)及化合物3(194.2mg,0.45mmol)共同放于反应瓶中，加入EDCI(86.3mg,0.45mmol),DMAP(1.2mg,0.01mmol)，加无水二氯甲烷1mL溶解，在冰水浴下搅拌，再加入三乙胺(62.5μL,0.45mmol)。室温下搅拌过夜，点板，反应基本完毕，加饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，合并有机相，干燥过滤，浓缩，过硅胶柱层析纯化得到化合物4(145mg,产率71％).1H NMR(400MHz,CDCl3)δ7.78–7.28(m,16H),6.25(d,J＝3.0Hz,1H),5.68(t,J＝8.0Hz,1H),5.54(d,J＝2.7Hz,1H),4.65(d,J＝12.5Hz,1H),4.44(d,J＝12.5Hz,1H),3.85(t,J＝9.3Hz,1H),2.87(dd,J＝20.4,10.5Hz,2H),2.50–2.12(m,8H),1.71–1.62(m,1H),1.60(s,2H),1.57–1.50(m,5H),1.25(s,5H),1.15–1.06(m,2H).13CNMR(100MHz,CDCl3)δ173.5,171.2,169.5,138.9,135.1,130.7,129.2,128.3,120.4,109.6,100.1,81.2,66.6,63.4,60.1,42.8,36.8,34.3,32.1,29.8,28.9,28.8,25.9,24.8,24.6,24.0,18.1.HRMS(ESI)calcd for C42H47NNaO7[M+Na]+700.3245,found 700.3250.
化合物5的合成：
将化合物4(86mg,0.13mmol)溶解于无水二氯甲烷中，在冰水浴的条件下搅拌，依次交替逐滴滴加三乙基硅烷和三氟乙酸。知道黄色不再消失，反应基本完成。直接旋干容积过硅胶柱层析纯化得到化合物5(40mg,产率72％).1H NMR(400MHz,MeOD-d4)δ6.17(d,J＝3.2Hz,1H),5.67(dd,J＝17.9,5.4Hz,2H),4.70(d,J＝12.6Hz,1H),4.51(d,J＝12.6Hz,1H),4.03(t,J＝9.3Hz,1H),3.05(t,J＝8.7Hz,1H),2.92(d,J＝9.5Hz,1H),2.59–2.06(m,10H),1.62(d,J＝5.5Hz,4H),1.56(s,3H),1.35(s,5H),1.08(t,J＝12.8Hz,1H).13C NMR(100MHz,MeOD-d4)δ175.1,171.8,141.0,136.8,131.2,120.4,82.9,67.8,64.8,61.6,43.9,37.7,35.0,30.8,30.8,29.8,29.8,26.6,26.5,25.9,25.5,24.7,18.1.HRMS(ESI)calcd for C23H33NNaO7[M+Na]+458.2149,found 458.2154.
化合物6的合成：
将MMB(65.0mg,0.25mmol)和PPh3(64.5mg,0.25mmol)以及4-氨基苯甲酸(33.8mg,0.25mmol)放于反应瓶中，置换氩气，加入2.5mL无水THF溶解，在冰水浴的条件下搅拌，逐滴加入DIAD(49μL,0.25mmol)，缓慢升温到室温，室温下搅拌4h，点板反应基本完毕，加入饱和氯化铵溶液淬灭反应，乙酸乙酯萃取三次，饱和食盐水洗，干燥过滤，浓缩过硅胶柱纯化得到黄色固体化合物6(90mg,产率95％).1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.6Hz,2H),6.57(d,J＝8.6Hz,2H),6.16(d,J＝3.5Hz,1H),5.69(t,J＝8.3Hz,1H),5.45(d,J＝3.2Hz,1H),4.77(d,J＝12.6Hz,1H),4.60(d,J＝12.6Hz,1H),4.05(d,J＝7.0Hz,2H),3.80(t,J＝9.3Hz,1H),2.92(dd,J＝14.8,5.8Hz,1H),2.84(d,J＝9.4Hz,1H),2.50–2.05(m,6H),1.62(dd,J＝16.4,8.8Hz,1H),1.49(s,3H),1.06(t,J＝12.6Hz,1H)；13C NMR(100MHz,CDCl3)δ169.5,166.3,151.2,138.6,135.4,131.7,130.2,120.5,119.1,113.8,81.1,66.5,63.3,60.1,42.8,36.7,25.9,24.7,23.9,18.1.HRMS(ESI)calcd for C22H26NO5[M+H]+384.1805,found 384.1807.
化合物7的合成：
将化合物3(80.9mg,0.19mmol)和HATU(95.1mg,0.25mmol)共同溶解于无水DMF(4mL)中,之后加入DIPEA(44μL,0.25mmol)。反应液加热到40°搅拌2h,然后加入化合物6(48.0mg,0.13mmol)，在该温度下继续搅拌2h，取样点板，反应基本完毕，加入饱和氯化铵溶液淬灭，乙酸乙酯萃取三次，合并有机相，饱和食盐水洗三次，干燥，过滤浓缩，硅胶柱层析纯化得到黄色固体化合物7(81mg,产率81％).1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.7Hz,2H),7.64(d,J＝8.0Hz,2H),7.52–7.27(m,16H),6.20(d,J＝3.5Hz,1H),5.76(t,J＝8.3Hz,1H),5.51(d,J＝3.1Hz,1H),4.87(d,J＝12.5Hz,1H),4.70(d,J＝12.6Hz,1H),3.86(t,J＝9.3Hz,1H),3.03–2.92(m,1H),2.89(d,J＝9.4Hz,1H),2.51–2.12(m,8H),1.89(s,1H),1.63(dd,J＝14.7,7.3Hz,3H),1.55(s,3H),1.25(s,7H),1.12(t,J＝12.7Hz,2H).13C NMR(100MHz,CDCl3)δ177.5,172.2,169.6,166.0,138.7,135.2,130.9,130.6,129.1,128.3,128.1,128.1,128.0,120.6,119.0,81.2,67.0,63.4,60.2,42.9,36.8,29.8,28.5,25.9,25.1,24.7,24.0,18.1.HRMS(ESI)calcd for C49H53N2O8[M+H]+797.3796,found 797.3781.
