CN114805269B - 毛萼内酯素b衍生物与其在制备抗肿瘤药物中的应用 - Google Patents

毛萼内酯素b衍生物与其在制备抗肿瘤药物中的应用 Download PDF

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CN114805269B
CN114805269B CN202210370822.3A CN202210370822A CN114805269B CN 114805269 B CN114805269 B CN 114805269B CN 202210370822 A CN202210370822 A CN 202210370822A CN 114805269 B CN114805269 B CN 114805269B
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cancer
acetone
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普诺·白玛丹增
孙汉董
周元飞
颜秉超
杨谦
杜雪
胡坤
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Kunming Institute of Botany of CAS
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Abstract

本发明公开了毛萼内酯素B衍生物与其在制药中的应用。属于药物技术领域。本发明提供了毛萼内酯素B及其衍生物新的药用用途，可用于制备抗肿瘤药物。本发明化合物对人宫颈癌细胞株（Hela），卵巢癌细胞株（SK‑OV‑3），肝癌细胞株（SK‑HEP‑1），结肠癌株（CACO2），乳腺癌细胞株（MDA‑MB‑231），前列腺癌细胞株（PC‑3），结肠癌细胞株（SW480），人肺癌紫杉醇耐药株（A549/Taxol）等细胞均有较显著的抑制作用。提供毛萼内酯素B及其衍生物在细胞水平上抑制多种肿瘤细胞的生长，具有强细胞毒作用。

Description

毛萼内酯素B衍生物与其在制备抗肿瘤药物中的应用
技术领域
本发明属于药物技术领域，具体地，本发明涉及毛萼内酯素B衍生物与其药物组合物，它们的制备方法，及其在制药中的应用。
背景技术
肿瘤是人类健康的重要威胁，对映-贝壳杉烷型二萜被报道具有广泛的抗肿瘤活性。其中基于A环环系的改造及14位羟基的修饰是目前提升抗肿瘤活性的关键。国内外研究者将该类化合物A环、D环及C-14位羟基进行酯化衍生化(见ZL201611034438.7；ZL200710133915.X；ZL201010509348.5；ZL201110178862.X；ZL201310423035.1)。毛萼内酯素B衍生物的A环具有特殊的重排结构，该类型化合物在抗肿瘤用途方面尚未报道。
发明内容
本发明目的是提供毛萼内酯素B及其衍生物及其药物组合物与其制备方法，它们在制备抗肿瘤药物中的应用。本发明通过创造性的研究发现毛萼内酯素B及其衍生物对对宫颈癌细胞(Hela)，结肠癌细胞(CACO2)，人卵巢癌细胞(SK-OV-3)，人肝癌细胞(SK-HEP-1，高转移)，人结肠癌细胞(SW480)，人肺癌紫杉醇耐药株细胞(A549/Taxol)，前列腺癌细胞(PC-3)，乳腺癌细胞(MDA-MB-231)，L02(人正常肝细胞)具有潜在的治疗效果。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
如下结构式所示的毛萼内酯素B及其衍生物
其中R为以下官能团：
本发明同时提供了毛萼内酯素B衍生物的制备方法，该方法以毛萼内酯素B为起始原料，通过酯化反应得到毛萼内酯素B衍生物，
该方法包括如下步骤：氩气保护下，将毛萼内酯素B溶解在0.1～0.5mL的二氯甲烷中，加入EDCI及DMAP，将反应置于室温中反应1～12个小时，TLC检测反应完全后，饱和NaHCO3淬灭，EtOAc萃取，饱和食盐水洗涤、无水MgSO4干燥，过滤，浓缩后柱层析纯化或经过制备纯化，分离得到毛萼内酯素B衍生物。
本发明同时提供了毛萼内酯素B衍生物在制备抗肿瘤药物中的应用。
以及，毛萼内酯素B衍生物在制备宫颈癌、结肠癌、卵巢癌、肺癌、前列腺癌、乳腺癌、肝癌的药物中的应用。
本发明另外还提供了一种药物组合物，含有毛萼内酯素B或其衍生物任其一或任其组合及可药用载体。
所述的药物组合物的剂型为粉剂、颗粒剂、片剂、胶囊剂、丸剂、溶液、悬浮液或注射液。
此外，本发明还提供了所述的药物组合物的制备方法，先按上述制备毛萼内酯素B衍生物的方法，分离得到毛萼内酯素B衍生物，然后再加入可药用载体。
同时，本发明提供了所述的药物组合物在制备抗肿瘤药物中的应用。
以及，所述的药物组合物在制备宫颈癌、结肠癌、卵巢癌、肺癌、前列腺癌、乳腺癌、肝癌的药物中的应用。
本发明化合物用作药物时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有0.1-99％，优选0.5-90％的本发明化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体和/或赋形剂。
所述的药用载体或赋形剂是一种或多种固体、半固体和液体稀释剂、填料以及药物制品辅剂。将本发明的药物组合物以单位体重服用量的形式使用。本发明的药物可经多种形式(液体制剂、固体制剂、注射剂、外用制剂、喷剂、复方制剂)给药。
与现有技术相比，本发明具备如下的优益性：
1.本发明提供了一类新的毛萼内酯素B衍生物，填补了现有技术的空白。
2.本发明提供了制备毛萼内酯素B衍生物的方法，该方法原料易得，易于操作，收率高，适于工业化生产。
3.本发明提供了毛萼内酯素B衍生物作为有效成分的药物组合物，为新的抗肿瘤药物提供了具有较好药用作用的新的药物。
4.本发明的毛萼内酯素B衍生物对人宫颈癌细胞株(Hela)，卵巢癌细胞株(SK-OV-3)，肝癌细胞株(SK-HEP-1)，结肠癌株(CACO2)，乳腺癌细胞株(MDA-MB-231)，前列腺癌细胞株(PC-3)，结肠癌细胞株(SW480)，人肺癌紫杉醇耐药株(A549/Taxol)都有较好的抑制效果。
5.毛萼内酯素B衍生物可作为药物用于治疗相关的疾病。可用于制备抗肿瘤药物，用于制备宫颈癌、结肠癌、卵巢癌、肺癌、前列腺癌、乳腺癌、肝癌的药物。
附图说明
图1毛萼内酯素B及其衍生物的IC50示意图；
图2毛萼内酯素B衍生物结构示意图。
具体实施方式
下面结合附图，用本发明的实施例来对本发明作进一步的说明，但不以任何方式对本发明加以限制，基于本发明教导所作的任何变换或改进，均落入本发明的保护范围
实施例1
1.先制备毛萼内酯素B：
制备中间体L：将化合物K溶解在(1～100mL)的丙酮中，在0℃冰浴条件下添加琼斯试剂(10mL)反应15分钟，使用TLC检测反应完全后，使用异丙醇淬灭，加水稀释后EtOAc萃取，饱和食盐水洗涤，无水MgSO4干燥，过滤，浓缩后柱层析纯化，得到无定型固体化合物L，经质谱、一维和二维核磁共振鉴定化合物为中间体L。
制备中间体M：将化合物L溶解在(1～100mL)的1，2-二氯乙烷中，在0℃冰浴条件下加入NaBH(OAc)3(1～50g)后随后缓慢滴加乙酸(0.1～1mL)反应10分钟，使用TLC检测反应完全后，使用丙酮淬灭，加水稀释后EtOAc萃取，饱和食盐水洗涤，无水MgSO4干燥，过滤，浓缩后柱层析纯化，得到无定型固体化合物，经质谱、一维和二维核磁共振鉴定化合物为中间体M。
制备中间体N：将化合物M溶解在(1～100mL)的二氯甲烷中，在0℃冰浴条件下依次添加DIPEA(1～50mL)以及TMSCl(1～50mL)，在冰浴条件下反应30分钟后减压浓缩。浓缩后产品溶解于乙腈，后依次添加DBU(1～50mL)和对甲苯磺酰叠氮(1～50mL)反应2小时后滴加TBAF(1～50g)反应30分钟，使用TLC检测反应完全后，加水稀释加EtOAc萃取，饱和食盐水洗涤，无水MgSO4干燥，过滤，浓缩后柱层析纯化，得到无定型固体化合物，经质谱、一维和二维核磁共振鉴定化合物为中间体N。
制备中间体O：将化合物N溶解在(1～100mL)的二氯甲烷中，在0℃冰浴条件下依次添加NaHCO3(1～10g)以及戴斯-马丁试剂(1～10g)，在冰浴条件下反应10分钟，使用TLC检测反应完全后，使用Na2O3S2淬灭，加水稀释加EtOAc萃取，饱和食盐水、洗涤，无水MgSO4干燥，过滤，浓缩后柱层析纯化，得到无定型固体化合物，经质谱、一维和二维核磁共振鉴定化合物为中间体O。
制备毛萼内酯素B：将化合物O溶解于(1～50mL)甲苯中，放置于110℃加热搅拌下充分反应两个小时。TLC检测反应完全后，将反应挪到室温，待冷却后，直接减压浓缩，浓缩后柱层析纯化，得到无定型白色固体化合物，经质谱、一维和二维核磁共振鉴定化合物为毛萼内酯素B。
2.制备毛萼内酯素B衍生物：
氩气保护下，将毛萼内酯素B(10～20mg)溶解在(0.1～0.5mL)的二氯甲烷中，加入EDCI(10～50mg)及DMAP(10～50mg)，将反应置于室温中反应1～12个小时，TLC检测反应完全后，饱和NaHCO3淬灭，EtOAc萃取，饱和食盐水洗涤、无水MgSO4干燥，过滤，浓缩后柱层析纯化或经过制备纯化，得到化合物经质谱、一维共振鉴定的衍生物1-63。
实施例2
毛萼内酯素B衍生物核磁、质谱数据：
Data for 1:1H NMR(600MHz,Acetone-d6)δ＝6.09(s,1H),5.67(s,1H),5.59(s,1H),4.93(d,J＝10.8,1H),4.87(d,J＝10.8,1H),4.52(dt,J＝14.3,3.6,1H),4.06(d,J＝3.7,1H),2.88(dd,J＝11.7,3.3,1H),2.49(dd,J＝9.2,2.6,1H),2.48–2.41(m,1H),2.23(dd,J＝13.8,11.8,1H),2.20–2.15(m,1H),2.11(t,J＝7.4,1H),1.99–1.92(m,2H),1.90(dd,J＝13.9,3.3,1H),1.82–1.73(m,1H),1.68–1.62(m,1H),1.49(q,J＝7.4,2H),1.24(s,3H),1.21(s,3H),0.86(t,J＝7.4,3H)；HRESIMS(m/z):[M+Na]+calcd for C24H30O7Na+430.1884,found 430.1892.
