CN116102416B - 补骨脂乙素衍生物及其制备方法和在制备抗癌药物中的应用 - Google Patents
补骨脂乙素衍生物及其制备方法和在制备抗癌药物中的应用 Download PDFInfo
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/86—Ketones containing a keto group bound to a six-membered aromatic ring containing —CHO groups
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
- C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/80—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明以补骨脂乙素为原料，通过Reimer‑Tiemann反应、席夫碱反应、曼尼希反应等对补骨脂乙素的A环进行结构修饰，合成了三种补骨脂乙素衍生物，分别具有如式I、式II和式VII所示的结构式：
Description
技术领域
本发明属于药物化学技术领域，具体是补骨脂乙素衍生物及其制备方法，以及以补骨脂乙素系列衍生物为活性成分的药物组合物在治疗癌症中的应用。
背景技术
天然产物具有结构复杂性、多样性，是一个天然形成的“组合化学样品库”，亦是新药研发中发现先导化合物/候选药物的重要来源之一。另外，天然产物又具有多靶点、低毒性的独特优势，从中寻求安全、有效的单体化合物用于癌症治疗、逆转肿瘤细胞耐药及降低毒副反应不失为癌症治疗研究的亮点，也是中药现代化的一种体现。
补骨脂乙素(isobavachalcone)来源于中药补骨脂(Psoralea corylifolia L.)，从结构上属于查尔酮类黄酮，具有三个酚羟基、A环上有1个异戊烯基取代。补骨脂乙素作为补骨脂中主要活性成分之一，具有多种机制的抗肿瘤作用，如抑制Akt信号通路而抑制多种肿瘤细胞的增殖，诱导急性髓系白血病HL-60细胞ROS依赖的线粒体凋亡和分化，调控ERK/RSK2信号通路而诱导肝癌HepG2和HepG3B细胞凋亡，下调ER+乳腺癌细胞中CD44的表达而提高对E2诱导的紫杉醇耐药敏感性等。
发明内容
本发明的目的在于提供一系列具有新结构的补骨脂乙素衍生物，采用生物电子等排体替换和骨架迁越原理，通过Reimer-Tiemann反应、席夫碱反应、曼尼希反应等对补骨脂乙素的A环进行结构修饰，以提高补骨脂乙素衍生物的抗癌活性。
为实现上述目的，本发明提供了一系列补骨脂乙素衍生物，分别具有如式I、式II或式III所示的结构式：
式III中，R是
式I所示的补骨脂乙素衍生物的制备方法为：将补骨脂乙素溶解于氯仿中，加入25％的氢氧化钠溶液，在30℃温度下搅拌至反应结束后，调节pH至酸性，加入萃取液萃取，蒸干萃取液获得浸膏，纯化得到式I所示的补骨脂乙素衍生物。
式II所示的补骨脂乙素衍生物的制备方法为：将式I所示的补骨脂乙素衍生物溶于无水乙醇中，加入氨基胍和冰乙酸，在50℃温度下搅拌至反应结束后，萃取并纯化得到式II所示的补骨脂乙素衍生物。
式III所示的补骨脂乙素衍生物的制备方法为：将补骨脂乙素溶解在乙腈中，加入芳香醛和吗啉，在80℃温度下反应3-12小时，纯化即可得到式III所示的补骨脂乙素衍生物；
所述的芳香醛包括对溴苯甲醛、3,4,5-三甲氧基苯甲醛或对三氟甲基苯甲醛。
上述式I、式II和式III所示的补骨脂乙素衍生物都以补骨脂乙素为基础原料，制备方法简单，能够快速大量地制备补骨脂乙素衍生物，操作简单可行，无污染，成本低廉，收率稳定，且重复性好。制备的补骨脂乙素衍生物I-1、II-1、III-3、III-9和III-10对7种癌细胞具有较强的细胞毒性。其中，补骨脂乙素衍生物III-9具有显著抑制人非小细胞肺癌H1975细胞增殖、诱导凋亡的作用。
本发明还提供了式I、式II和式III所示的补骨脂乙素衍生物在制备抗癌药物中的应用，所述的癌细胞为肺癌细胞、乳腺癌细胞、肝癌细胞、鼻咽癌细胞或宫颈癌细胞。
本发明的三种补骨脂乙素衍生物对7种癌细胞具有较强的细胞毒性。其中，补骨乙质素衍生物III-9具有显著抑制人非小细胞肺癌H1975细胞增殖、诱导凋亡的作用，具有很好的抗癌药的应用前景。
所述的补骨脂乙素衍生物被用于制成肠道或非肠道组合药的剂型。剂型为液体制剂、片剂、颗粒剂、冲剂、丸剂、胶囊、缓释剂、滴丸剂或注射剂。剂型的给药方式为口服给药或注射给药。
附图说明
图1是补骨脂乙素衍生物III-9对人肺癌H1975细胞增殖的影响。
图2是补骨脂乙素衍生物III-9诱导人肺癌H1975细胞凋亡的作用。
图3是补骨脂乙素衍生物III-9对人肺癌H1975细胞内的Bax、Bcl-2蛋白的表达的影响。
具体实施方式
以下结合实施例进一步说明发明。
实施例1.补骨脂乙素衍生物I-1的制备：