化合物8的合成：
制备方法同化合物3的制备方法，无色油状物，产率80％；1H NMR(400MHz,MeOD-d4)δ8.00(d,J＝8.2Hz,2H),7.74(d,J＝8.3Hz,2H),6.18(d,J＝3.4Hz,1H),5.81(t,J＝8.3Hz,1H),5.66(d,J＝3.1Hz,1H),4.95(d,J＝12.7Hz,1H),4.79(d,J＝12.7Hz,1H),4.07(t,J＝9.3Hz,1H),3.19–3.07(m,1H),2.99(d,J＝9.5Hz,1H),2.65–2.37(m,6H),2.30–2.10(m,4H),1.83–1.63(m,5H),1.60(s,3H),1.44(d,J＝2.9Hz,4H),1.13(t,J＝13.0Hz,1H).13CNMR(100MHz,MeOD-d4)δ174.9,171.8,167.4,144.8,140.8,136.8,131.6,131.3,126.1,120.6,120.2,82.9,68.2,64.8,61.6,43.9,38.0,37.7,33.6,30.7,29.9,29.8,26.6,26.5,25.6,24.7,18.1.HRMS(ESI)calcd for C30H39N2O8[M+H]+555.2710,found 555.2703.
化合物10的合成：
化合物9(500mg,2.39mmol)溶于无水20mL THF中，加入N-甲基吗啉(289μL,2.63mmol)，冷却到零下10度，再加入氯甲酸异丁酯(341μL,2.63mmol)，搅拌5分钟后，加入O-三苯甲基羟胺(658mg,2.39mmol)，缓慢升温到室温，反应过夜。过滤，滤液浓缩，加乙酸乙酯重新溶解，依次用饱和碳酸氢钠溶液和食盐水溶液洗，干燥，过滤浓缩，硅胶柱层析纯化得到白色固体化合物(1.07g,产率95％).1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.34-7.48(m,15H),3.35(t,J＝5.8Hz,2H),1.75-1.86(m 3H),1.61(s,1H),1.44(s,1H),1.27(s,3H),1.07(s,2H).13C NMR(100MHz,CDCl3)δ177.2,141.2,129.1,128.2,93.4,33.9,32.5,31.1,29.8,28.2,27.8,23.3.HRMS(ESI)calcd for C26H28BrNNaO2[M+Na]+488.1196,found488.1201.化合物11的合成：
将化合物10(1.63g,3.5mmol)和对羟基苯甲酸甲酯(152mg,1mmol)及碳酸钾(552mg,4mmol)共同放于反应瓶中，加入无水DMF 15mL，40度下搅拌4h后，取样，点板家饱和食盐水淬灭，EA萃取三次，合并有机相家饱和食盐水洗三次，干燥过滤浓缩硅胶柱层析纯化得到白色固体化合物(473mg,产率88％).1H NMR(400MHz,CDCl3)δ7.97(d,J＝7.7Hz,2H),7.40(d,J＝55.4Hz,16H),6.88(d,J＝8.0Hz,2H),3.95(t,J＝6.0Hz,2H),3.88(s,3H),1.77–1.54(m,5H),1.31(d,J＝17.6Hz,3H),1.10(s,2H).13C NMR(100MHz,CDCl3)δ177.2,167.1,163.0,141.2,131.7,129.2,128.3,122.5,114.2,100.1,68.1,52.0,31.2,29.8,29.0,28.9,25.8,23.5.HRMS(ESI)calcd for C34H35NNaO5[M+Na]+560.2407,found560.2412.
化合物12的合成：
化合物11(509mg,0.95mmol)溶解于9.4mL 1:1的THF:水中，加入LiOH.H2O(795mg,1.89mmol)，室温下反应过夜，反应完毕后，用2N盐酸溶液调节pH到2-3，用乙酸乙酯萃取三次，饱和食盐水洗一次，干燥过滤，浓缩硅胶柱层析纯化得到白色固体化合物(355mg,产率72％).1H NMR(400MHz,DMSO-d6)δ12.58(s,1H),10.16(s,1H),7.87(d,J＝8.8Hz,2H),7.30(d,J＝9.3Hz,15H),6.98(d,J＝8.8Hz,2H),3.97(t,J＝6.4Hz,2H),1.78(t,J＝6.6Hz,1H),1.67–1.55(m,2H),1.24(q,J＝16.2Hz,5H),1.02(d,J＝6.7Hz,2H)；13C NMR(100MHz,DMSO-d6)δ162.2,142.5,131.3,128.9,127.5,127.4,122.9,114.2,91.7,67.6,31.9,28.9,28.3,28.0,25.1,24.6.HRMS(ESI)calcd for C33H32NO5[M-H]–522.2286,found 522.2283.
化合物13的合成：
将MMB(28.5mg,0.11mmol),DIC(33mg,0.16mmol),DMAP(1.3mg,0.01mmol)及化合物12共同溶于无水二氯甲烷(1mL)中，冰水浴下搅拌15min后，缓慢升温到室温，室温下搅拌过夜，点板反应基本完毕，加饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取三次，干燥过滤浓缩过硅胶柱层析纯化得到白色固体化合物13(50.8mg,产率62％).1H NMR(400MHz,CDCl3)δ7.95(d,J＝8.8Hz,2H),7.81–7.27(m,16H),6.88(d,J＝8.8Hz,2H),6.23(d,J＝3.4Hz,1H),5.77(t,J＝8.3Hz,1H),5.52(d,J＝3.1Hz,1H),4.87(d,J＝12.6Hz,1H),4.70(d,J＝12.6Hz,1H),3.95(t,J＝6.4Hz,2H),3.86(t,J＝9.3Hz,1H),2.98(t,J＝9.0Hz,1H),2.90(d,J＝9.4Hz,1H),2.52–2.14(m,6H),1.76–1.67(m,3H),1.61(s,3H),1.56(s,3H),1.25(s,4H),1.15(d,J＝12.5Hz,2H).13C NMR(100MHz,CDCl3)δ177.3,169.5,166.2,163.3,141.2,138.8,135.3,131.8,130.5,129.2,128.3,122.0,120.6,114.3,81.2,68.2,66.8,63.5,60.1,42.9,36.8,29.8,29.5,29.0,28.9,28.8,26.0,25.8,24.7,24.0,18.2.HRMS(ESI)calcd for C48H50NO8[M-H]–768.3542,found 768.3538.