Data for 2:1H NMR(600MHz,Acetone-d6)δ＝6.09(s,1H),5.68(d,J＝1.4,1H),5.59(d,J＝1.3,1H),5.49(s,1H),4.96(d,J＝10.8,1H),4.91(d,J＝10.8,1H),4.58(dt,J＝14.2,3.7,1H),4.02(d,J＝3.6,1H),3.33(s,1H),2.88(dd,J＝11.7,3.3,1H),2.48(dd,J＝9.3,2.3,1H),2.47–2.41(m,1H),2.24(dd,J＝13.9,11.7,1H),2.05(s,3H),1.99–1.95(m,1H),1.92(s,1H),1.90(dd,J＝13.8,3.4,1H),1.87(s,3H),1.78(s,1H),1.66(s,1H),1.25(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C25H30O7Na+465.1884,found465.1889.
Data for 3:1H NMR(600MHz,Acetone-d6)δ＝6.09(s,1H),5.67(d,J＝1.4,1H),5.59(s,1H),4.93(d,J＝10.8,1H),4.87(d,J＝10.8,1H),4.52(dt,J＝14.3,3.7,1H),4.04(d,J＝3.7,1H),2.88(dd,J＝11.7,3.3,1H),2.49(dd,J＝9.1,2.6,1H),2.47–2.40(m,1H),2.27–2.09(m,3H),1.99–1.93(m,2H),1.90(dd,J＝13.9,3.3,1H),1.82–1.73(m,1H),1.69–1.61(m,1H),1.51–1.44(m,2H),1.32–1.25(m,8H),1.24(s,3H),1.21(s,3H),0.87(t,J＝7.0,3H)；HRESIMS(m/z):[M+Na]+calcd for C28H38O7Na+509.2510,found 509.2516.
Data for 4:1H NMR(600MHz,Acetone-d6)δ＝6.09(s,1H),5.67(s,1H),5.60(s,1H),4.93(d,J＝10.8,1H),4.87(d,J＝10.8,1H),4.52(dt,J＝14.3,3.5,1H),4.06(d,J＝3.6,1H),3.33(s,1H),2.89(dd,J＝11.5,3.1,1H),2.49(dd,J＝9.2,2.5,1H),2.45–2.39(m,1H),2.26–2.08(m,3H),1.98–1.93(m,2H),1.90(dd,J＝13.9,3.2,1H),1.82–1.73(m,1H),1.68–1.60(m,1H),1.51–1.43(m,2H),1.33–1.24(m,10H),1.24(s,3H),1.21(s,3H),0.90–0.85(m,3H)；HRESIMS(m/z):[M+Na]+calcd for C29H40O7Na+523.2666,found523.2658.
Data for 5:1H NMR(600MHz,Acetone-d6)δ＝6.10(s,1H),5.63(d,J＝1.4,1H),5.61(t,J＝1.0,1H),4.91(d,J＝10.9,1H),4.86(d,J＝10.8,1H),4.52(dd,J＝14.3,3.6,1H),4.11(d,J＝3.5,1H),3.35(s,1H),2.89–2.88(m,1H),2.48(dd,J＝9.3,2.4,1H),2.46–2.39(m,1H),2.23(dd,J＝13.9,11.8,1H),1.99–1.95(m,1H),1.93(d,J＝14.2,1H),1.89(dd,J＝13.8,3.3,1H),1.82–1.72(m,1H),1.67–1.60(m,1H),1.51–1.43(m,1H),1.23(s,3H),1.20(s,3H),0.86–0.79(m,3H),0.76(dt,J＝8.8,4.5,1H)；HRESIMS(m/z):[M+K]+calcd for C24H28O7K+467.1467,found 467.1463.
Data for 6:1H NMR(600MHz,Acetone-d6)δ＝6.08(s,1H),5.64(d,J＝1.4,1H),5.59(s,1H),4.94(d,J＝10.8,1H),4.88(d,J＝10.8,1H),4.56(dd,J＝14.3,3.7,1H),4.13(dd,J＝3.6,1.0,1H),3.32(s,1H),3.02–2.96(m,1H),2.89–2.88(m,1H),2.49(dd,J＝9.2,2.5,1H),2.47–2.40(m,1H),2.23(dd,J＝13.8,11.7,1H),2.13–2.09(m,4H),1.98–1.93(m,2H),1.92–1.87(m,2H),1.84–1.73(m,2H),1.68–1.61(m,1H),1.24(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C25H30O7Na+465.1884,found 465.1882.
Data for 7:1H NMR(600MHz,Acetone-d6)δ＝6.11–6.08(m,1H),5.63(d,J＝1.4,1H),5.59(t,J＝1.0,1H),4.93(d,J＝10.8,1H),4.88(d,J＝10.8,1H),4.54(dd,J＝14.3,3.7,1H),4.06(d,J＝3.7,1H),3.36–3.30(m,1H),2.88(dd,J＝11.7,3.3,1H),2.60–2.56(m,1H),2.49(dd,J＝9.2,2.5,1H),2.47–2.39(m,1H),2.23(dd,J＝13.9,11.7,1H),2.00–1.92(m,2H),1.90(dd,J＝13.9,3.3,1H),1.83–1.70(m,3H),1.70–1.62(m,3H),1.62–1.55(m,2H),1.55–1.47(m,2H),1.24(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd forC26H32O7Na+479.2040,found479.2042.
Data for 8:HRESIMS(m/z):1H NMR(600MHz,Acetone-d6)δ＝6.62(q,J＝2.3,1H),6.10(s,1H),5.67(d,J＝1.4,1H),5.60(s,1H),4.97(d,J＝10.8,1H),4.90(d,J＝10.8,1H),4.58(dd,J＝14.2,3.7,1H),4.06(d,J＝3.7,1H),3.38(d,J＝3.9,1H),2.89(dd,J＝11.7,3.4,1H),2.50(dd,J＝9.1,2.4,1H),2.48–2.36(m,5H),2.24(dd,J＝13.9,11.7,1H),2.00–1.93(m,2H),1.93–1.86(m,3H),1.83–1.74(m,1H),1.66(s,1H),1.25(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C26H30O7Na+477.1884,found 477.1888.
Data for 9:1HNMR(600MHz,Acetone-d6)δ＝6.10(s,1H),5.67(d,J＝1.4,1H),5.61(s,1H),4.93(d,J＝10.8,1H),4.86(d,J＝10.8,1H),4.55(dd,J＝14.3,3.7,1H),4.25(dd,J＝8.7,4.1,1H),4.17(d,J＝3.6,1H),3.82–3.75(m,2H),3.38–3.32(m,1H),2.89(dd,J＝11.7,3.4,1H),2.51(dd,J＝9.1,2.7,1H),2.48–2.40(m,1H),2.24(dd,J＝13.9,11.7,1H),2.13–2.09(m,1H),1.99–1.93(m,2H),1.93–1.84(m,3H),1.84–1.74(m,2H),1.69–1.63(m,1H),1.24(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C25H30O8Na+481.1833,found 481.1842.
