CN105601493A - 一种基于蒽醌结构的紫草素类似物的制备方法及其应用 - Google Patents
一种基于蒽醌结构的紫草素类似物的制备方法及其应用 Download PDFInfo
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Abstract
本发明公开了一种基于蒽醌结构的紫草素类似物的制备方法及其应用,基于蒽醌结构的紫草素类似物为2-(4-取代苯基-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌衍生物,其制备方法是以1,4-二羟基蒽醌为原料,经羟烷基化在1,4-二羟基蒽醌的2位引入羟烷基得到;本发明与紫草素相比,对正常细胞的毒性明显降低,对这些化合物进行进一步的研究和开发,将为研制临床上可用的高效低毒的抗肿瘤药物打下良好的基础。
Description
技术领域
本发明涉及一种用于抗肿瘤的紫草素类似物,具体是一种基于蒽醌结构的紫草素类似物的制备方法及其应用。
背景技术
恶性肿瘤是严重威胁人类健康的疾病。尽管目前临床上的抗肿瘤药物种类繁多,但这些药物在发挥治疗作用的同时,对正常细胞也产生较大的毒害作用。这些副作用降低了化疗药物的临床疗效。因此,发展选择性地作用于肿瘤细胞而不伤害或少伤害正常细胞的抗肿瘤药具有十分重要的临床意义。
天然产物是药物先导结构的重要来源。临床许多常用的药物,特别是抗肿瘤药物均来自于天然产物。紫草素是植物紫草中的有效成分,有着显著的抗肿瘤活性。科研工作者以紫草素为先导化合物对其进行结构修饰与改造,合成了大量的结构类似物及衍生物。但现有技术对紫草素的修饰局限于对其结构中羟基的改造(EuropeanJournalofMedicinalChemistry,44,1410-1414,2009.)(EuropeanJournalofMedicinalChemistry,45,6005-6011,2010.)(EuropeanJournalofMedicinalChemistry,46,3420-3427,2011.)(BioorganicMedicinalChemistryLetters,24,4304-4307,2014.)(中国专利,公开号:CN103145583)(中国专利,公开号:CN103130680)(中国专利,公开号:CN102617342)未能提供对其侧链末端甲基进行修饰的内容。
紫草素的结构由两部分组分,一是含有羟基的萘茜环,二是含有羟基的侧链部分。同时,目前文献所报道的紫草素衍生物大多是在保留其萘茜母核结构的基础上对其羟基进行结构修饰(JournalofMedicinalChemistry,38,1044-1047,1995.)(EuropeanJournalofMedicinalChemistry,45,2713-2718,2010.)(EuropeanJournalofMedicinalChemistry,46,3934-3941,2011.)(BioorganicMedicinalChemistryLetters,22,1582-1586,2012.),未能提供将萘茜环修饰为醌茜环的内容。而醌茜环为绝大多数蒽环类抗肿瘤抗生素(如阿霉素,米托蒽醌等)的核心结构。
发明内容
由于现有技术对紫草素的修饰局限于对其结构中羟基的改造,未能提供对其侧链末端甲基进行修饰的内容;同时,现有技术未能提供将萘茜环修饰为醌茜环的内容。本发明针对现有技术存在的不足,完成了对紫草素侧链末端甲基和萘茜环的修饰,提供了一种可用于抗肿瘤的基于蒽醌结构的紫草素类似物的制备方法。
本发明是通过以下技术方案实现的,一种基于蒽醌结构的紫草素类似物,即2-(4-取代苯基-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌衍生物,具有如下的结构通式:
所述的R具体为氢,2-甲基,3-甲基,4-甲基,2-甲氧基,3-甲氧基,4-甲氧基,2-氟,3-氟,4-氟,2-氯,3-氯,4-氯,2-溴,3-溴,4-溴。
一种基于蒽醌结构的紫草素类似物的制备方法是以1,4-二羟基-9,10-蒽醌(醌茜)为原料,与β,γ-不饱和醛经羟烷基化反应得到,合成了共计16个目标化合物,目标化合物的结构见表1。
表1紫草素类似物的结构:
Compd. | R- |
3a | 氢 |
3b | 2-甲基 |
3c | 3-甲基 |
3d | 4-甲基 |
3e | 2-甲氧基 |
3f | 3-甲氧基 |
3g | 4-甲氧基 |
3h | 2-氟 |
3i | 3-氟 |
3j | 4-氟 |
3k | 2-氯 |
3l | 3-氯 |
3m | 4-氯 |
3n | 2-溴 |
3o | 3-溴 |
3p | 4-溴 |
进一步的,一种基于蒽醌结构的紫草素类似物的制备方法,具体步骤如下:1,4-二羟基蒽醌(0.5mmol)溶于甲醇(10ml)中,加入氢氧化钠溶液(1N,2.5ml);氮气保护下,加入溶于水(2mL)的连二亚硫酸钠(1.0mmol);搅拌10分钟后,加入β,γ-不饱和醛(1.0mmol),于0°C下反应3小时;将反应液倒入10mL加有30%双氧水(2mL)的冰水中,搅拌10分钟;加入盐酸溶液(3N,1mL)酸化,二氯甲烷萃取,饱和碳酸氢钠溶液洗,水洗,饱和食盐水洗,无水硫酸镁干燥;柱层析分离,得橙红色固体。
一种基于蒽醌结构的紫草素类似物,可应用在制备抗肿瘤药物中。
本发明的优点及有益效果如下:
(1)本发明化合物的制备方法简单,使用价廉易得的原料,只需一步反应即可得到目标化合物;
(2)将紫草素侧链末端甲基修饰为苯环后,得到的化合物对正常细胞没有显示出毒害作用,明显地改善了该类化合物对肿瘤细胞和正常细胞的选择性;
(3)首次对紫草素侧链末端的甲基进行结构修饰并将萘茜环修饰为醌茜环,丰富了紫草素类化合物的构效关系。
体外抗肿瘤实验表明,本发明提供的一种基于蒽醌结构的紫草素类似物与紫草素相比,对正常细胞的毒性明显降低,对这些化合物进行进一步的研究和开发,将为研制临床上可用的高效低毒的抗肿瘤药物打下良好的基础。
附图说明
图1为本发明化合物合成线路图。
具体实施方式
下面对本发明的实施例作详细说明:本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
实施例1:
2-(4-取代苯基-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌衍生物3a-p的合成通法:
1,4-二羟基蒽醌1(0.5mmol)溶于甲醇(10ml)中,加入氢氧化钠溶液(1N,2.5ml)。氮气保护下,加入溶于水(2mL)的连二亚硫酸钠(1.0mmol)。搅拌10分钟后,加入β,γ-不饱和醛2(1.0mmol),于0°C下反应3小时。将反应液倒入10mL加有30%双氧水(2mL)的冰水中,搅拌10分钟。加入盐酸溶液(3N,1mL)酸化,二氯甲烷萃取,饱和碳酸氢钠溶液洗,水洗,饱和食盐水洗,无水硫酸镁干燥。柱层析分离,得橙红色固体3。
2-(4-苯基-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3a
收率80%;mp130-132oC;1HNMR(400MHz,CDCl3)δ13.48(s,1H),12.91(s,1H),8.33-8.35(m,2H),7.82-7.84(m,2H),7.51(s,1H),7.36-7.38(m,2H),7.29-7.32(m,2H),7.21-7.24(m,1H),6.55(d,J=16.0Hz,1H),6.28(dt,J=16.0,8.0Hz,1H),5.19(dt,J=8.0,4.0Hz,1H),2.88-2.95(m,1H),2.57-2.65(m,1H),2.53(d,J=4.0Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.4,157.9,155.2,145.1,136.9,134.6,134.4,134.1,133.5,133.4,128.6,127.5,127.0,126.2,125.8,125.1,112.5,111.8,68.5,40.6.HRMS(ESI):m/zcaclcdforC24H17O5[(M-H+)-],385.1076;found,385.1075.
2-(4-(2-甲基苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3b
收率51%;mp112-114oC;1HNMR(400MHz,CDCl3)δ13.50(s,1H),12.91(s,1H),8.34-8.36(m,2H),7.83-7.85(m,2H),7.52(s,1H),7.41-7.43(m,1H),7.12-7.16(m,3H),6.73(d,J=16.0Hz,1H),6.16(dt,J=15.6,7.6Hz,1H),5.20(dt,J=8.4,4.4Hz,1H),2.91-2.98(m,1H),2.62-2.69(m,1H),2.53(d,J=4.0Hz,1H),2.32(s,3H).13CNMR(100MHz,CDCl3)δ187.4,186.5,157.9,155.3,145.1,136.1,135.1,134.6,134.4,133.6,133.4,132.1,130.3,127.4,127.0,127.0,126.4,126.1,125.9,125.6,112.5,111.8,68.5,40.8,19.8.HRMS(ESI):m/zcaclcdforC25H19O5[(M-H+)-],399.1232;found,399.1234.
2-(4-(3-甲基苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3c
收率90%;mp147-149oC;1HNMR(400MHz,CDCl3)δ13.48(s,1H),12.91(s,1H),8.33-8.35(m,2H),7.82-7.84(m,2H),7.51(s,1H),7.15-7.21(m,3H),7.04(d,J=4.0Hz,1H),6.51(d,J=16.0Hz,1H),6.26(dt,J=15.6,7.2Hz,1H),5.18-5.20(m,1H),2.88-2.94(m,1H),2.53-2.63(m,2H),2.33(s,3H).13CNMR(100MHz,CDCl3)δ187.4,186.4,157.9,155.2,145.1,138.1,136.8,134.6,134.4,134.3,133.6,133.4,128.5,128.3,127.0,127.0,126.9,125.8,124.9,123.4,112.5,111.8,68.5,40.6,21.4.HRMS(ESI):m/zcaclcdforC25H19O5[(M-H+)-],399.1232;found,399.1237.