称取补骨脂乙素300mg(0.92mmol/L)溶解于8mL氯仿中，加入25％氢氧化钠4mL，在30℃油浴中持续搅拌12小时，用薄层层析色谱(TLC)监控反应。待反应结束后，用稀盐酸调pH至酸性，加入乙酸乙酯萃取3次。利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用二氯甲烷：甲醇＝200:1至30:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物I-1(39.6mg)。黄色粉末，产率为12.2％；1H-NMR(DMSO-d6,300MHz)：δ14.61(s,2-OH),11.93(s,4-OH),10.30(1H,s,-CHO),9.89(s,4′-OH),8.85(1H,s,H-6),7.87(2H,d,J＝16.6Hz,H-α和H-β),7.82(2H,d,J＝8.3Hz,H-2′和H-6′),6.89(2H,d,J＝8.3Hz,H-3′和H-5′),5.16(m,H-2″),3.28(2H,d,J＝7.2Hz,H-1″),1.74(3H,s,H-5″),1.63(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ195.8(-C＝O),192.4(-CHO),167.5(C-2),163.8(C-4),160.9(C-4′),146.1(C-β),138.0(C-3″),131.7(C-6),131.7(C-2′和H-6′),125.5(C-1′),121.0(C-2″),116.5(C-5),116.0(C-α),115.5(C-3),114.6(C-3′和H-5′),113.7(C-1),25.5(C-5″),20.6(C-1″),17.7(C-4′)；HR-ESI-MS:calculated for C23H26N3O5 +[M+H]+m/z 353.1311,found 353.1383。
实施例2.补骨脂乙素衍生物II-1的制备：
称取实施例1的产物(补骨脂乙素衍生物I-1,25mg，0.07mmol/L)溶解于3mL无水乙醇中，加入氨基胍40mg(0.54mmol/L)、冰乙酸200μL，在50℃油浴中持续搅拌5小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用二氯甲烷：甲醇＝50:1至20:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物II-1(13.3mg)。淡黄色粉末，产率为46.6％；1H-NMR(DMSO-d6,300MHz)：δ14.27(s,2-OH),11.92(s,4′-OH),10.39(s,-NH-),10.30(s,4-OH),8.37(1H,s,H-6),8.51(s,-CH＝N-),7.95(m,H-α),7.89(m,H-β),7.86(3H,s,氨基胍),7.80(2H,d,J＝8.6Hz,H-2′和H-6′),6.89 2H,d,J＝8.5Hz,H-3′和H-5′),5.17(m,H-2″),3.29(2H,d,J＝6.3Hz,H-1″),1.75(3H,s,H-5″),1.63(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ192.3(-C＝O),164.5(C-4),160.7(C-2),160.3(-C＝NH),154.8(C-4′),148.5(-CH＝N-),145.6(C-β),131.9(C-3″),131.6(C-2′和C-6′),131.3(C-6),125.6(C-1′),116.9(C-α),115.9(C-3′和C-5′),115.8(C-3),113.6(C-1),121.7(C-2″),111.5(C-5),25.5(C-5″),21.2(C-1″),17.8(C-4″)；HR-ESI-MS:calculated for C22H25N4O4 +[M+H]+m/z409.1876found 409.1872。
实施例3.补骨脂乙素衍生物III-1的制备：
称取补骨脂乙素120mg(0.37mmol/L)溶解于6mL乙腈中，加入过量的4-吡啶甲醛400μL、吗啉200μL(2.29mmol/L)，在80℃油浴中持续搅拌8小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚：乙酸乙酯＝10:1至5:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物III-1(112.6mg)。黄色粉末，产率为60.9％；1H-NMR(DMSO-d6,300MHz)：δ13.93(s,2-OH),12.25(s,4′-OH),10.25(s,4-OH),8.73(2H,d,J＝5.6Hz,H-4″′和H-6″′),8.12(1H,s,H-6),7.87(2H,d,J＝6.1Hz,H-2′和H-6′),7.80(1H,d,J＝15.4Hz,H-β),7.77(2H,d,J＝6.8Hz,H-3″′和H-7″′),7.72(1H,d,J＝15.4Hz,H-α),6.90(2H,d,J＝8.6Hz,H-3′和H-5′),4.93(1H,s,H-1″′),3.75(4H,m,H-9″′和H-10″′),3.27(2H,d,J＝6.7Hz,H-1″),2.54(4H,t,J＝8.2Hz,H-8″′和H-11″′),1.71(3H,s,H-5″),1.61(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.7(-C＝O),163.1(C-2),160.6(C-4),160.5(C-4′),144.8(C-β),147.1(C-2″′、C-4″′和C-6″′),131.3(C-2′和C-6′),131.0(C-3″),129.3(C-6),125.1(C-1′),124.0(C-2″),122.0(C-3″′和C-7″′),117.0(C-α),115.8(C-3′和C-5′),113.0(C-1),99.8(C-5),65.6(C-9″′和C-10″′),59.8(C-1″′),51.8(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.7(C-4″)；HR-ESI-MS:calculated for C30H32N2O5Na+[M+Na]+m/z523.2203found 523.2206.