Data for 10:1H NMR(600MHz,Acetone-d6)δ＝7.81(d,J＝1.8,1H),7.10(d,J＝3.5,1H),6.65–6.59(m,1H),6.14(s,1H),5.85(s,1H),5.65(s,1H),4.98(d,J＝10.8,1H),4.92(d,J＝10.8,1H),4.62(dd,J＝14.2,3.4,1H),4.14(d,J＝3.6,1H),3.49(d,J＝3.9,1H),2.91(dd,J＝11.7,3.3,1H),2.55(dd,J＝9.1,2.7,1H),2.53–2.46(m,1H),2.25(dd,J＝13.9,11.7,1H),2.02–1.96(m,2H),1.92(dd,J＝13.9,3.3,1H),1.86–1.77(m,1H),1.73–1.67(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C25H26O8Na+477.1520,found 477.1524.
Data for 11:1H NMR(600MHz,Acetone-d6)δ＝7.86(dd,J＝5.0,1.3,1H),7.66(dd,J＝3.8,1.3,1H),7.18(dd,J＝5.0,3.7,1H),6.15(s,1H),5.85(d,J＝1.4,1H),5.66(s,1H),5.00(d,J＝10.8,1H),4.93(d,J＝10.8,1H),4.64(dd,J＝14.2,3.5,1H),4.13(s,1H),3.51(s,1H),2.91(dd,J＝11.7,3.4,1H),2.56(dd,J＝9.1,2.7,1H),2.54–2.46(m,1H),2.25(dd,J＝13.9,11.7,1H),2.03–1.97(m,2H),1.92(dd,J＝13.9,3.4,1H),1.87–1.77(m,1H),1.73–1.67(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcdfor C25H26O7SNa+493.1291,found 493.1289.
Data for 12:1H NMR(600MHz,Acetone-d6)δ＝7.05(s,1H),6.71(s,1H),6.18(s,1H),6.12(s,1H),5.79(d,J＝1.4,1H),5.61(d,J＝1.0,1H),4.99(d,J＝10.8,1H),4.95(d,J＝10.8,1H),4.64(dd,J＝14.2,3.6,1H),4.07(d,J＝3.6,1.1,1H),3.44(d,J＝3.9,1H),2.90(dd,J＝11.7,3.3,1H),2.52(dd,J＝9.3,2.4,1H),2.50–2.44(m,1H),2.25(dd,J＝13.9,11.7,1H),2.02–1.93(m,2H),1.91(dd,J＝13.9,3.4,1H),1.85–1.77(m,1H),1.70–1.65(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C25H27NO7Na+476.1680,found 476.1677.
Data for 13:1H NMR(600MHz,Acetone-d6)δ＝8.40(d,J＝2.1,1H),7.72(d,J＝2.0,1H),6.16(s,1H),5.92(s,1H),5.67(s,1H),4.97(d,J＝10.8,1H),4.90(d,J＝10.8,1H),4.60(dd,J＝14.2,3.7,1H),4.19(d,J＝3.6,1H),3.52(s,1H),2.92(dd,J＝11.7,3.3,1H),2.58(dd,J＝9.2,3.0,1H),2.56–2.48(m,1H),2.25(dd,J＝13.9,11.7,1H),2.00(dd,J＝12.4,8.1,2H),1.93–1.90(m,1H),1.86–1.78(m,1H),1.75–1.68(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C24H25NO8Na+456.1653,found 456.1654.
Data for 14:1H NMR(600MHz,Acetone-d6)δ＝9.25(s,1H),8.34(s,1H),6.16(s,1H),5.90(s,1H),5.67(s,1H),4.98(d,J＝10.8,1H),4.91(d,J＝10.9,1H),4.62(dd,J＝14.2,3.6,1H),4.20(d,J＝3.7,1H),3.54(d,J＝3.9,1H),2.92(dd,J＝11.7,3.4,1H),2.58(dd,J＝9.0,2.9,1H),2.55–2.48(m,1H),2.26(dd,J＝13.8,11.8,1H),2.03–1.99(m,2H),1.92(dd,J＝13.8,3.3,1H),1.86–1.78(m,1H),1.71(ddt,J＝15.7,6.6,3.0,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C24H25NO7SNa+472.1424,found472.1428.
Data for 15:1H NMR(600MHz,Acetone-d6)δ＝9.50(s,1H),6.16(s,1H),6.02(d,J＝1.4,1H),5.68(d,J＝1.2,1H),5.00(d,J＝10.8,1H),4.94(d,J＝10.8,1H),4.65(dd,J＝14.2,3.5,1H),4.22(d,J＝3.6,1H),3.60–3.58(m,1H),2.93(dd,J＝11.7,3.4,1H),2.62–2.60(m,1H),2.59–2.52(m,1H),2.26(dd,J＝13.8,11.7,1H),2.04–2.01(m,2H),1.93(dd,J＝13.9,3.4,1H),1.88–1.81(m,1H),1.77–1.71(m,1H),1.26(s,3H),1.23(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C23H24N2O7SNa+495.1196,found 495.1198.
Data for 16:1H NMR(600MHz,Acetone-d6)δ＝6.09(s,1H),5.63(s,1H),5.59(s,1H),4.93(d,J＝10.8,1H),4.88(d,J＝10.8,1H),4.53(dd,J＝14.3,3.4,1H),4.08(d,J＝3.6,1H),3.32(d,J＝4.1,1H),2.88(dd,J＝11.7,3.3,1H),2.80(s,1H),2.48(dd,J＝9.2,2.4,1H),2.47–2.40(m,1H),2.23(dd,J＝13.9,11.7,1H),2.16–2.10(m,1H),1.99–1.92(m,2H),1.90(dd,J＝13.9,3.3,1H),1.82–1.72(m,3H),1.65(s,3H),1.61–1.55(m,1H),1.31–1.24(m,3H),1.24(s,3H),1.21(s,3H),1.20–1.13(m,1H)；HRESIMS(m/z):[M–H]–calcd forC27H33O7 –469.2232,found 469.2233.
Data for 17:1H NMR(600MHz,Acetone-d6)δ＝6.82–6.77(m,1H),6.10(s,1H),5.67(d,J＝1.4,1H),5.60(s,1H),4.97(d,J＝10.8,1H),4.90(d,J＝10.8,1H),4.58(dd,J＝14.3,3.7,1H),4.06(d,J＝3.7,1H),3.38(d,J＝4.1,1H),2.88(dd,J＝11.7,3.4,1H),2.50(dd,J＝9.2,2.3,1H),2.47–2.41(m,1H),2.24(dd,J＝13.9,11.7,1H),2.17–2.12(m,2H),2.08–2.06(m,2H),2.00–1.93(m,2H),1.90(dd,J＝13.9,3.4,1H),1.83–1.74(m,1H),1.69–1.62(m,1H),1.61–1.51(m,4H),1.25(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C27H32O7Na+491.2040,found 491.2041.
Data for 18:1H NMR(600MHz,Acetone-d6)δ＝7.86–7.82(m,2H),7.66–7.62(m,1H),7.51–7.47(m,2H),6.16(s,1H),5.90(d,J＝1.5,1H),5.66(s,1H),5.02(d,J＝10.8,1H),4.96(d,J＝10.8,1H),4.65(dt,J＝14.3,3.7,1H),4.14(d,J＝3.5,1H),3.53(s,1H),2.92(dd,J＝11.7,3.4,1H),2.57(dd,J＝9.1,2.5,1H),2.55–2.48(m,1H),2.26(dd,J＝13.8,11.8,1H),2.00(d,J＝14.3,2H),1.92(dd,J＝13.9,3.3,1H),1.88–1.79(m,1H),1.74–1.68(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C27H28O7Na+478.1727,found 478.1726.
Data for 19:1H NMR(800MHz,Acetone-d6)δ＝88.80–8.76(m,2H),7.69–7.65(m,2H),6.18(s,1H),5.95(d,J＝1.4,1H),5.68(d,J＝1.0,1H),5.00(d,J＝10.7,1H),4.94(d,J＝10.7,1H),4.63(dd,J＝14.2,3.6,1H),4.21(d,J＝3.6,1H),3.57(dt,J＝4.8,2.3,1H),2.93(dd,J＝11.7,3.4,1H),2.60(dd,J＝9.3,3.0,1H),2.56–2.50(m,1H),2.26(dd,J＝13.9,11.8,1H),2.04–2.02(m,2H),1.93(dd,J＝13.9,3.4,1H),1.85–1.84(m,1H),1.74–1.72(m,1H),1.26(s,3H),1.23(s,3H)；HRESIMS(m/z):[M+H]+calcd for C26H28NO7+466.1860,found 466.1863.
Data for 20:1H NMR(800MHz,Acetone-d6)δ＝9.01(d,J＝1.5,1H),8.84(d,J＝2.4,1H),8.75(dd,J＝2.3,1.5,1H),6.18(s,1H),6.00(d,J＝1.4,1H),5.69(s,1H),5.00(d,J＝10.7,1H),4.95(d,J＝10.8,1H),4.64(dd,J＝14.2,3.6,1H),4.24(d,J＝3.5,1H),3.58(d,J＝3.1,1H),2.93(dd,J＝11.8,3.4,1H),2.61(d,J＝7.7,1H),2.57–2.52(m,1H),2.27(dd,J＝13.9,11.8,1H),2.04–2.02(m,2H),1.93(dd,J＝13.9,3.4,1H),1.87–1.82(m,1H),1.76–1.72(m,1H),1.26(s,3H),1.23(s,3H)；HRESIMS(m/z):[M+H]+calcd forC25H27N2O7 +467.1813,found 467.1815.