化合物14的合成：
合成步骤同化合物5，得到目标物14(产率：89％).1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.3Hz,2H),6.88(d,J＝8.3Hz,2H),6.20(d,J＝2.9Hz,1H),5.78(t,J＝8.3Hz,1H),5.49(d,J＝2.5Hz,1H),4.86(d,J＝12.6Hz,1H),4.71(d,J＝12.6Hz,1H),4.00(s,2H),3.87(t,J＝9.2Hz,1H),3.00(t,J＝9.7Hz,1H),2.90(d,J＝9.4Hz,1H),2.53–2.28(m,4H),2.27–2.13(m,3H),1.79(s,2H),1.75–1.63(m,3H),1.56(s,3H),1.25(s,5H),1.13(t,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3)δ169.6,166.2,163.3,138.8,135.3,131.8,130.9,122.1,120.6,114.4,81.2,68.1,67.0,63.4,60.2,43.0,36.8,32.9,32.1,29.8,28.9,28.8,26.0,25.8,25.0,24.0,18.2.HRMS(ESI)calcd for C29H37NNaO8[M+Na]+550.2411,found 550.2414.
化合物15的合成：
将MMB(264mg,1.0mmol),PPh3(393mg,1.5mmol)和香豆酸(210mg,1.5mmol)放于反应瓶中，置换氩气，加入无水THF(10mL)溶解，冰水浴下搅拌加入DIAD(0.3mL,1.5mmol)，缓慢升温到室温，室温下搅拌4h，取样点板，反应基本完毕，加饱和氯化铵溶液淬灭反应，EA萃取三次，合并有机相饱和食盐水洗三次，干燥，过滤，浓缩硅胶柱层析纯化的白色固体化合物15(285mg,产率69％)。1H NMR(400MHz,CDCl3)δ7.62(d,J＝15.9Hz,1H),7.38(d,J＝8.5Hz,2H),7.13-6.99(m,1H),6.87(d,J＝8.4Hz,2H),6.26(d,J＝8.9Hz,1H),6.23(d,J＝3.6Hz,1H),5.72(t,J＝7.9Hz,1H),5.57(d,J＝3.3Hz,1H),4.76(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.89(t,J＝9.3Hz,1H),2.98(t,J＝9.1Hz,1H),2.91(d,J＝9.4Hz,1H),2.51–2.11(m,6H),1.73–1.64(m,1H),1.55(s,3H),1.12(t,J＝12.6Hz,1H).13C NMR(100MHz,CDCl3)δ169.9,167.3,158.6,145.7,138.5,134.9,130.6,130.1,126.3,120.8,116.0,114.1,81.2,66.8,63.3,60.3,42.6,36.5,25.8,24.5,23.8,17.9.HRMS(ESI)calcdfor C24H30NO6[M+NH4]+428.2068,found 428.2067.化合物16的合成：
将化合物15(130mg,0.32mmol)和化合物10(517mg,1.11mmol)共同溶解于无水15mL DMF中，加入无水碳酸钾(177mg,1.28mmol)，40度下搅拌4小时，反应基本完成，加饱和食盐水淬灭反应，EA萃取三次，合并有机相，饱和食盐水洗三次，干燥，过滤浓缩硅胶柱层析纯化得到黄色固体化合物16(181mg,产率71％)。1H NMR(400MHz,CDCl3)δ7.79–7.58(m,2H),7.54–7.27(m,17H),6.88(d,J＝7.8Hz,2H),6.27(d,J＝16.4Hz,2H),5.74(t,J＝7.6Hz,1H),5.56(s,1H),4.78(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.93(s,2H),3.87(t,J＝9.3Hz,1H),2.99(t,J＝9.6Hz,1H),2.90(d,J＝9.3Hz,1H),2.56–2.30(m,4H),2.30–2.13(m,2H),1.77–1.59(m,5H),1.56(s,3H),1.31(d,J＝17.5Hz,3H),1.26(s,2H),1.18–1.09(m,2H).13C NMR(100MHz,CDCl3)δ169.4,167.0,161.2,145.4,141.1,138.8,135.2,130.6,129.9,129.0,128.1,126.7,120.3,114.9,114.6,114.0,81.1,68.0,66.7,63.3,60.0,42.8,36.7,29.7,28.9,28.7,25.9,25.6,24.7,23.9,18.0.HRMS(ESI)calcd for C50H52NO8[M-H]–794.3693,found 794.3695.
化合物17的合成：
制备方法同化合物5的制备方法，(产率82％).1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.63(d,J＝16.0Hz,1H),7.43(d,J＝7.5Hz,2H),6.87(d,J＝7.8Hz,2H),6.26(d,J＝14.9Hz,2H),5.74(t,J＝8.2Hz,1H),5.56(s,1H),4.76(d,J＝12.5Hz,1H),4.59(d,J＝12.6Hz,1H),3.96(s,2H),3.87(t,J＝9.3Hz,1H),3.01(t,J＝10.3Hz,1H),2.90(d,J＝9.4Hz,1H),2.50–2.15(m,8H),1.77(s,2H),1.72–1.64(m,3H),1.56(s,3H),1.46(s,2H),1.42–1.36(m,2H),1.17–1.09(m,1H).13C NMR(100MHz,CDCl3)δ173.8,169.7,167.2,161.3,145.5,138.9,135.3,130.9,130.0,126.8,120.6,115.1,114.7,81.3,68.1,67.0,63.5,60.2,42.9,36.8,32.1,29.8,29.0,28.9,26.1,25.8,24.9,24.0,18.2.HRMS(ESI)calcdfor C31H38NO8[M-H]–552.2603,found552.2600.
化合物18a-18c的合成：
制备方法同化合物10的制备方法。
白色固体，产率90％，1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),7.33(s,15H),3.41(t,J＝6.4Hz,2H),1.79(s,2H),1.70–1.59(m,2H),1.26–1.16(m,2H),1.09(d,J＝6.1Hz,2H).13C NMR(100MHz,DMSO-d6)δ170.1,142.4,128.9,127.5,127.4,91.7,34.8,31.9,31.7,26.9,23.8.HRMS(ESI)calcd for C25H26BrNNaO2[M+Na]+474.1039,found 474.1042.