实施例4.补骨脂乙素衍生物III-2的制备：
称取补骨脂乙素120mg(0.37mmol/L)溶解于4mL乙腈中，加入过量的苯甲醛113.5μL(1.11mmol/L)、吗啉97μL(1.11mmol/L)，在80℃油浴中持续搅拌10小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚:乙酸乙酯＝5:1的洗脱溶剂进行洗脱，得到补骨脂乙素衍生物III-2(61.6mg)。黄色粉末，产率为33.3％；1H-NMR(DMSO-d6,300MHz)：δ13.93(s,2-OH),10.20(s,4-OH),8.0(1H,s,H-6),7.78(1H,m,H-β),7.76(2H,d,J＝8.9Hz,H-3″′和H-7″′),7.72(1H,m,H-α),7.54(2H,d,J＝7.4Hz,H-2′和H-6′),7.36(m,H-4″′、H-5″′和H-6″′),6.89(2H,d,J＝8.5Hz,H-3′和H-5′),5.21(1H,m,H-2″),4.80(1H,s,H-1″′),3.70(m,H-9″′和H-10″′),3.30(2H,d,J＝6.8Hz,H-1″),2.57(m,H-8″′和H-11″′),1.74(3H,s,H-5″),1.63(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.6(-C＝O),162.7(C-2),161.2(C-4),160.4(C-4′),144.4(C-β和C-2″′),131.3(C-2′和C-6′),130.9(C-3″),129.0(C-6、C-4″′和C-6″′),128.1(C-3″′和C-7″′),128.0(C-1′),125.7(C-5″′),122.2(C-2″),117.3(C-α),117.1(C-3),115.9(C-3′和C-5′),115.4(C-1),112.6(C-5),65.7(C-9″′和C-10″′),59.8(C-1″′),51.8(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.8(C-4″)；HR-ESI-MS:calculated for C31H33NO5Na+[M+Na]+m/z 522.2251found 522.2253.
实施例5.补骨脂乙素衍生物III-3的制备：
称取补骨脂乙素300mg(0.93mmol/L)溶解于3.5mL乙腈中，加入对溴苯甲醛324mg(1.75mmol/L)、吗啉162μL(1.85mmol/L)，在80℃油浴中持续搅拌3小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚:乙酸乙酯＝10:1至5:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物III-3(85.4mg)。黄色粉末，产率为15.9％；1H-NMR(DMSO-d6,300MHz)：δ13.91(s,2-OH),10.20(s,4′-OH),7.96(1H,s,H-6),7.72(m,H-4″′、H-6″′、H-α和H-β),7.64(s,4-OH),7.59(2H,d,J＝6.4Hz,H-2′和H-6′),7.47(2H,d,J＝6.7Hz,H-3″′和H-7″′),6.87(2H,d,J＝6.7Hz,H-3′和H-5′),5.20(m,H-2″),4.70(1H,s,H-1″′),3.67(m,H-9″′和H-10″′),3.27(m,H-1″),2.54(m,H-8″′和H-11″′),1.73(3H,s,H-5″),1.62(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.6(-C＝O),162.7(C-2),161.2(C-4),160.4(C-4′),144.4(C-β),139.1(C-2″′),131.9(C-4″′和C-6″′),131.3(C-2′和C-6′),130.9(C-3″′和C-7″′),130.2(C-6和C-3″),129.1(C-1′),125.7(C-2″),122.2(C-5″′),121.1(C-α),117.1(C-3),115.9(C-3′和C-5′)，115.5(C-1),112.7(C-5),73.5(C-1″′),65.9(C-9″′和C-10″′),48.6(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.8(C-4″)；HR-ESI-MS:calculated for C31H33BrNO5 +[M+H]+578.1537found 578.1540.