Data for 21:1H NMR(800MHz,Acetone-d6)δ＝9.35(s,1H),9.06(s,2H),6.19–6.17(m,1H),5.98(d,J＝1.4,1H),5.68(d,J＝1.0,1H),4.99(d,J＝10.7,1H),4.93(d,J＝10.7,1H),4.64–4.61(m,1H),4.27(s,1H),3.60(s,1H),2.93(dd,J＝11.8,3.4,1H),2.61(d,J＝5.8,1H),2.56–2.51(m,1H),2.26(dd,J＝13.9,11.7,1H),2.04–2.01(m,2H),1.92(dd,J＝13.9,3.4,1H),1.87–1.81(m,1H),1.75–1.71(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+H]+calcd for C25H27N2O7 +467.1813,found 467.1817.
Data for 22:1H NMR(600MHz,Acetone-d6)δ＝7.96–7.84(m,2H),7.34–7.18(m,2H),6.16(s,1H),5.88(s,1H),5.66(s,1H),5.01(d,J＝10.8,1H),4.95(d,J＝10.7,1H),4.68–4.58(m,1H),4.17(d,J＝3.7,1H),3.53(s,1H),2.98(s,1H),2.57(dd,J＝9.2,2.6,1H),2.54–2.46(m,1H),2.25(dd,J＝13.9,11.8,1H),2.00(d,J＝14.3,2H),1.91(dd,J＝13.8,3.3,1H),1.88–1.76(m,1H),1.75–1.66(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C27H27FO7Na+505.1633,found 505.1632.
Data for 23:1H NMR(600MHz,Acetone-d6)δ＝7.85–7.80(m,2H),7.57–7.52(m,2H),6.16(s,1H),5.90(d,J＝1.4,1H),5.66(s,1H),5.01(d,J＝10.8,1H),4.94(d,J＝10.8,1H),4.64(d,J＝14.2,1H),4.19(s,1H),3.53(s,1H),2.94–2.92(m,1H),2.57(dd,J＝9.1,2.6,1H),2.54–2.48(m,1H),2.25(dd,J＝13.9,11.7,1H),2.03–1.98(m,2H),1.91(dd,J＝13.9,3.3,1H),1.87–1.79(m,1H),1.74–1.68(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd for C27H26ClO7 –497.1373,found 497.1372.
Data for 24:1H NMR(600MHz,Acetone-d6)δ＝7.78–7.73(m,2H),7.73–7.68(m,2H),6.16(s,1H),5.90(s,1H),5.66(s,1H),5.00(d,J＝10.8,1H),4.94(d,J＝10.8,1H),4.63(dd,J＝14.2,3.6,1H),4.16(d,J＝3.6,1H),3.53(s,1H),2.92(dd,J＝11.8,3.3,1H),2.57(dd,J＝9.1,2.6,1H),2.55–2.48(m,1H),2.25(dd,J＝13.9,11.8,1H),2.03–1.98(m,2H),1.92(dd,J＝13.9,3.3,1H),1.87–1.79(m,1H),1.74–1.68(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C27H27BrO7Na+565.0832,found 565.0826.
Data for 25:1H NMR(600MHz,Acetone-d6)δ＝8.02(d,J＝8.1,2H),7.86(d,J＝8.1,2H),6.16(s,1H),5.94(s,1H),5.67(s,1H),5.00(d,J＝10.7,1H),4.94(d,J＝10.8,1H),4.63(dt,J＝14.3,3.5,1H),4.19(d,J＝3.5,1H),3.56(d,J＝3.8,1H),2.92(dd,J＝11.8,3.3,1H),2.58(d,J＝8.6,1H),2.55–2.50(m,1H),2.25(dd,J＝13.8,11.8,1H),2.03–1.99(m,2H),1.91(dd,J＝14.0,3.3,1H),1.86–1.80(m,1H),1.74–1.69(m,1H),1.25(s,3H),1.21(s,3H)；HRESIMS(m/z):[M–H]–calcd for C27H26NO9 –508.1613,found 508.1613.
Data for 26:1H NMR(600MHz,Acetone-d6)δ＝7.80–7.77(m,2H),7.02–6.98(m,2H),6.15(s,1H),5.84(d,J＝1.4,1H),5.65(s,1H),5.02(d,J＝10.8,1H),4.96(d,J＝10.8,1H),4.65(dd,J＝14.2,3.3,1H),4.12(d,J＝3.5,1H),3.87(s,3H),3.50(d,J＝3.9,1H),2.91(dd,J＝11.7,3.3,1H),2.55(dd,J＝9.2,2.3,1H),2.53–2.47(m,1H),2.25(dd,J＝13.9,11.8,1H),2.03–1.96(m,2H),1.91(dd,J＝13.9,3.3,1H),1.86–1.78(m,1H),1.72–1.67(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd for C28H29O8 –493.1868,found 493.1865.
Data for 27:1H NMR(600MHz,Acetone-d6)δ＝7.72(d,J＝7.9,2H),7.30(d,J＝7.9,2H),6.16(s,1H),5.87(s,1H),5.65(d,J＝1.3,1H),5.02(d,J＝10.8,1H),4.96(d,J＝10.8,1H),4.65(dd,J＝14.3,3.3,1H),4.14(d,J＝3.5,1H),3.51(d,J＝3.8,1H),2.92(dd,J＝11.8,3.2,1H),2.56(dd,J＝9.1,2.3,1H),2.54–2.48(m,1H),2.39(s,3H),2.25(dd,J＝13.8,11.8,1H),2.03–1.97(m,2H),1.92(dd,J＝13.9,3.3,1H),1.86–1.80(m,1H),1.73–1.68(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd for C28H29O7 –477.1919,found 477.1919.
Data for 28:1H NMR(600MHz,Acetone-d6)δ＝8.38–8.34(m,2H),8.10–8.05(m,2H),6.18(s,1H),5.97(s,1H),5.69(s,1H),5.01(d,J＝10.8,1H),4.94(d,J＝10.8,1H),4.64(dt,J＝14.2,3.7,1H),4.22(d,J＝3.7,1H),3.59(d,J＝3.8,1H),2.93(dd,J＝11.7,3.3,1H),2.60–2.59(m,1H),2.57–2.50(m,1H),2.26(dd,J＝13.9,11.8,1H),2.03–2.00(m,2H),1.92(dd,J＝13.9,3.3,1H),1.88–1.80(m,1H),1.76–1.70(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd for C28H26F3O7 –531.1636,found 531.1629.
Data for 29:1H NMR(800MHz,Acetone-d6)δ＝8.43(d,J＝5.1,1H),7.63(dt,J＝5.1,1.5,1H),7.34(s,1H),6.18(s,1H),5.96(d,J＝1.4,1H),5.68(d,J＝1.0,1H),4.99(d,J＝10.8,1H),4.92(d,J＝10.7,1H),4.63–4.60(m,1H),4.24(d,J＝3.6,1H),3.58(s,1H),2.93(dd,J＝11.8,3.4,1H),2.62–2.60(m,1H),2.55–2.51(m,1H),2.26(dd,J＝13.9,11.7,1H),2.04–2.00(m,2H),1.92(dd,J＝13.9,3.4,1H),1.87–1.81(m,1H),1.76–1.71(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd for C26H25FNO7 –482.1621,found482.1623.
Data for 30:1H NMR(800MHz,Acetone-d6)δ＝8.66(d,J＝2.3,1H),8.58(d,J＝4.8,1H),7.62(dd,J＝6.1,4.9,1H),6.15(s,1H),5.99(d,J＝1.5,1H),5.67(d,J＝1.0,1H),4.98(d,J＝10.7,1H),4.91(d,J＝10.7,1H),4.60(dd,J＝14.2,3.6,1H),4.23(d,J＝3.7,1H),3.54(s,1H),2.93(dd,J＝11.7,3.4,1H),2.60–2.58(m,1H),2.56–2.50(m,1H),2.26(dd,J＝13.9,11.8,1H),2.01(dd,J＝7.5,3.5,2H),1.92(dd,J＝13.9,3.4,1H),1.86–1.80(m,1H),1.76–1.71(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd forC26H25FNO7 –482.1621,found 482.1624.