(产率:87％).1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),7.33(s,15H),3.50(t,J＝6.7Hz,2H),1.83–1.70(m,3H),1.35–1.22(m,3H),1.22–1.03(m,4H),0.97(d,J＝6.8Hz,2H).13C NMR(100MHz,DMSO-d6)δ170.3,142.5,128.9,127.7,127.5,127.4,126.6,91.7,35.1,32.1,28.1,27.7,27.3.HRMS(ESI)calcd for C27H30BrNNaO2[M+Na]+502.1352,found502.1358.
(产率:95％).1H NMR(400MHz,DMSO-d6)δ12.43(s,1H),9.62(s,15H),5.79(t,J＝6.0Hz,2H),4.06(d,J＝5.8Hz,4H),3.66–3.56(m,2H),3.46(t,J＝24.8Hz,6H),3.25(d,J＝5.3Hz,2H).13C NMR(100MHz,DMSO-d6)δ170.3,142.5,128.9,127.5,127.4,91.7,35.2,32.2,32.0,28.5,28.2,27.9,27.4,24.7.HRMS(ESI)calcd forC28H32BrNNaO2[M+Na]+516.1509,found 516.1512.
化合物19a-19c的合成：
化合物19a-19c的制备方法同化合物16的制备方法。
(产率:81％).1H NMR(400MHz,CDCl3)δ7.65(d,J＝15.9Hz,1H),7.44(d,J＝8.5Hz,5H),7.33(s,13H),6.87(d,J＝8.2Hz,2H),6.27(t,J＝9.5Hz,2H),5.74(t,J＝8.0Hz,1H),5.56(d,J＝2.9Hz,1H),4.78(d,J＝12.5Hz,1H),4.59(d,J＝12.6Hz,1H),3.94–3.82(m,3H),2.99(t,J＝8.9Hz,1H),2.89(d,J＝9.4Hz,1H),2.53–2.12(m,7H),1.67(s,6H),1.56(s,3H),1.31(d,J＝19.8Hz,2H),1.17–1.09(m,1H).13C NMR(100MHz,CDCl3)δ177.1,169.5,167.1,161.3,145.5,141.3,138.9,135.3,130.7,130.0,129.2,128.3,126.8,120.5,115.0,114.7,114.1,100.1,81.2,67.9,66.9,63.5,60.1,42.9,36.8,29.8,29.8,28.9,26.0,25.6,24.8,24.0,18.1.HRMS(ESI)calcd for C49H51NNaO8[M+Na]+804.3507,found804.3510.
(产率:77％)。1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.65(d,J＝15.8Hz,1H),7.45(d,J＝8.2Hz,4H),7.33(s,13H),6.88(d,J＝7.9Hz,2H),6.27(d,J＝15.5Hz,2H),5.74(t,J＝8.0Hz,1H),5.56(s,1H),4.78(d,J＝12.4Hz,1H),4.59(d,J＝12.5Hz,1H),3.95(t,J＝5.3Hz,2H),3.87(t,J＝9.2Hz,1H),2.99(t,J＝10.2Hz,1H),2.90(d,J＝9.3Hz,1H),2.54–2.11(m,6H),1.79–1.68(m,3H),1.61(d,J＝18.0Hz,3H),1.56(s,3H),1.43–1.32(m,3H),1.25(s,3H),1.17–1.09(m,2H).13C NMR(100MHz,CDCl3)δ169.5,167.1,161.4,145.5,141.2,138.9,135.3,130.8,130.0,129.9,129.2,128.2,127.8,126.8,120.5,115.0,114.7,81.2,68.2,66.9,63.5,60.1,42.9,36.8,29.8,29.2,29.1,26.0,25.9,24.8,24.0,18.2.HRMS(ESI)calcd for C51H54NO8[M-H]–808.3855,found 808.3853.
(产率:86％).1H NMR(400MHz,CDCl3)δ7.65(d,J＝15.9Hz,1H),7.54–7.27(m,18H),6.89(d,J＝8.3Hz,2H),6.26(t,J＝10.1Hz,2H),5.74(t,J＝8.0Hz,1H),5.56(d,J＝2.6Hz,1H),4.78(d,J＝12.5Hz,1H),4.59(d,J＝12.6Hz,1H),3.96(t,J＝6.4Hz,2H),3.87(t,J＝9.3Hz,1H),2.98(t,J＝9.0Hz,1H),2.89(d,J＝9.4Hz,1H),2.52–2.12(m,6H),1.74(dd,J＝19.4,11.9Hz,3H),1.54(d,J＝14.7Hz,4H),1.39(d,J＝7.0Hz,3H),1.23(d,J＝22.6Hz,6H),1.17–1.08(m,3H).13C NMR(100MHz,CDCl3)δ177.4,169.5,167.1,161.3,145.5,141.2,138.9,135.3,130.7,129.9,129.1,128.2,127.7,127.4,126.7,120.4,115.0,114.6,81.2,68.2,66.8,63.4,60.1,42.8,36.8,29.8,29.2,29.1,26.0,24.7,24.0,18.1.HRMS(ESI)calcd for C52H56NO8[M-H]–822.4011,found 822.4008.
化合物20a-20c的合成：
制备方法同化合物17的制备方法：
(产率:83％).1H NMR(400MHz,CDCl3)δ9.36(s,1H),7.60(d,J＝15.9Hz,1H),7.40(d,J＝8.5Hz,2H),6.84(d,J＝8.5Hz,2H),6.29–6.17(m,2H),5.71(t,J＝8.0Hz,1H),5.54(d,J＝3.0Hz,1H),4.74(d,J＝12.5Hz,1H),4.58(d,J＝12.6Hz,1H),3.96–3.81(m,3H),3.00(t,J＝8.8Hz,1H),2.88(d,J＝9.4Hz,1H),2.47–2.12(m,8H),1.75(dd,J＝16.1,10.0Hz,2H),1.68(d,J＝7.4Hz,3H),1.54(s,3H),1.44(s,2H),1.10(t,J＝12.5Hz,1H).13CNMR(100MHz,CDCl3)δ169.8,167.1,161.1,145.4,138.8,135.1,130.8,130.0,126.7,120.6,115.0,114.7,81.3,67.8,67.0,63.4,60.3,42.8,36.7,32.7,29.8,28.8,26.0,25.5,25.1,24.9,23.9,18.1.HRMS(ESI)calcd for C30H36NO8[M-H]–538.2446,found538.2442.