实施例6.补骨脂乙素III-4的制备：
称取补骨脂乙素150mg(0.46mmol/L)溶解于4mL乙腈中，加入对氯苯甲醛75mg(0.53mmol/L)、吗啉75μL(0.86mmol/L)，在80℃油浴中持续搅拌12小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚:乙酸乙酯＝200:1至50:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物III-4(63.1mg)。淡黄色粉末，产率为25.7％；1H-NMR(DMSO-d6,300MHz)：δ13.90(s,2-OH),13.08(s,4′-OH),10.14(s,4-OH),7.95(1H,s,H-6),7.76(m,H-α),7.72(2H,d,J＝8.7Hz,H-2′和H-6′),7.68(H-β),7.54(2H,d,J＝8.5Hz,H-4″′和H-6″′),7.45(2H,d,J＝8.4Hz,H-3″′和H-7″′),7.36(m,H-5″′),6.88(2H,d,J＝8.5Hz,H-3′和H-5′),5.20(m,H-2″),4.73(1H,s,H-1″′),3.68(m,H-9″′和H-10″′),3.28(m,H-1″),2.45(m,H-8″′和H-11″′),1.73(3H,s,H-5″),1.62(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.5(-C＝O),162.7(C-2),161.1(C-4),160.4(C-4′),144.4(C-β),132.5(C-3″),138.7(C-2″′),131.2(C-2′和C-6′),130.9(C-3″′和C-7″′),129.8(C-4″′和C-6″′),128.9(C-6),125.7(C-1′和C-5″′),123.8(C-2″),122.1(C-α),117.1(C-3),115.9(C-3′和C-5′),115.5(C-1),112.6(C-5),73.4(C-1″′),65.9(C-9″′和C-10″′),51.8(C-8″′和C-11″′),25.5(C-5″),21.3(C-1″),17.7(C-4″)；HR-ESI-MS:calculated for C31H32ClNO5Na+[M+Na]+m/z556.1861found 556.1862.
实施例7.补骨脂乙素衍生物III-5的制备：
称取补骨脂乙素150mg(0.46mmol/L)溶解于4mL乙腈中，加入对氟苯甲醛75mg(0.60mmol/L)、吗啉75μL(0.86mmol/L)，在80℃油浴中持续搅拌12小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚:乙酸乙酯＝200:1至50:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物III-5(22.4mg)。淡黄色粉末，产率为9.4％；1H-NMR(DMSO-d6,300MHz)：δ13.91(s,2-OH),13.19(s,4′-OH),10.16(s,4-OH),7.96(1H,d,J＝15.5Hz,H-β),7.71(1H,s,H-6),7.75(2H,d,J＝8.7Hz,H-2′和H-6′),7.69(1H,d,J＝15.5Hz,H-α),7.54(m,H-3″′和H-7″′),7.21(m,H-4″′和H-6″′),6.88(2H,d,J＝8.6Hz,H-3′和H-5′),5.21(m,H-2″),4.73(1H,s,H-1″′),3.67(m,H-9″′和H-10″′),3.28(m,H-1″),2.44(m,H-8″′和H-11″′),1.73(3H,s,H-5″),1.63(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.5(-C＝O),162.6(C-2),161.2(C-4),160.4(C-4′),153.8(C-5″′),144.4(C-β),139.4(C-2″′),131.2(C-2′和C-6′),130.8(C-3″),130.1(C-3″′和C-7″′),129.6(C-6),125.7(C-1′),122.2(C-2″),117.1(C-4″′和C-6″′),115.6(C-3、C-3′和C-5′),115.4(C-α),114.8(C-1),112.6(C-5),73.3(C-1″′),65.9(C-9″′和C-10″′),63.3(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.7(C-4″)；HR-ESI-MS:calculated for C31H32FNO5Na+[M+Na]+m/z540.2157found 540.2159.