Data for 31:1H NMR(600MHz,Acetone-d6)δ＝8.60(d,J＝5.0,1H),7.68(dd,J＝6.6,1.5,2H),6.18(s,1H),5.96(d,J＝1.5,1H),5.68(s,1H),5.62(d,J＝1.7,1H),4.98(d,J＝10.8,1H),4.91(d,J＝10.8,1H),4.61(dd,J＝14.2,3.4,1H),4.25(d,J＝3.6,1H),3.58(t,J＝3.7,1H),2.93(dd,J＝11.7,3.3,1H),2.64–2.59(m,1H),2.57–2.48(m,1H),2.26(dd,J＝13.9,11.7,1H),2.03–1.99(m,1H),1.92(dd,J＝13.8,3.3,1H),1.84(ddt,J＝16.4,8.6,4.5,1H),1.73(ddt,J＝15.8,6.6,3.0,1H),1.25(s,3H),1.22(d,J＝2.7,3H)；HRESIMS(m/z):[M–H]–calcd for C26H25ClNO7 –498.1325,found 498.1325.
Data for 32:1H NMR(600MHz,Acetone-d6)δ＝8.71(s,1H),8.65(d,J＝4.9,1H),7.57(d,J＝4.9,1H),6.13(s,1H),6.00(s,1H),5.65(s,1H),4.99(d,J＝10.8,1H),4.93(d,J＝10.8,1H),4.61(dd,J＝14.2,3.5,1H),4.30(dt,J＝3.4,1.6,1H),3.54(d,J＝4.1,1H),2.93(dd,J＝11.8,3.3,1H),2.62–2.58(m,1H),2.57–2.51(m,1H),2.25(dd,J＝13.8,11.7,1H),2.03–1.98(m,2H),1.91(dd,J＝13.8,3.3,1H),1.86–1.79(m,1H),1.76–1.70(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd for C26H25ClNO7 –498.1325,found498.1324.
Data for 33:1HNMR(600MHz,Acetone-d6)δ＝8.84(d,J＝2.4,1H),8.68(dd,J＝5.4,2.3,1H),7.55(d,J＝4.7,1H),6.13(s,1H),6.00(s,1H),5.65(d,J＝2.5,1H),4.99(dd,J＝10.8,2.4,1H),4.94(dd,J＝10.8,2.5,1H),4.64–4.57(m,1H),4.34(s,1H),3.54(s,1H),2.95–2.92(m,1H),2.60(d,J＝7.9,1H),2.57–2.51(m,1H),2.29–2.21(m,1H),2.02–1.97(m,2H),1.91(dd,J＝13.8,3.2,1H),1.86–1.77(m,1H),1.75–1.69(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+K]+calcd for C26H26BrNO7K+582.0524,found582.0528.
Data for 34:1H NMR(600MHz,Acetone-d6)δ＝8.58(d,J＝5.0,1H),7.82(d,J＝1.4,1H),7.70(dd,J＝5.0,1.3,1H),6.17(s,1H),5.94(s,1H),5.68(s,1H),4.98(d,J＝10.8,1H),4.91(d,J＝10.8,1H),4.60(dd,J＝14.3,3.2,1H),4.31(d,J＝3.4,1H),3.58–3.55(m,1H),2.95–2.92(m,1H),2.60–2.59(m,1H),2.55–2.48(m,1H),2.28–2.22(m,1H),2.03–1.99(m,2H),1.90(dd,J＝13.9,3.3,1H),1.85–1.79(m,1H),1.74–1.68(m,1H),1.23(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+K]+calcd for C26H26BrNO7K+582.0524,found582.0527.
Data for 35:1H NMR(600MHz,Acetone-d6)δ＝7.29–7.25(m,2H),7.21–7.17(m,3H),6.09(s,1H),5.67(d,J＝1.4,1H),5.58(s,1H),4.92(d,J＝10.8,1H),4.86(d,J＝10.8,1H),4.51(dd,J＝14.3,3.5,1H),4.07(d,J＝3.5,1H),3.28(d,J＝4.1,1H),2.91–2.88(m,1H),2.82–2.79(m,2H),2.57–2.45(m,3H),2.45–2.40(m,1H),2.23(dd,J＝13.8,11.7,1H),1.98–1.92(m,2H),1.90(dd,J＝13.9,3.3,1H),1.81–1.73(m,1H),1.67–1.62(m,1H),1.24(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C29H32O7Na+515.2046,found 515.2040.
Data for 36:1H NMR(600MHz,Acetone-d6)δ＝7.70–7.64(m,2H),7.58(d,J＝16.0,1H),7.44(dd,J＝5.1,1.9,3H),6.41(d,J＝16.0,1H),6.14(s,1H),5.79(d,J＝1.4,1H),5.64(d,J＝1.0,1H),4.98(d,J＝10.8,1H),4.93(d,J＝10.8,1H),4.61(dd,J＝14.3,3.5,1H),4.13(d,J＝3.5,1H),3.45–3.40(m,1H),2.90(dd,J＝11.7,3.3,1H),2.53(dd,J＝9.2,2.6,1H),2.51–2.45(m,1H),2.25(dd,J＝13.9,11.7,1H),2.02–1.95(m,2H),1.91(dd,J＝13.8,3.4,1H),1.85–1.77(m,1H),1.71–1.65(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C29H30O7Na+513.1893,found 513.1884.
Data for 37:1HNMR(600MHz,Acetone-d6)δ＝7.52–7.49(m,1H),7.45–7.36(m,5H),6.14(s,1H),5.77(d,J＝1.4,1H),5.66–5.62(m,1H),5.00(d,J＝10.8,1H),4.94(d,J＝10.8,1H),4.63(dd,J＝14.2,3.6,1H),4.16(d,J＝3.7,1H),3.47(d,J＝3.9,1H),2.92(d,J＝3.4,1H),2.54(dd,J＝9.1,2.4,1H),2.51–2.45(m,1H),2.25(dd,J＝13.8,11.8,1H),2.02–1.99(m,2H),1.99–1.98(m,3H),1.92(dd,J＝13.9,3.4,1H),1.86–1.77(m,1H),1.72–1.66(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C30H32O7Na+527.2040,found 527.2049.
Data for 38:1H NMR(600MHz,Acetone-d6)δ＝7.81–7.74(m,2H),7.57(d,J＝16.0,1H),7.21(t,J＝8.7,2H),6.37(d,J＝16.0,1H),6.13(s,1H),5.79(s,1H),5.64(s,1H),4.97(d,J＝10.8,1H),4.93(d,J＝10.8,1H),4.60(dd,J＝14.3,3.3,1H),4.12(d,J＝3.6,1H),3.42(s,1H),2.91(d,J＝3.3,1H),2.53(dd,J＝9.2,2.6,1H),2.51–2.44(m,1H),2.25(dd,J＝13.8,11.8,1H),2.01–1.95(m,2H),1.91(dd,J＝13.9,3.3,1H),1.85–1.76(m,1H),1.71–1.65(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd forC29H29FO7Na+531.1790,found 531.1793.
Data for 39:1HNMR(600MHz,Acetone-d6)δ＝7.72(d,J＝8.4,2H),7.56(d,J＝16.0,1H),7.50–7.43(m,2H),6.43(d,J＝16.0,1H),6.13(s,1H),5.79(d,J＝1.4,1H),5.64(s,1H),4.97(d,J＝10.8,1H),4.92(d,J＝10.8,1H),4.60(dd,J＝14.3,3.2,1H),4.13(d,J＝3.6,1H),3.42(d,J＝4.1,1H),2.92–2.90(m,1H),2.53(dd,J＝9.1,2.6,1H),2.51–2.44(m,1H),2.25(dd,J＝13.9,11.8,1H),2.01–1.95(m,2H),1.91(dd,J＝13.9,3.3,1H),1.84–1.77(m,1H),1.71–1.65(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcdfor C29H29ClO7Na+547.1494,found 547.1499.
Data for 40:1H NMR(600MHz,Acetone-d6)δ＝7.65(d,J＝8.6,2H),7.62(d,J＝8.6,2H),7.55(d,J＝16.0,1H),6.45(d,J＝16.0,1H),6.13(s,1H),5.79(d,J＝1.4,1H),5.64(s,1H),4.97(d,J＝10.8,1H),4.92(d,J＝10.8,1H),4.60(dd,J＝14.3,3.6,1H),4.13(d,J＝3.6,1H),3.42(d,J＝3.9,1H),2.90(dd,J＝11.7,3.4,1H),2.53(dd,J＝9.2,2.6,1H),2.51–2.44(m,1H),2.25(dd,J＝13.9,11.7,1H),2.01–1.95(m,2H),1.91(dd,J＝13.9,3.3,1H),1.84–1.76(m,1H),1.71–1.65(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C29H29BrO7Na+591.0989,found 591.0990.
Data for 41:1H NMR(600MHz,Acetone-d6)δ＝8.31–8.26(m,2H),8.01–7.97(m,2H),7.68(d,J＝16.1,1H),6.64(d,J＝16.0,1H),6.14(s,1H),5.82(d,J＝1.4,1H),5.65(t,J＝1.0,1H),4.97(d,J＝10.8,1H),4.92(d,J＝10.8,1H),4.60(dd,J＝14.3,3.7,1H),4.14(d,J＝3.7,1H),3.44(s,1H),2.93–2.90(m,1H),2.54(dd,J＝9.1,2.7,1H),2.52–2.46(m,1H),2.25(dd,J＝13.9,11.7,1H),2.02–1.96(m,2H),1.92(dd,J＝13.9,3.3,1H),1.85–1.77(m,1H),1.72–1.66(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcdfor C29H29NO9Na+558.1735,found 558.1735.