(产率:87％).1H NMR(400MHz,CDCl3)δ7.60(t,J＝16.9Hz,1H),7.42(d,J＝8.2Hz,2H),6.86(d,J＝8.1Hz,2H),6.25(d,J＝15.8Hz,2H),5.72(t,J＝8.1Hz,1H),5.55(d,J＝2.4Hz,1H),4.73(t,J＝15.5Hz,1H),4.59(d,J＝12.6Hz,1H),3.94(t,J＝6.1Hz,2H),3.86(t,J＝9.3Hz,1H),3.00(t,J＝8.8Hz,1H),2.89(d,J＝9.4Hz,1H),2.51–2.11(m,8H),1.78–1.65(m,3H),1.63(d,J＝11.4Hz,2H),1.54(s,3H),1.41(d,J＝7.4Hz,2H),1.33(s,4H),1.11(t,J＝12.7Hz,1H).13C NMR(100MHz,CDCl3)δ169.7,167.1,161.3,145.4,138.9,135.2,130.7,130.0,126.7,120.5,115.0,114.7,81.3,68.2,67.0,63.4,60.2,42.9,36.7,29.8,29.1,29.0,26.0,25.9,25.4,24.9,24.0,18.1.HRMS(ESI)calcd for C32H41NNaO8[M+Na]+590.2724,found590.2728.
(产率:82％).1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.64(d,J＝15.9Hz,1H),7.44(d,J＝8.6Hz,2H),6.88(d,J＝8.6Hz,2H),6.31–6.20(m,2H),5.74(t,J＝8.2Hz,1H),5.56(d,J＝3.1Hz,1H),4.77(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.96(t,J＝6.4Hz,2H),3.87(t,J＝9.3Hz,1H),3.05–2.95(m,1H),2.90(d,J＝9.4Hz,1H),2.50–2.11(m,8H),1.76(dd,J＝14.1,6.7Hz,2H),1.69–1.59(m,3H),1.56(s,3H),1.43(s,2H),1.32(s,6H),1.13(t,J＝12.6Hz,1H).13C NMR(100MHz,CDCl3)δ169.7,167.2,161.3,145.5,138.9,135.2,130.8,130.0,126.7,120.6,115.0,114.6,81.2,68.2,67.0,63.5,60.2,42.9,36.7,33.1,29.8,29.3,29.2,29.2,29.1,26.0,25.4,24.8,24.0,18.2.HRMS(ESI)calcd forC33H43NNaO8[M+Na]+604.2881,found604.2885.
化合物21a-21c的合成：
将MMB(1.0mmol),PPh3(1.5mmol)和不同取代基的香豆酸(1.5mmol)放于反应瓶中，置换氩气，加入无水THF(10mL)溶解，冰水浴下搅拌加入DIAD(1.5mmol)，缓慢升温到室温，室温下搅拌4h，取样点板，反应基本完毕，加饱和氯化铵溶液淬灭反应，EA萃取三次，合并有机相饱和食盐水洗三次，干燥，过滤，浓缩硅胶柱层析纯化的白色固体化合物21a-21c。
白色固体(产率:63％)1H NMR(400MHz,CDCl3)δ7.89(d,J＝16.1Hz,1H),7.32(d,J＝8.6Hz,1H),6.97(s,1H),6.50–6.41(m,2H),6.37(d,J＝16.1Hz,1H),6.22(d,J＝3.5Hz,1H),5.73(t,J＝8.2Hz,1H),5.55(d,J＝3.1Hz,1H),4.74(d,J＝12.5Hz,1H),4.60(d,J＝12.5Hz,1H),3.88(t,J＝9.3Hz,1H),3.81(s,3H),3.11–2.99(m,1H),2.92(d,J＝9.4Hz,1H),2.50–2.12(m,6H),1.65(dd,J＝22.8,9.8Hz,1H),1.55(s,3H),1.12(t,J＝12.5Hz,1H).13C NMR(100MHz,CDCl3)δ170.1,168.2,160.5,160.2,141.6,138.7,135.3,131.0,130.8,120.9,115.7,114.5,108.2,99.3,81.4,67.0,63.5,60.4,55.6,42.9,36.7,26.1,25.0,24.0,18.1.HRMS(ESI)calcd for C25H28NaO7[M+Na]+463.1727,found 463.1730.
白色固体(产率:55％).1H NMR(400MHz,CDCl3)δ7.62(d,J＝15.9Hz,1H),7.07(dd,J＝8.2,1.8Hz,1H),7.00(d,J＝1.8Hz,1H),6.92(d,J＝8.2Hz,1H),6.25(dd,J＝9.7,6.2Hz,2H),5.88(s,1H),5.75(t,J＝8.3Hz,1H),5.56(d,J＝3.2Hz,1H),4.78(d,J＝12.4Hz,1H),4.60(d,J＝12.5Hz,1H),3.94(s,3H),3.88(t,J＝9.3Hz,1H),3.09–2.98(m,1H),2.91(d,J＝9.4Hz,1H),2.55–2.14(m,6H),1.70(dd,J＝16.9,9.1Hz,1H),1.56(s,3H),1.14(t,J＝12.6Hz,1H).13C NMR(100MHz,CDCl3)δ169.4,166.8,148.2,146.8,145.6,138.8,135.0,130.8,126.6,123.2,120.3,114.7,114.6,109.2,81.0,66.9,63.3,60.0,55.9,42.7,36.6,25.8,24.7,23.8,18.0.HRMS(ESI)calcd for C25H29O7[M+H]+441.1908,found 441.1910.