实施例8.补骨脂乙素衍生物III-6的制备：
称取补骨脂乙素150mg(0.46mmol/L)溶解于4mL乙腈中，加入对硝基苯甲醛95mg(0.63mmol/L)、吗啉75μL(0.86mmol/L)，在80℃油浴中持续搅拌12小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚:乙酸乙酯＝3:1的洗脱溶剂进行洗脱，得到补骨脂乙素衍生物III-6(84.4mg)。淡黄色粉末，产率为33.7％；1H-NMR(DMSO-d6,300MHz)：δ13.91(s,4′-OH),10.19(s,4-OH),8.26(2H,d,J＝8.7Hz,H-4″′和H-6″′),8.06(1H,s,H-6),7.84(2H,d,J＝8.7Hz,H-2′和H-6′),7.78(1H,d,J＝15.3Hz,H-β),7.76(2H,d,J＝8.4Hz,H-3″′和H-7″′),7.71(1H,d,J＝15.3Hz,H-α),6.89(2H,d,J＝8.6Hz,H-3′和H-5′),5.17(m,H-2″),4.96(1H,s,H-1″′),3.74(m,H-9″′和H-10″′),3.28(m,H-1″),2.61(m,H-8″′和H-11″′),1.72(3H,s,H-5″),1.61(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.6(-C＝O),162.9(C-2),160.7(C-4),160.5(C-4′),147.0(C-2″′),144.6(C-β和C-5″′),131.3(C-2′和C-6′),131.0(C-3″),129.3(C-6),129.2(C-3″′和C-7″′),125.6(C-1′),124.2(C-4″′和C-6″′),122.0(C-2″),117.0(C-α),116.2(C-3),115.9(C-3′和C-5′),115.7(C-1),112.9(C-5),72.9(C-1″′),65.7(C-9″′和C-10″′),51.9(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.7(C-4″)；HR-ESI-MS:calculated for C31H32N2O7Na+[M+Na]+m/z567.2102found 567.2103.
实施例9.补骨脂乙素衍生物III-7的制备：
称取补骨脂乙素150mg(0.46mmol/L)溶解于4mL乙腈中，加入对甲酰基苯甲醛95mg(0.63mmol/L)、吗啉75μL(0.86mmol/L)，在80℃油浴中持续搅拌12小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用二氯甲烷:甲醇＝50:1至5:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物III-7(46.1mg)。淡黄色粉末，产率为18.8％；1H-NMR(DMSO-d6,300MHz)：δ14.01(s,-COOH),13.92(s,4′-OH),7.99(1H,s,H-6),7.94(2H,d,J＝8.1Hz,H-4″′和H-6″′),7.72(m,H-2′、H-6′、H-α和H-β),7.64(2H,d,J＝8.1Hz,H-3″′和H-7″′),6.88(2H,d,J＝8.6Hz,H-3′和H-5′),5.21(m,H-2″),4.77(1H,s,H-1″′),3.69(m,H-9″′和H-10″′),3.27(m,H-1″),2.42(m,H-8″′和H-11″′),1.73(3H,s,H-5″),1.62(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.6(-C＝O),162.7(C-12″′),161.2(C-2),160.5(C-4和C-4′),144.5(C-2″′),144.3(C-β),131.3(C-3″),130.9(C-4″′和C-6″′),130.0(C-6),129.9(C-2′和C-6′),129.2(C-3″′和C-7″′),128.1(C-5″′),125.7(C-1′),122.2(C-2″),117.1(C-α),117.0(C-3),115.9(C-3′和C-5′),115.5(C-1),112.7(C-5),73.9(C-1″′),65.9(C-9″′和C-10″′),51.9(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.8(C-4″)；HR-ESI-MS:calculated for C32H33NO7Na+[M+Na]+m/z 566.2149found 566.2151.
实施例10.补骨脂乙素衍生物III-8的制备：
称取补骨脂乙素150mg(0.46mmol/L)溶解于4mL乙腈中，加入对甲氧基苯甲醛95mg(0.69mmol/L)、吗啉75μL(0.86mmol/L)，在80℃油浴中持续搅拌12小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚:乙酸乙酯＝3:1的洗脱溶剂进行洗脱，得到补骨脂乙素衍生物III-8(63.0mg)。淡黄色粉末，产率为25.9％；1H-NMR(DMSO-d6,300MHz)：δ13.42(s,2-OH),13.1(s,4′-OH),10.15(s,4-OH),7.91(1H,s,H-6),7.72(m,H-α和H-β),7.75(2H,d,J＝8.7Hz,H-2′和H-6′),7.40(2H,d,J＝8.6Hz,H-3″′和H-7″′),6.94(2H,d,J＝8.6Hz,H-4″′和H-6″′),6.87(2H,d,J＝8.5Hz,H-3′和H-5′),5.22(m,H-2″),4.65(1H,s,H-1″′),3.71(3H,s,-OCH3),3.66(m,H-9″′和H-10″′),3.28(m,H-1″),2.43(m,H-8″′和H-11″′),1.74(3H,s,H-5″),1.63(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.5(-C＝O),162.6(C-2),161.6(C-4),160.3(C-5″′),158.8(C-4′),131.5(C-2″′),144.3(C-β),131.2(C-3″),114.3(C-4″′和C-6″′),129.0(C-6),130.8(C-2′和C-6′),129.4(C-3″′和C-7″′),125.7(C-1′),122.3(C-2″),117.8(C-α),117.1(C-3),115.8(C-3′和C-5′),115.3(C-1),112.7(C-5),73.7(C-1″′),66.0(C-9″′和C-10″′),55.1(-OCH3),51.8(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.7(C-4″)；HR-ESI-MS:C32H36NO6 +[M+H]+m/z 530.2534.