Data for 42:1HNMR(600MHz,Acetone-d6)δ＝7.65–7.59(m,2H),7.52(d,J＝15.9,1H),7.00–6.96(m,2H),6.23(d,J＝15.9,1H),6.12(s,1H),5.76(d,J＝1.4,1H),5.62(d,J＝1.1,1H),4.96(d,J＝10.8,1H),4.92(d,J＝10.8,1H),4.60(dd,J＝14.3,3.6,1H),4.11(d,J＝3.6,1H),3.84(s,3H),3.39(d,J＝3.9,1H),2.91–2.88(m,1H),2.51(dd,J＝9.2,2.6,1H),2.48–2.43(m,1H),2.23(dd,J＝13.9,11.8,1H),2.00–1.93(m,2H),1.92–1.88(m,1H),1.83–1.75(m,1H),1.69–1.64(m,1H),1.24(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C30H32O8Na+543.1995,found 543.1989.
Data for 43:1H NMR(600MHz,Acetone-d6)δ＝7.58–7.52(m,3H),7.25(d,J＝7.9,2H),6.34(d,J＝16.0,1H),6.13(s,1H),5.78(d,J＝1.4,1H),5.64(d,J＝1.1,1H),4.97(d,J＝10.8,1H),4.93(d,J＝10.8,1H),4.61(dd,J＝14.3,3.6,1H),4.13(d,J＝3.6,1H),3.43–3.40(m,1H),2.92–2.89(m,1H),2.52(dd,J＝9.2,2.6,1H),2.50–2.44(m,1H),2.36(s,3H),2.25(dd,J＝13.9,11.8,1H),2.01–1.95(m,2H),1.91(dd,J＝13.9,3.4,1H),1.83–1.77(m,1H),1.70–1.65(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcdfor C30H32O7Na+527.2040,found527.2035.
Data for 44:1H NMR(600MHz,Acetone-d6)δ＝7.51(d,J＝15.9,1H),7.33(d,J＝2.0,1H),7.17(dd,J＝8.3,2.0,1H),6.98(d,J＝8.3,1H),6.28(d,J＝15.9,1H),6.13(s,1H),5.77(d,J＝1.3,1H),5.64(s,1H),4.95(q,J＝10.8,2H),4.61(dd,J＝14.3,3.6,1H),4.12(d,J＝3.6,1H),3.87(s,3H),3.86(s,3H),3.40(s,1H),2.92–2.89(m,1H),2.52(dd,J＝9.1,2.4,1H),2.50–2.44(m,1H),2.24(dd,J＝13.9,11.8,1H),2.01–1.93(m,2H),1.91(dd,J＝13.9,3.3,1H),1.84–1.76(m,1H),1.70–1.65(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C31H34O9Na+573.2095,found 573.2091.
Data for 45:1H NMR(600MHz,Acetone-d6)δ＝7.99(s,1H),7.64(d,J＝1.9,1H),7.51(d,J＝15.8,1H),6.91(d,J＝1.9,1H),6.16–6.11(m,2H),5.76(s,1H),5.64–5.62(m,1H),4.99–4.90(m,2H),4.59(dd,J＝14.3,3.6,1H),4.11(d,J＝3.4,1H),3.42–3.37(m,1H),2.92–2.89(m,1H),2.51(dd,J＝9.3,2.6,1H),2.50–2.44(m,1H),2.24(dd,J＝13.8,11.7,1H),1.97(dd,J＝17.4,13.0,2H),1.91(dd,J＝13.9,3.3,1H),1.83–1.76(m,1H),1.71–1.65(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C27H28O8Na+503.1686,found 503.1676.
Data for 46:1H NMR(600MHz,Acetone-d6)δ＝8.65(d,J＝5.2,2H),7.64–7.59(m,2H),7.53(d,J＝16.1,1H),6.65(d,J＝16.0,1H),6.14(s,1H),5.81(d,J＝1.4,1H),5.65(t,J＝1.0,1H),4.97(d,J＝10.8,1H),4.92(d,J＝10.8,1H),4.60(dd,J＝14.3,3.6,1H),4.23–4.18(m,1H),3.44(s,1H),2.94–2.90(m,1H),2.54(dd,J＝9.1,2.7,1H),2.53–2.44(m,1H),2.25(dd,J＝13.9,11.7,1H),2.03–1.95(m,2H),1.91(dd,J＝13.9,3.3,1H),1.86–1.75(m,1H),1.72–1.64(m,1H),1.25(s,3H),1.22(s,4H)；HRESIMS(m/z):[M+H]+calcd forC27H30NO7 +492.2018,found 492.2017.
Data for 47:1H NMR(600MHz,Acetone-d6)δ＝7.22–7.15(m,2H),7.15–7.09(m,2H),6.11(s,1H),5.70(s,1H),5.61(s,1H),4.98–4.91(m,1H),4.91–4.85(m,1H),4.59–4.52(m,1H),4.18–4.13(m,1H),3.37(s,1H),3.25–3.18(m,1H),3.12–3.04(m,4H),2.92–2.88(m,1H),2.54–2.49(m,1H),2.49–2.41(m,1H),2.28–2.20(m,1H),2.00–1.93(m,2H),1.92–1.88(m,1H),1.84–1.74(m,1H),1.69–1.63(m,1H),1.23(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C30H32O7Na+537.1884,found 537.1893.
Data for 48:1HNMR(600MHz,Acetone-d6)δ＝7.86–7.79(m,1H),7.63(d,J＝8.4,1H),7.57–7.50(m,2H),7.38(t,J＝7.4,1H),6.18(s,1H),5.95(s,1H),5.73–5.67(m,1H),5.01(d,J＝10.8,1H),4.95(d,J＝10.7,1H),4.65(dd,J＝14.2,3.5,1H),4.23(d,J＝3.6,1H),3.56(d,J＝3.8,1H),2.93(dd,J＝11.8,3.3,1H),2.60–2.57(m,1H),2.56–2.50(m,1H),2.26(dd,J＝13.8,11.8,1H),2.04–1.98(m,2H),1.92(dd,J＝14.0,3.3,1H),1.88–1.79(m,1H),1.75–1.69(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+K]+calcd forC29H28O8K+543.1416,found543.1426.
Data for 49:1H NMR(600MHz,Acetone-d6)δ＝7.69(d,J＝8.1,1H),7.48(d,J＝8.3,1H),7.31–7.27(m,1H),7.13–7.08(m,1H),7.06(d,J＝2.2,1H),6.17(s,1H),5.92(s,1H),5.67(s,1H),5.01(d,J＝10.8,1H),4.97(d,J＝10.8,1H),4.65(dd,J＝14.2,3.6,1H),4.14(dd,J＝3.6,1.5,1H),3.55–3.51(m,1H),2.92(dd,J＝11.7,3.3,1H),2.56(dd,J＝9.2,2.6,1H),2.54–2.48(m,1H),2.26(dd,J＝13.9,11.8,1H),2.03–1.97(m,2H),1.92(dd,J＝13.9,3.3,1H),1.87–1.80(m,1H),1.73–1.68(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C29H29NO7Na+526.1836,found 526.1839.
Data for 50:1H NMR(600MHz,Acetone-d6)δ＝8.03(d,J＝8.1,1.3,2H),8.00(s,1H),7.57–7.52(m,1H),7.51–7.46(m,1H),6.19(s,1H),5.92(s,1H),5.69(s,1H),5.02(d,J＝10.8,1H),4.94(d,J＝10.8,1H),4.66(dd,J＝14.2,3.4,1H),4.21(d,J＝3.4,1H),3.56(s,1H),2.95–2.92(m,1H),2.58(dd,J＝9.2,2.7,1H),2.56–2.49(m,1H),2.26(dd,J＝13.9,11.8,1H),2.04–1.98(m,2H),1.92(dd,J＝13.9,3.3,1H),1.87–1.79(m,1H),1.75–1.69(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C29H28O7SNa+543.1448,found 543.1449.
Data for 51:1H NMR(800MHz,Acetone-d6)δ＝8.56(d,J＝6.9,1H),8.22(s,1H),7.56(d,J＝9.2,1H),7.38–7.31(m,1H),6.99(t,J＝6.7,1H),6.16(s,1H),5.90(s,1H),5.66(s,1H),5.02(d,J＝10.8,1H),4.98(d,J＝10.8,1H),4.67(dd,J＝14.2,3.5,1H),4.15(d,J＝3.6,1H),3.51(s,1H),2.93–2.91(m,1H),2.56(dd,J＝9.1,2.5,1H),2.54–2.50(m,1H),2.25(dd,J＝13.9,11.8,1H),1.99–1.96(m,2H),1.92(dd,J＝13.9,3.4,1H),1.86–1.80(m,1H),1.73–1.69(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcdfor C28H28N2O7Na+527.1792,found527.1789.