黄色固体(产率:54％).1H NMR(400MHz,CDCl3)δ7.58(d,J＝15.9Hz,1H),6.74(s,2H),6.30–6.21(m,2H),5.80(s,1H),5.75(t,J＝8.2Hz,1H),5.55(d,J＝3.2Hz,1H),4.77(d,J＝12.5Hz,1H),4.60(d,J＝12.5Hz,1H),3.92(s,6H),3.88(t,J＝9.3Hz,1H),3.05(ddd,J＝12.0,9.1,3.1Hz,1H),2.91(d,J＝9.4Hz,1H),2.53–2.13(m,6H),1.73–1.66(m,1H),1.56(s,3H),1.14(t,J＝12.7Hz,1H).13C NMR(100MHz,CDCl3)δ169.5,166.9,147.4,145.9,139.1,137.6,135.3,131.1,125.7,120.4,115.2,105.3,81.2,67.2,63.5,60.1,56.5,43.0,36.8,26.1,25.0,24.0,18.2.HRMS(ESI)calcd for C26H30NaO8[M+Na]+493.1833,found 483.1838.
化合物22a-22c的合成：
制备方法同化合物16的制备方法
白色固体(产率:57％).1H NMR(400MHz,CDCl3)δ7.90(d,J＝16.0Hz,1H),7.59–7.28(m,16H),6.52–6.35(m,3H),6.23(d,J＝2.9Hz,1H),5.74(t,J＝8.1Hz,1H),5.54(s,1H),4.76(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.93(t,J＝6.6Hz,2H),3.90–3.79(m,4H),3.05(t,J＝9.8Hz,1H),2.92(d,J＝9.4Hz,1H),2.52–2.12(m,6H),1.76–1.66(m,3H),1.61(s,4H),1.56(s,3H),1.28(s,3H),1.18–1.09(m,2H).13C NMR(100MHz,CDCl3)δ169.6,167.8,162.7,160.2,141.3,138.9,135.5,130.9,130.8,129.2,128.3,120.5,116.2,115.0,106.0,99.0,81.2,68.2,67.0,63.5,60.1,55.6,42.9,36.8,29.8,29.1,26.2,25.8,25.0,24.0,18.2.HRMS(ESI)calcd for C51H54NO9[M-H–824.3804,found824.3800.
白色固体(产率:69％).1H NMR(400MHz,CDCl3)δ7.73(s,1H),7.62(d,J＝15.8Hz,1H),7.46(s,2H),7.33(s,13H),7.06(d,J＝8.2Hz,1H),7.01(s,1H),6.84(d,J＝8.1Hz,1H),6.27(d,J＝14.9Hz,2H),5.74(t,J＝8.0Hz,1H),5.56(s,1H),4.78(d,J＝12.6Hz,1H),4.60(d,J＝12.5Hz,1H),3.99(t,J＝6.3Hz,2H),3.93–3.81(m,4H),3.02(t,J＝10.2Hz,1H),2.91(dd,J＝19.2,9.8Hz,3H),2.54–2.14(m,6H),1.73(dt,J＝26.5,9.7Hz,5H),1.56(s,3H),1.29(s,3H),1.17–1.09(m,2H).13C NMR(100MHz,CDCl3)δ169.48,167.00,162.65,151.16,149.71,145.70,138.99,135.28,130.88,129.15,128.22,127.02,122.91,120.38,114.91,112.50,110.20,81.20,68.97,66.99,63.45,60.06,56.12,42.89,36.79,28.92,26.06,25.72,24.87,24.01,18.14.HRMS(ESI)calcd for C51H54NO9[M-H]–824.3804,found824.3802.
黄色固体(产率:44％).1H NMR(400MHz,CDCl3)δ7.59(d,J＝15.8Hz,1H),7.46(s,2H),7.32(s,14H),6.71(s,2H),6.31(d,J＝15.9Hz,1H),6.23(s,1H),5.74(t,J＝8.1Hz,1H),5.55(s,1H),4.78(d,J＝12.5Hz,1H),4.60(d,J＝12.6Hz,1H),3.95(t,J＝6.5Hz,2H),3.90–3.80(m,7H),3.03(t,J＝9.1Hz,1H),2.90(d,J＝9.4Hz,1H),2.53–2.11(m,6H),1.84(d,J＝15.8Hz,2H),1.70–1.62(m,3H),1.55(s,3H),1.30(d,J＝19.8Hz,3H),1.25(s,2H),1.16–1.07(m,2H).13C NMR(100MHz,CDCl3)δ177.4,169.4,166.7,153.8,145.7,141.2,139.8,139.0,135.1,131.0,129.4,129.2,129.1,128.2,127.4,126.8,120.3,116.4,105.4,93.4,81.1,73.5,67.1,63.4,60.0,56.2,42.8,36.7,29.9,29.7,26.0,25.5,24.8,23.9,18.1.HRMS(ESI)calcd for C52H57NNaO10[M+Na]+878.3875,found 878.3880.
化合物23a-23c的合成：
制备方法同化合物17的制备方法：
白色固体(产率:83％).1H NMR(400MHz,CDCl3)δ7.89(d,J＝16.0Hz,1H),7.37(s,1H),6.42(dd,J＝24.4,12.9Hz,3H),6.22(s,1H),5.74(t,J＝8.0Hz,1H),5.54(s,1H),4.74(d,J＝12.4Hz,1H),4.60(d,J＝12.4Hz,1H),3.97(s,2H),3.90–3.74(m,4H),3.07(t,J＝9.3Hz,1H),2.92(d,J＝9.3Hz,1H),2.50–2.12(m,8H),1.78(s,2H),1.72–1.61(m,3H),1.56(s,3H),1.52–1.37(m,4H),1.13(t,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3)δ169.7,167.8,162.6,160.2,141.3,138.9,135.5,131.0,130.9,120.5,116.3,115.1,106.1,99.1,81.3,68.1,67.1,63.5,60.2,55.7,43.0,36.8,32.1,29.8,29.1,28.9,26.3,25.8,25.2,24.1,22.8,18.2.HRMS(ESI)calcd for C32H40NO9[M-H]–582.2709,found 582.2706.