实施例11.补骨脂乙素衍生物III-9的制备：
称取补骨脂乙素160mg(0.49mmol/L)溶解于4mL乙腈中，加入3,4,5-三甲氧基苯甲醛200mg(1.02mmol/L)、吗啉87μL(0.99mmol/L)，在80℃油浴中持续搅拌3小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用二氯甲烷:甲醇＝200:1至100:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物III-9(35.0mg)。黄色粉末，产率为12.1％；1H-NMR(DMSO-d6,300MHz)：δ13.94(s,2-OH),13.48(s,4′-OH),10.16(s,4-OH),7.92(1H,s,H-6),7.77(1H,d,J＝15.2Hz,H-β),7.74(2H,d,J＝7.7Hz,H-2′和H-6′),7.69(1H,d,J＝15.2Hz,H-α),6.86(2H,d,J＝8.6Hz,H-3″′和H-7″′),6.84(2H,d,J＝7.1Hz,H-3′和H-5′),5.24(m,H-2″),4.59(1H,s,H-1″′),4.11(9H,s,-OCH3),3.75(m,H-9″′和H-10″′),3.61(m,H-1″),3.33(m,H-8″′和H-11″′),1.74(3H,s,H-5″),1.60(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.5(-C＝O),162.4(C-2),161.7(C-4),160.4(C-4′),153.0(C-4″′和C-6″′),144.3(C-β),137.0(C-5″′),135.3(C-2″′),131.2(C-2′和C-6′),130.7(C-3″),129.1(C-6),125.7(C-1′),122.2(C-2″),117.5(C-α),117.2(C-3),115.9(C-1、C-3′和C-5′),115.5(C-5),112.5(C-3″′和C-7″′),74.6(C-1″′),66.0(C-9″′和C-10″′),55.9(4″′-OCH3和6″′-OCH3),55.8(5″′-OCH),55.7(C-8″′和C-11″′),25.5(C-5″),21.3(C-1″),17.7(C-4″)；HR-ESI-MS:calculated for C34H39NO8Na+(M+Na)+m/z 612.2568found 612.2570.
实施例12.补骨脂乙素衍生物III-10的制备：
称取补骨脂乙素300mg(0.93mmol/L)溶解于10mL乙腈中，加入过量的对三氟甲基苯甲醛252.6μL、吗啉162μL(1.85mmol/L)，在80℃油浴中持续搅拌5小时，用TLC监控反应。待反应结束后，加入乙酸乙酯萃取3次，并利用旋转蒸发仪减压蒸干乙酸乙酯溶剂后，提取浸膏经正相硅胶(300～400目)柱色谱分离，用石油醚:乙酸乙酯＝10:1至4:1的洗脱溶剂进行梯度洗脱，得到补骨脂乙素衍生物III-10(76.9mg)。黄色粉末，产率为14.6％；1H-NMR(DMSO-d6,300MHz)：δ13.91(s,4′-OH),10.18(s,4-OH),7.99(1H,s,H-6),7.75(m,H-2′、H-6′、H-α和H-β),7.75(m,H-3″′、H-4″′、H-6″′和H-7″′),6.88(2H,d,J＝8.5Hz,H-3′和H-5′),5.20(m,H-2″),4.82(1H,s,H-1″′),4.10(m,H-9″′和H-10″′),3.69(m,H-8″′和H-11″′),3.28(m,H-1″),1.72(3H,s,H-5″),1.62(3H,s,H-4″)；13C-NMR(DMSO-d6,75MHz)：δ191.5(-C＝O),162.8(C-2),161.1(C-4),160.4(C-4′),144.4(C-β和C-2″′),131.2(C-2′和C-6′),130.9(C-3″),129.2(C-6和C-1′),129.1(C-5″′),128.8(C-3″′和C-7″′),125.9(C-4″′和C-6″′),125.7(-CF3),122.1(C-2″),117.1(C-α),116.8(C-3),115.9(C-3′和C-5′),115.6(C-1),112.7(C-5),73.5(C-1″′),65.9(C-9″′和C-10″′),51.8(C-8″′和C-11″′),25.5(C-5″),21.4(C-1″),17.7(C-4″)；HR-ESI-MS:calculated for C32H32F3NO5Na+[M+Na]+m/z590.2125found 590.2125.