Data for 52:1HNMR(600MHz,Acetone-d6)δ＝9.08(dd,J＝7.0,1.8,1H),8.80(dd,J＝4.1,1.8,1H),8.31(s,1H),7.30(dd,J＝7.0,4.1,1H),6.16(s,1H),5.88(s,1H),5.65(s,1H),5.04(d,J＝10.8,1H),4.99(d,J＝10.8,1H),4.70(dd,J＝14.3,3.6,1H),4.10(d,J＝3.4,1H),3.52(s,1H),2.93–2.92(m,1H),2.55(dd,J＝9.3,2.5,1H),2.53–2.48(m,1H),2.26(dd,J＝13.8,11.8,1H),2.03–1.96(m,2H),1.92(dd,J＝13.8,3.4,1H),1.87–1.79(m,1H),1.74–1.68(m,1H),1.27(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd forC27H27N3O7Na+528.1741,found528.1738.
Data for 53:1H NMR(600MHz,Acetone-d6)δ＝8.56(s,1H),6.15(s,1H),6.01(d,J＝1.4,1H),5.67(s,1H),5.01(d,J＝10.8,1H),4.95(d,J＝10.8,1H),4.66(dd,J＝14.2,3.9,1H),4.09(d,J＝3.9,1H),3.98(s,3H),3.53–3.50(m,1H),2.95–2.92(m,1H),2.57(dd,J＝9.2,3.2,1H),2.56–2.51(m,1H),2.26(dd,J＝13.8,11.8,1H),2.03–1.98(m,2H),1.93(dd,J＝13.9,3.4,1H),1.88–1.80(m,1H),1.76–1.70(m,1H),1.28(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C26H27N5O8Na+560.1752,found 560.1744.
Data for 54:1H NMR(600MHz,Acetone-d6)δ＝8.48–8.45(m,1H),8.05(d,J＝8.2,1H),7.99(dd,J＝8.5,4.3,2H),7.85(dd,J＝8.6,1.7,1H),7.68(ddd,J＝8.2,6.8,1.3,1H),7.62(ddd,J＝8.1,6.8,1.3,1H),6.20(s,1H),5.96(s,1H),5.69(t,J＝1.0,1H),5.05(d,J＝10.8,1H),5.00(d,J＝10.8,1H),4.70(dd,J＝14.3,3.6,1H),4.20(d,J＝3.5,1H),3.58(d,J＝3.9,1H),2.94(dd,J＝11.7,3.3,1H),2.60–2.58(m,1H),2.57–2.51(m,1H),2.27(dd,J＝13.8,11.8,1H),2.04–1.99(m,2H),1.93(dd,J＝13.9,3.4,1H),1.89–1.81(m,1H),1.76–1.70(m,1H),1.27(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+Na]+calcd forC31H30O7Na+537.1884,found 537.1893.
Data for 55:1H NMR(600MHz,Acetone-d6)δ＝7.34–7.32(m,1H),7.31–7.25(m,2H),6.99–6.95(m,1H),6.83(d,J＝8.1,1H),6.14(s,1H),5.79(s,1H),5.64(s,1H),4.98(d,J＝10.8,1H),4.91(d,J＝10.8,1H),4.81(t,J＝1.7,2H),4.60(dd,J＝14.2,3.3,1H),4.21(d,J＝3.4,1H),3.47(d,J＝3.9,1H),2.90(dd,J＝11.7,3.3,1H),2.54(dd,J＝9.1,2.6,1H),2.51–2.45(m,1H),2.25(dd,J＝13.9,11.7,1H),2.02–1.97(m,2H),1.91(dd,J＝13.9,3.4,1H),1.84–1.78(m,1H),1.71–1.66(m,1H),1.25(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+H]+calcd for C30H31O8 +519.2013,found 519.2017.
Data for 56:1H NMR(600MHz,Acetone-d6)δ＝8.53–8.48(m,1H),8.16–8.11(m,1H),8.08–8.04(m,1H),7.95–7.91(m,1H),7.90–7.84(m,1H),7.78–7.72(m,1H),6.19(s,1H),6.03(s,1H),5.70(s,1H),5.08–4.97(m,2H),4.73–4.66(m,1H),4.20(s,1H),3.61(s,1H),2.97–2.92(m,1H),2.60–2.54(m,2H),2.31–2.23(m,1H),2.10–2.08(m,2H),1.96–1.91(m,1H),1.90–1.83(m,1H),1.79–1.72(m,1H),1.28(s,3H),1.23(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C30H29NO7Na+538.1836,found 538.1842.
Data for 57:1H NMR(600MHz,Acetone-d6)δ＝9.25(s,1H),8.21–8.17(m,2H),8.05–8.01(m,1H),8.00–7.96(m,1H),6.21(s,1H),6.09(s,1H),5.72(s,1H),5.03(d,1H),4.99(d,J＝10.8,1H),4.68(dd,J＝14.2,3.4,1H),4.29(d,J＝3.5,1H),3.65(d,J＝3.9,1H),2.95(dd,J＝11.8,3.3,1H),2.63(dd,J＝9.1,3.1,1H),2.60–2.55(m,1H),2.28(dd,J＝13.8,11.8,1H),2.09–2.06(m,2H),1.95–1.92(m,1H),1.88–1.83(m,1H),1.79–1.74(m,1H),1.28(s,3H),1.23(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C29H28N2O7Na+539.1789,found 539.1794.
Data for 58:1H NMR(600MHz,Acetone-d6)δ＝7.57(dt,J＝7.7,1.3,1H),7.49(t,J＝8.0,1H),7.46–7.42(m,2H),7.41(dd,J＝2.6,1.5,1H),7.25(ddd,J＝8.2,2.6,1.1,1H),7.23–7.20(m,1H),7.07–7.04(m,2H),6.13(s,1H),5.87(s,1H),5.63(s,1H),5.00(d,J＝10.8,1H),4.93(d,J＝10.8,1H),4.63(dd,J＝14.3,3.6,1H),4.16(d,J＝3.6,1H),3.51(s,1H),2.94–2.91(m,1H),2.56(dd,J＝9.2,2.6,1H),2.52–2.46(m,1H),2.25(dd,J＝13.8,11.7,1H),2.03–1.97(m,2H),1.91(dd,J＝13.9,3.3,1H),1.85–1.79(m,1H),1.72–1.67(m,1H),1.25(s,3H),1.21(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C33H32O8Na+579.1989,found579.1985.
Data for 59:1H NMR(600MHz,Acetone-d6)δ＝8.11(d,J＝5.1,1H),7.94(d,J＝7.8,1H),7.82(d,J＝7.7,1H),7.67(d,J＝7.7,2H),7.59(t,J＝7.8,1H),7.51(t,J＝7.7,2H),7.42(t,J＝7.4,1H),6.16(s,1H),5.92(s,1H),5.67(s,1H),5.03(d,J＝10.6,1H),5.01–4.95(m,1H),4.73–4.63(m,1H),4.22(s,1H),3.60–3.54(m,1H),2.96–2.92(m,1H),2.61–2.57(m,1H),2.56–2.50(m,1H),2.29–2.22(m,1H),2.03–1.98(m,2H),1.95–1.91(m,1H),1.88–1.80(m,1H),1.75–1.69(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M–H]–calcd for C33H31O7 –539.2075,found 539.2084.
Data for 60:1H NMR(600MHz,Acetone-d6)δ＝8.69(d,J＝4.8,2H),7.99–7.95(m,2H),7.92–7.88(m,2H),7.74–7.69(m,2H),6.18(s,1H),5.94(s,1H),5.68(s,1H),5.03(d,J＝10.8,1H),4.97(d,J＝10.8,1H),4.67(dd,J＝14.2,3.6,1H),4.18(d,J＝3.6,1H),3.57(d,J＝3.9,1H),2.93(dd,J＝11.7,3.3,1H),2.59(dd,J＝9.5,2.9,1H),2.56–2.50(m,1H),2.27(dd,J＝13.9,11.8,1H),2.04–2.00(m,2H),1.93(dd,J＝13.9,3.4,1H),1.89–1.81(m,1H),1.76–1.69(m,1H),1.27(s,3H),1.23(s,3H)；HRESIMS(m/z):[M+H]+calcd forC32H32NO7 +542.2173,found542.2180.
Data for 61:1H NMR(600MHz,Acetone-d6)δ＝7.79–7.74(m,2H),7.27(t,J＝7.5,2H),7.25–7.21(m,2H),7.19–7.14(m,1H),7.01–6.96(m,2H),6.15(s,1H),5.84(s,1H),5.64(s,1H),5.01(d,J＝10.8,1H),4.96(d,J＝10.8,1H),4.65(dd,J＝14.3,3.6,1H),4.15–4.06(m,3H),3.50(s,1H),2.91(dd,J＝11.8,3.4,1H),2.70(t,J＝7.1,2H),2.56–2.53(m,1H),2.53–2.46(m,1H),2.25(dd,J＝13.9,11.7,1H),2.03–1.96(m,2H),1.94–1.89(m,1H),1.86–1.77(m,5H),1.72–1.67(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+K]+calcd for C37H40O8K+651.2355,found 651.2352.