白色固体(产率:72％).1H NMR(400MHz,CDCl3)δ7.61(d,J＝15.8Hz,1H),7.06(d,J＝7.5Hz,1H),7.01(s,1H),6.84(d,J＝8.1Hz,1H),6.32–6.17(m,2H),5.74(t,J＝8.2Hz,1H),5.55(d,J＝3.0Hz,1H),4.77(d,J＝12.5Hz,1H),4.60(d,J＝12.5Hz,1H),4.03(s,2H),3.95–3.81(m,4H),3.03(t,J＝8.9Hz,1H),2.90(d,J＝9.4Hz,1H),2.54–2.12(m,8H),1.83(s,2H),1.69(dd,J＝17.7,7.5Hz,3H),1.56(s,3H),1.50–1.40(m,3H),1.13(t,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3)δ169.6,167.0,151.1,149.7,145.7,139.0,135.3,131.0,127.1,123.0,120.5,115.0,112.6,110.3,81.3,68.8,67.1,63.5,60.1,56.2,42.9,36.8,29.8,28.8,28.6,26.1,25.5,25.0,24.0,18.2.HRMS(ESI)calcd for C32H41NNaO9[M+Na]+606.2674,found 606.2675.
黄色固体(产率:69％).1H NMR(400MHz,CDCl3)δ9.02(s,1H),7.56(d,J＝15.9Hz,1H),6.70(s,2H),6.28(d,J＝15.9Hz,1H),6.22(d,J＝3.3Hz,1H),5.73(t,J＝8.1Hz,1H),5.54(d,J＝3.0Hz,1H),4.76(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.96(t,J＝6.0Hz,2H),3.91–3.78(m,7H),3.04(t,J＝8.9Hz,1H),2.89(d,J＝9.4Hz,1H),2.54–2.09(m,8H),1.68(d,J＝3.2Hz,3H),1.64(d,J＝11.3Hz,2H),1.54(s,3H),1.44(s,2H),1.37–1.30(m,2H),1.11(t,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3)δ169.6,166.7,153.7,145.6,139.7,139.0,135.1,131.1,129.5,120.4,116.6,105.6,81.3,73.5,67.3,63.4,60.2,56.3,42.9,36.7,29.9,29.8,28.8,26.0,25.4,25.3,25.0,24.0,22.8,18.1.HRMS(ESI)calcd for C33H42NO10[M-H]–612.2814,found 612.2812.
化合物24的合成：
将MMB(322mg,1.22mmol),PPh3(479mg,1.83mmol)和邻羟基肉桂酸(300mg,1.83mmol)放于反应瓶中，置换氩气，加入无水THF(10mL)溶解，冰水浴下搅拌加入DIAD(0.36mL,1.83mmol)，缓慢升温到室温，室温下搅拌4h，取样点板，反应基本完毕，加饱和氯化铵溶液淬灭反应，EA萃取三次，合并有机相饱和食盐水洗三次，干燥，过滤，浓缩硅胶柱层析纯化的白色固体化合物24(344mg,产率:68％)。1H NMR(400MHz,CDCl3)δ7.96(d,J＝16.1Hz,1H),7.42(dd,J＝7.8,1.4Hz,1H),7.25–7.19(m,1H),6.90(t,J＝7.5Hz,2H),6.85(d,J＝8.0Hz,1H),6.59(d,J＝16.1Hz,1H),6.22(d,J＝3.5Hz,1H),5.75(t,J＝8.1Hz,1H),5.55(d,J＝3.2Hz,1H),4.76(d,J＝12.4Hz,1H),4.62(d,J＝12.4Hz,1H),3.89(t,J＝9.3Hz,1H),3.16–3.02(m,1H),2.93(d,J＝9.4Hz,1H),2.53–2.13(m,6H),1.68(t,J＝12.5Hz,1H),1.56(s,3H),1.13(t,J＝12.5Hz,1H).13C NMR(100MHz,CDCl3)δ170.2,167.8,155.8,141.5,138.8,135.3,131.8,131.3,129.7,121.5,120.8,117.9,116.6,81.4,67.5,63.5,60.3,43.0,36.7,29.8,26.2,25.2,24.0,18.2.HRMS(ESI)calcd for C24H26NaO6[M+Na]+433.1622,found 433.1625.
化合物25的合成：
制备方法同化合物16的制备，白色固体，产率76％。1H NMR(400MHz,CDCl3)δ8.02(d,J＝15.8Hz,1H),7.75(s,1H),7.48(d,J＝7.2Hz,4H),7.33(s,14H),6.95(t,J＝7.4Hz,1H),6.89(d,J＝8.1Hz,1H),6.51(d,J＝16.0Hz,1H),6.23(s,1H),5.72(d,J＝7.5Hz,1H),5.54(s,1H),4.84–4.51(m,2H),3.97(d,J＝5.8Hz,2H),3.86(t,J＝9.0Hz,1H),2.97(s,1H),2.89(d,J＝9.3Hz,1H),2.32(ddt,J＝32.3,25.8,11.7Hz,6H),1.76(s,2H),1.70(s,2H),1.55(s,3H),1.31(d,J＝21.6Hz,2H),1.26(s,3H),1.11(t,J＝12.3Hz,2H).13C NMR(100MHz,CDCl3)δ169.5(2C),167.3,158.0,141.3,138.8,135.3,131.9,130.6,129.3,129.2,129.1,128.2,127.4,123.2,120.7,120.5,117.7,112.3,81.2,68.4,66.8,63.4,60.1,42.8,36.8,32.0,29.8,29.5,28.9,26.0,25.8,24.7,24.0,22.8,18.1.HRMS(ESI)calcd for C50H52NO8[M-H]–794.3698,found794.3695.
化合物26的合成：
化合物26的制备方法同化合物17的制备方法，产率63％。1H NMR(400MHz,CDCl3)δ9.59(s,1H),8.05(d,J＝16.1Hz,1H),7.48(d,J＝7.4Hz,1H),7.33(t,J＝7.6Hz,1H),6.94(t,J＝7.5Hz,1H),6.88(d,J＝8.1Hz,1H),6.49(d,J＝16.1Hz,1H),6.22(s,1H),5.74(t,J＝7.8Hz,1H),5.55(s,1H),4.70(dd,J＝24.7,12.7Hz,2H),3.99(t,J＝5.0Hz,2H),3.87(t,J＝9.3Hz,1H),3.01(t,J＝9.4Hz,1H),2.90(d,J＝9.4Hz,1H),2.58–2.03(m,8H),1.80(s,2H),1.73–1.59(m,3H),1.55(s,3H),1.48(s,2H),1.41(d,J＝8.2Hz,2H),1.12(t,J＝12.8Hz,1H).13C NMR(100MHz,CDCl3)δ169.8(2C),167.9,158.1,141.6,138.8,135.0,132.2,130.7,128.7,123.0,120.8,120.7,117.2,112.3,81.2,68.6,67.2,63.5,60.4,42.8,36.7,29.8,29.8,29.0,28.6,26.0,25.8,24.9,23.9,18.1.HRMS(ESI)calcd forC31H39NNaO8[M+Na]+576.2568,found 576.2573.