实施例13、MTT法检测实施例1—12制备的12种补骨脂乙素衍生物对七种癌细胞(人肺癌H1975和A549细胞、人乳腺癌MDA-MB-231和MCF-7细胞、人肝癌SMMC-7721细胞、人鼻炎癌CNE-2Z细胞、人宫颈癌HeLa细胞)的细胞毒性：
(1)实验材料：
细胞株：人肺癌H1975和A549细胞、人乳腺癌MDA-MB-231和MCF-7细胞、人肝癌SMMC-7721细胞、人鼻炎癌CNE-2Z细胞、人宫颈癌HeLa细胞购买于中国上海细胞库。
试剂与材料：紫杉醇、MTT购自美国Sigma公司；补骨脂乙素购自成都曼思特生物科技有限公司；DMEM或RPMI1640培养液、DMSO、0.25％胰蛋白酶、青霉素和链霉素购自美国Gibco公司；96孔培养板购自Corning公司；胎牛血清购自中国杭州四季青生物技术公司。
仪器：SP-DJ系列垂直净化工作台(上海普通物理光学仪器厂)，二氧化碳培养箱(Thermo Scientific公司)，多功能酶标仪(美国BioTek公司)，倒置显微镜(日本Olympus公司)。
(2)方法：
将上述七种癌细胞分别接种于DMEM或RPMI1640(含10％灭活胎牛血清，100IU/l青霉素，100μg/mL链霉素)，置5％ CO2、37℃饱和湿度环境下培养并传代。取对数生长期的肿瘤细胞，用0.25％胰蛋白酶消化制成单细胞悬液，按每孔5000个细胞的密度接种于96孔板中，置于培养箱中培养。过夜培养后，处理不同浓度的化合物以及紫杉醇(阳性对照组)，每个处理3个复孔，继续培养72小时(补骨脂乙素衍生物III-9对人肺癌H1975细胞作用24小时、48小时及72小时)。培养结束后，每孔加入10μL浓度为5g/L的MTT溶液继续孵育4小时，弃去培养液，并加入DMSO 150μL，置于37℃孵育30分钟，微量振荡器振荡10分钟使结晶物充分溶解，用酶标仪在570nm波长下检测每孔的吸光度(A)值，计算细胞存活率：细胞存活率/％＝实验组A570 nm/对照组A570nm×100％，绘制剂量效应曲线。
(3)实验结果：从表1结果可看出，本发明的补骨脂乙素衍生物I-1、II-1、III-1—III-6、III-8—III-10对H1975细胞具有较强的细胞毒性，其半数抑制浓度(IC50)值范围为4.35～13.79μmol/L；补骨脂乙素衍生物II-1和III-9对A549细胞具有一定的细胞毒性，其半数抑制浓度(IC50)分别为15.04和14.21μmol/L；补骨脂乙素衍生物I-1、II-1、III-1—III-6、III-8—III-10对MDA-MB-231细胞具有较强的细胞毒性，其半数抑制浓度(IC50)值范围为5.88～19.52μmol/L；补骨脂乙素衍生物I-1、II-1、III-1—III-10对MCF-7细胞具有较强的细胞毒性，其半数抑制浓度(IC50)值范围为4.14～17.24μmol/L；补骨脂乙素衍生物I-1、II-1、III-1、III-3—III-5、III-8—III-10对SMMC-7721细胞具有较强的细胞毒性，其半数抑制浓度(IC50)值范围为5.67～18.73μmol/L；补骨脂乙素衍生物I-1、II-1、III-1—III-10对CNE-2Z细胞具有较强的细胞毒性，其半数抑制浓度(IC50)值范围为7.11～19.84μmol/L；补骨脂乙素衍生物I-1、III-2、III-3、III-5、III-6、III-8—III-10对HeLa细胞具有较强的细胞毒性，其半数抑制浓度(IC50)值范围为10.16～17.38μmol/L。
表1.补骨脂乙素衍生物对七种癌细胞的细胞毒性(72小时,IC50,μmol/L)
图1结果还显示，随着补骨脂乙素衍生物III-9给药浓度的增加及作用时间的延长，人肺癌H1975细胞存活率逐渐降低，呈现浓度、时间依赖性。
实施例14、补骨脂乙素衍生物III-9诱导人肺癌H1975细胞凋亡的作用：
(1)实验材料：
试剂与材料：6孔培养板购自Corning公司；Annexin V-FITC/PI双染试剂盒购自贝博生物。
仪器：流式细胞仪(美国BD公司)。