Data for 62:1H NMR(600MHz,Acetone-d6)δ＝9.19(s,1H),9.10–9.07(m,2H),8.18(d,J＝2.1,1H),8.08–8.05(m,1H),7.96–7.91(m,1H),7.69(t,J＝7.8,1H),6.17(s,1H),5.93(s,1H),5.67(s,1H),5.03(d,J＝10.7,1H),4.97(d,J＝10.8,1H),4.68(dd,J＝14.3,3.6,1H),4.19(dd,J＝3.7,1.4,1H),3.59(s,1H),2.93(dd,J＝11.7,3.3,1H),2.59(d,J＝9.3,1H),2.57–2.50(m,1H),2.27(dd,J＝13.9,11.8,1H),2.04–2.00(m,2H),1.93(dd,J＝13.9,3.3,1H),1.89–1.81(m,1H),1.76–1.69(m,1H),1.26(s,3H),1.23(s,3H)；HRESIMS(m/z):[M+Na]+calcd for C31H30N2O7Na+565.1945,found 565.1936.
Data for 63:1H NMR(600MHz,Acetone-d6)δ＝9.13(d,J＝2.6,1H),8.80(s,1H),8.61(dd,J＝4.7,1.5,1H),8.26(ddd,J＝8.4,2.7,1.4,1H),7.98(s,1H),7.56(dd,J＝8.3,4.7,1H),6.15(s,1H),5.86(s,1H),5.65(s,1H),5.00(d,J＝10.8,1H),4.95(d,J＝10.8,1H),4.65(dd,J＝14.3,3.2,1H),4.14(d,J＝3.5,1H),3.50(s,1H),2.91(dd,J＝11.7,3.4,1H),2.56(dd,J＝9.2,2.5,1H),2.54–2.47(m,1H),2.26(dd,J＝13.9,11.8,1H),2.04–1.97(m,2H),1.92(dd,J＝13.9,3.4,1H),1.87–1.78(m,1H),1.73–1.67(m,1H),1.26(s,3H),1.22(s,3H)；HRESIMS(m/z):[M+H]+calcd for C29H30N3O7 +532.2078,found 532.2086.
实施例3
细胞毒实验流程：
(1)实验材料
细胞株：人正常肝细胞(LO2)，宫颈癌细胞株(Hela)，卵巢癌细胞株(SK-OV-3)，肝癌细胞株(SK-HEP-1)，结肠癌株(CACO2)，乳腺癌细胞株(MDA-MB-231)，前列腺癌细胞株(PC-3)，结肠癌细胞株(SW480)，人肺癌紫杉醇耐药株(A549/Taxol)等九株细胞。
(2)实验原理
MTS为一种全新的MTT类似物，全称为3-(4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2-(4-sulfopheny)-2H-tetrazoliu-m，是一种黄色染料。活细胞线粒体中琥珀酸脱氢酶能够代谢还原MTS，生成可溶性的甲臜(Formazan)化合物，其含量可用酶标仪在490nm处进行测定。在通常情况下，甲臜生成量与活细胞数成正比，据此可根据光密度OD值推测出活细胞的数目。
(3)实验方法：MTS法检测细胞活性。
①接种细胞：用含10％胎牛血清的培养液(DMEM或者RMPI1640)配成单个细胞悬液，以每孔3000～15000个细胞接种到96孔板，每孔体积100μL，贴壁细胞提前12～24h接种培养。
②加入待测化合物溶液：化合物用DMSO溶解，化合物用DMSO溶解，化合物以40μM、8μM、1.6μM、0.32μM、0.064μM浓度复筛，每孔终体积200μL，每种处理均设3个复孔。
③显色：37℃培养48h后，贴壁细胞弃孔内培养液，每孔加MTS溶液20μL以及培养液100μL；悬浮细胞弃100μL培养上清液，每孔加20μL的MTS溶液；设3个空白复孔(MTS溶液20μL和培养液100μL的混合液)，继续孵育2～4h，使反应充分进行。
④比色：选择492nm波长，多功能酶标仪(MULTISKAN FC)读取各孔光吸收值，记录结果，以浓度为横坐标，细胞存活率为纵坐标绘制细胞生长曲线，应用两点法(Reed andMuench法)计算化合物的IC50值。
⑤阳性对照物：每次实验均设顺铂(DDP)和紫杉醇(Taxol)两个阳性化合物，以浓度为横坐标，细胞存活率为纵坐标绘制细胞生长曲线，应用两点法(Reed and Muench法)计算化合物的IC50值。
(4)实验结果见图1。
本发明的毛萼内酯素B衍生物对人宫颈癌细胞株(Hela)，卵巢癌细胞株(SK-OV-3)，肝癌细胞株(SK-HEP-1)，结肠癌株(CACO2)，乳腺癌细胞株(MDA-MB-231)，前列腺癌细胞株(PC-3)，结肠癌细胞株(SW480)，人肺癌紫杉醇耐药株(A549/Taxol)都有较好的抑制作用。
制剂实施例
在以下制剂实施例中，选择常规试剂，并按照现有常规方法进行制剂制备，本应用例仅体现本发明所述毛萼内酯素B衍生物制备成不同的制剂，对具体试剂和操作不作具体限定。
1.将毛萼内酯素B衍生物任其一或任其组合用DMSO溶解后，按常规方法加注射用水，精滤，灌封灭菌制成注射液，所述注射液的浓度为0.5～5mg/mL。
2.将毛萼内酯素B衍生物任其一或任其组合用DMSO溶解后，将其溶于无菌注射用水中，搅拌使其溶解，用无菌抽滤漏斗过滤，再无菌精滤，分装于安瓿中，低温冷冻干燥后无菌熔封，得粉针剂。
3.将毛萼内酯素B衍生物任其一或任其组合按其与赋形剂质量比为9:1的比例加入赋形剂，制成粉剂。
4.将毛萼内酯素B衍生物任其一或任其组合按其与赋形剂质量比为5:1的比例加入赋形剂，制粒压片。
5.将毛萼内酯素B衍生物任其一或任其组合按常规口服液制备方法制成口服液。
6.将毛萼内酯素B衍生物任其一或任其组合按其与赋形剂质量比为5:1的比例加入赋形剂，制成胶囊。
7.将毛萼内酯素B衍生物任其一或任其组合按其与赋形剂质量比为5:1的比例加入赋形剂，制成颗粒剂。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (9)

1.如下结构式所示的毛萼内酯素B衍生物，
其中R为以下官能团：
2.权利要求1所述的毛萼内酯素B衍生物的制备方法，其特征在于，该方法以毛萼内酯素B为起始原料，通过酯化反应得到毛萼内酯素B衍生物，
该方法包括如下步骤：氩气保护下，将毛萼内酯素B溶解在0.1～0.5mL的二氯甲烷中，加入EDCI、DMAP和相应的酸，将反应置于室温中反应1～12个小时，TLC检测反应完全后，饱和NaHCO3淬灭，EtOAc萃取，饱和食盐水洗涤、无水MgSO4干燥，过滤，浓缩后柱层析纯化或经过制备纯化，分离得到毛萼内酯素B衍生物。
3.权利要求1所述的毛萼内酯素B衍生物在制备抗肿瘤药物中的应用。
4.权利要求1所述的毛萼内酯素B衍生物在制备治疗宫颈癌、结肠癌、卵巢癌、肺癌、前列腺癌、乳腺癌、肝癌的药物中的应用。
5.药物组合物，含有权利要求1所述的毛萼内酯素B衍生物任其一或任其组合及可药用载体的抗肿瘤药物。
6.根据权利要求5所述的药物组合物，其特征在于所述的药物组合物的剂型为粉剂、颗粒剂、片剂、胶囊剂、丸剂、溶液、悬浮液或注射液。
7.权利要求5所述的药物组合物的制备方法，其特征在于该方法以毛萼内酯素B为起始原料，通过酯化反应得到毛萼内酯素B衍生物，然后再加入可药用载体，
该方法包括如下步骤：氩气保护下，将毛萼内酯素B溶解在0.1～0.5mL的二氯甲烷中，加入EDCI、DMAP及相应的酸，将反应置于室温中反应1～12个小时，TLC检测反应完全后，饱和NaHCO3淬灭，EtOAc萃取，饱和食盐水洗涤、无水MgSO4干燥，过滤，浓缩后柱层析纯化或经过制备纯化，分离得到毛萼内酯素B衍生物，然后再加入可药用载体。
8.权利要求5所述的药物组合物在制备抗肿瘤药物中的应用。
9.权利要求5所述的药物组合物在制备治疗宫颈癌、结肠癌、卵巢癌、肺癌、前列腺癌、乳腺癌、肝癌的药物中的应用。
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