化合物27的合成：
将MMB(500mg,1.89mmol),PPh3(745mg,2.84mmol)和3-羟基肉桂酸(466mg,2.84mmol)放于反应瓶中，置换氩气，加入无水THF(10mL)溶解，冰水浴下搅拌加入DIAD(0.56mL,2.84mmol)，缓慢升温到室温，室温下搅拌4h，取样点板，反应基本完毕，加饱和氯化铵溶液淬灭反应，EA萃取三次，合并有机相饱和食盐水洗三次，干燥，过滤，浓缩硅胶柱层析纯化的白色固体化合物27(504mg,产率:65％)。1H NMR(400MHz,CDCl3)δ7.60(d,J＝16.0Hz,1H),7.21(t,J＝7.7Hz,1H),7.11(s,1H),7.01(d,J＝8.2Hz,2H),6.90(d,J＝8.4Hz,1H),6.35(d,J＝16.0Hz,1H),6.23(d,J＝3.0Hz,1H),5.71(t,J＝8.1Hz,1H),5.56(d,J＝2.6Hz,1H),4.74(d,J＝12.5Hz,1H),4.59(d,J＝12.5Hz,1H),3.89(s,1H),3.00(t,J＝9.4Hz,1H),2.89(d,J＝9.4Hz,1H),2.49–2.09(m,6H),1.67(t,J＝10.8Hz,1H),1.54(s,3H),1.10(t,J＝12.7Hz,1H).13C NMR(100MHz,CDCl3)δ170.2,167.0,156.7,145.7,138.7,135.5,134.9,131.0,130.2,120.9,120.6,118.1,117.5,114.6,81.5,67.3,63.4,60.4,42.8,36.6,25.9,24.8,23.9,18.0.HRMS(ESI)calcd for C24H26NaO6[M+Na]+433.1622,found 433.1625.
化合物28的合成：
制备方法同化合物16的制备，白色固体，产率:62％。1H NMR(400MHz,CDCl3)δ7.65(d,J＝15.9Hz,1H),7.55–7.28(m,16H),7.08(d,J＝7.3Hz,1H),7.00(s,1H),6.92(d,J＝7.9Hz,1H),6.40(d,J＝15.9Hz,1H),6.25(s,1H),5.74(t,J＝8.0Hz,1H),5.56(s,1H),4.79(d,J＝12.4Hz,1H),4.61(d,J＝12.4Hz,1H),3.89(dt,J＝18.8,7.4Hz,3H),2.97(t,J＝10.3Hz,1H),2.89(d,J＝9.2Hz,1H),2.53–2.14(m,6H),1.70(d,J＝6.7Hz,6H),1.56(s,3H),1.38–1.28(m,5H),1.16–1.10(m,2H).13C NMR(100MHz,CDCl3)δ169.5,169.5,166.7,159.6,145.8,138.9,135.6,135.2,131.0,130.9,130.1,129.2,128.2,120.8,120.5,117.7,117.2,113.7,81.2,68.1,67.0,63.5,60.1,42.9,36.8,32.1,29.8,29.1,28.9,26.0,25.8,24.7,24.0,22.8,18.2.HRMS(ESI)calcd for C50H53NNaO8[M+Na]+818.3663,found 818.3668.
化合物29的合成：
化合物29的制备方法同化合物17的制备方法，产率82％。1H NMR(400MHz,CDCl3)δ7.62(d,J＝15.6Hz,1H),7.26(s,1H),7.00(dd,J＝45.0,19.0Hz,3H),6.37(d,J＝15.6Hz,1H),6.23(s,1H),5.73(s,1H),5.55(s,1H),4.75(d,J＝12.2Hz,1H),4.61(d,J＝12.4Hz,1H),3.97–3.79(m,3H),3.01(s,1H),2.89(d,J＝8.8Hz,1H),2.54–2.10(m,8H),1.83–1.61(m,5H),1.54(s,3H),1.49–1.34(m,4H),1.11(t,J＝12.5Hz,1H).13C NMR(100MHz,CDCl3)δ169.7,166.7,159.6,145.7,138.9,135.5,135.1,131.1,130.1,121.0,120.5,117.7,117.3,113.5,81.3,68.0,67.3,63.4,60.2,42.9,36.7,32.9,29.8,29.0,28.8,26.0,25.7,25.3,25.0,24.0,18.1.HRMS(ESI)calcd for C31H39NNaO8[M+Na]+576.2568,found576.2574.
实施例2：倍半萜内酯—SAHA衍生物的药理作用
将各种癌细胞配成2×105/mL细胞悬液，加入24孔板圆底细胞培养板内，分别加入倍半萜内酯—SAHA衍生物，每一测试浓度5孔，置37℃、5％CO2饱和湿度条件下培养18小时，用MTT法在酶联检测仪570nm波长测得吸光度(A)值，计算出本发明化合物对测试癌细胞的抑制作用。
表1倍半萜内酯—SAHA衍生物对各种癌细胞的抑制活性(IC50，μM)
表2倍半萜内酯—SAHA衍生物对各种癌细胞的抑制活性(IC50，μM)
其中HL-60、HL-60/ADR分别表示急性白血病细胞株、人白血病细胞株耐阿霉素细胞系。SR，选择系数：IC50HL-60/IC50HL-60/ADR
活性测试结果表明，筛选的化合物对受试细胞显示出抑制活性。因此测试化合物具有用于治疗癌症的用途。
本发明的化合物、用途和方法已经通过具体的实施例进行了描述。本领域技术人员可以借鉴本发明的内容适当改变原料、工艺条件等环节来实现相应的其它目的，其相关改变都没有脱离本发明的内容，所有类似的替换和改动对于本领域技术人员来说是显而易见的，都被视为包括在本发明的范围之内。

Claims (2)

1.化合物，其特征在于所述的结构如下：
。
2.如权利要求1所述的化合物在制备治疗癌症的药物中的用途，其中癌症为白血病。
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