(2)方法：取处于对数生长期的人非小细胞肺癌H1975细胞，按每孔3×105个细胞的密度接种于6孔板中，置于培养箱中培养至贴壁。然后，更换含有补骨脂乙素衍生物III-9(10μmol/L,20μmol/L,40μmol/L)或等体积DMSO的新鲜培养液，继续培养24小时。药物作用时间结束后，用0.25％胰酶消化细胞，并收集细胞，置于1500rpm离心10分钟，弃上清液。用预冷的Annexin V结合液重悬细胞，置冰浴，每管分别加入5μL的Annexin V-FITC染液和5μL的PI染液，避光染色20分钟后，用流式细胞仪检测分析。
(3)实验结果：图图2所示，随着补骨脂乙素衍生物III-9给药浓度(10μmol/L,20μmol/L,40μmol/L)的增加，诱导人肺癌H1975细胞凋亡比列逐渐升高，其凋亡率分别为6.95％、22.56％、42.27％。
实施例15.免疫蛋白印迹法检测补骨脂乙素衍生物III-9对人肺癌H1975细胞中Bax、Bcl-2蛋白表达的影响：
(1)实验材料：
抗体：PVDF膜、曝光液购自美国Millipore公司；Bax、Bcl-2抗体购自Proteintech公司。
仪器：凝胶成像系统(美国BIO-RAD公司)。
(2)方法：
取处于对数生长期的H1975细胞，按每孔3×105个细胞的密度接种于6孔板中，置于培养箱中培养过夜至贴壁。按实验设计，更换含有不同浓度化合物11(10μmol/L,20μmol/L,40μmol/L,80μmol/L)或等体积DMSO的新鲜培养液，继续培养24小时。培养结束后，收集细胞，置于2000rpm离心15分钟，弃上清液。每孔加入50μL含蛋白酶抑制剂的RIPA裂解液，置冰上裂解30分钟后，置15000rpm离心30分钟，取上清液用BCA法定量。每组取20μg蛋白进行SDS-PAGE电泳(积层胶恒压50V，分离胶恒压100V，电泳至溴酚蓝燃料到达凝胶最前沿，停止电泳)。
(转膜)：电泳结束后揭胶，并将凝胶浸于适量的Transfer buffer中。同时取适当大小的PVDF膜和4张3M滤纸，将PVDF先在无水甲醇中浸湿，然后同滤纸一起浸于Transferbuffer中，膜放阳极、胶放阴极，两面各垫2张3M滤纸，恒压60V，4℃层析柜中转膜2小时。
(封膜)：将转有蛋白的膜浸于含10％脱脂奶粉的TBST中封闭1小时。杂交：取出已封闭的膜，然后浸于一定比例稀释的Bax、Bcl-2一抗(含5％脱脂奶粉的TBST，pH 7.4配制)，在4℃过夜。TBST漂洗5次(每次5分钟)，再浸于1:2000稀释的二抗(含5％脱脂奶粉的TBST，pH 7.4配制)中，在室温1小时，TBST漂洗4次(每次5分钟)。配制显色液(ECL A0.5mL,ECL B0.5mL)，放置凝胶成像系统中显色分析。
(3)实验结果：图3结果显示，补骨脂乙素衍生物III-9在20μmol/L、40μmol/L、80μmol/L浓度条件下，上调促凋亡蛋白Bax的表达，而减少抗凋亡蛋白Bcl-2的表达，从而使Bax、Bcl-2的比例明显升高。
Claims (8)
1.补骨脂乙素衍生物，其特征在于，具有如式I所示的结构式：
2.权利要求1所述的补骨脂乙素衍生物的制备方法，其特征在于，包括以下步骤：
将补骨脂乙素溶解于氯仿中，加入25％的氢氧化钠溶液，在30℃温度下搅拌至反应结束后，调节pH至酸性，加入萃取液萃取，蒸干萃取液获得浸膏，纯化得到式I所示的补骨脂乙素衍生物。
3.补骨脂乙素衍生物，其特征在于，具有如式II所示的结构式：
4.权利要求3所述的补骨脂乙素衍生物的制备方法，其特征在于，包括以下步骤：
将式I所示的化合物溶于无水乙醇中，加入氨基胍和冰乙酸，在50℃温度下搅拌至反应结束后，萃取并纯化得到式II所示的补骨脂乙素衍生物；
式I所示的化合物的结构式为：
5.补骨脂乙素衍生物，其特征在于，具有如式III所示的结构通式：
其中R是4-溴苯基、3,4,5-三甲氧基苯基或4-三氟甲基苯基。
6.权利要求5所述的补骨脂乙素衍生物的制备方法，其特征在于，包括以下步骤：
将补骨脂乙素溶解在乙腈中，加入芳香醛和吗啉，在80℃温度下反应3-12小时，纯化即可得到式III所示的补骨脂乙素衍生物；
所述的芳香醛为对溴苯甲醛、3,4,5-三甲氧基苯甲醛或对三氟甲基苯甲醛。
7.权利要求1、3或5所述的补骨脂乙素衍生物在制备抗癌药物中的应用。
8.根据权利要求7所述补骨脂乙素衍生物在制备抗癌药物中的应用，其特征在于：所述的补骨脂乙素衍生物被配制为用于口服或注射给药的剂型。
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