2-(4-(4-甲基苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3d
收率70%;mp95-97oC;1HNMR(400MHz,CDCl3)δ13.47(s,1H),12.91(s,1H),8.32-8.35(m,2H),7.82-7.84(m,2H),7.50-7.54(m,1H),7.35(d,J=8.4Hz,1H),7.25-7.27(m,3H),6.51(d,J=15.6Hz,1H),6.22(dt,J=15.6,7.2Hz,1H),5.18(dt,J=8.4,4.0Hz,1H),2.88-2.94(m,1H),2.54-2.62(m,2H),2.33(s,3H).13CNMR(100MHz,CDCl3)δ187.3,186.4,157.9,155.2,145.2,137.3,134.5,134.4,134.1,133.5,133.4,129.3,129.2,127.0,127.0,126.8,126.1,125.8,123.9,112.4,111.7,68.4,40.6,21.2.HRMS(ESI):m/zcaclcdforC25H19O5[(M-H+)-],399.1232;found,399.1236.
2-(4-(2-甲氧基苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3e
收率49%;mp152-154oC;1HNMR(400MHz,CDCl3)δ13.50(s,1H),12.93(s,1H),8.35-8.37(m,2H),7.82-7.86(m,2H),7.53(s,1H),7.40-7.43(m,1H),7.20-7.24(m,1H),6.84-6.93(m,3H),6.26(dt,J=16.0,8.0Hz,1H),5.20(dt,J=8.0,4.0Hz,1H),3.84(s,3H),2.91-2.98(m,1H),2.59-2.67(m,1H),2.55(d,J=4.8Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.5,158.0,156.5,155.3,145.3,134.5,134.4,133.6,133.4,129.2,128.6,127.0,127.0,126.8,125.9,125.7,120.6,112.4,111.7,110.8,68.4,55.4,41.0.HRMS(ESI):m/zcaclcdforC25H19O6[(M-H+)-],415.1182;found,415.1175.
2-(4-(3-甲氧基苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3f
收率68%;mp127-129oC;1HNMR(400MHz,CDCl3)δ13.51(s,1H),12.92(s,1H),8.35-8.37(m,2H),7.83-7.86(m,2H),7.52(s,1H),7.21-7.25(m,1H),6.97(d,J=4.0Hz,1H),6.90(s,1H),6.79(d,J=8.0Hz,1H),6.52(d,J=16.0Hz,1H),6.24-6.32(m,1H),5.19-5.21(m,1H),3.82(s,3H),2.90-2.94(m,1H),2.60-2.65(m,1H),2.49(d,J=4.0Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.5,159.8,157.9,155.2,145.1,138.4,134.6,134.4,134.0,133.6,133.4,129.5,127.1,127.0,125.8,125.5,118.9,113.2,112.5,111.8,111.5,68.5,55.2,40.6.HRMS(ESI):m/zcaclcdforC25H19O6[(M-H+)-],415.1182;found,415.1177.
2-(4-(4-甲氧基苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3g
收率60%;mp127-129oC;1HNMR(400MHz,CDCl3)δ13.48(s,1H),12.92(s,1H),8.33-8.35(m,2H),7.82-7.85(m,2H),7.51(s,1H),7.30(d,J=8.0Hz,2H),6.84(d,J=8.0Hz,2H),6.49(d,J=16.0Hz,1H),6.12(dt,J=15.6,7.6Hz,1H),5.18(dt,J=8.0,4.0Hz,1H),3.80(m,3H),2.87-2.93(m,1H),2.57-2.61(m,1H),2.54(d,J=4.0Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.4,159.1,157.9,155.3,145.2,134.6,134.4,133.7,133.6,133.4,129.7,127.4,127.0,127.0,125.8,122.7,114.0,112.5,111.7,68.5,55.3,40.6.HRMS(ESI):m/zcaclcdforC25H19O6[(M-H+)-],415.1182;found,415.1178.
2-(4-(2-氟苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3h
收率49%;mp140-142oC;1HNMR(400MHz,CDCl3)δ13.49(s,1H),12.91(s,1H),8.34-8.36(m,2H),7.83-7.85(m,2H),7.51(s,1H),7.42-7.46(m,1H),7.17-7.20(m,1H),7.00-7.10(m,2H),6.69(d,J=16.0Hz,1H),6.36(dt,J=15.6,7.6Hz,1H),5.22(dt,J=8.0,4.0Hz,1H),2.91-2.97(m,1H),2.62-2.70(m,1H),2.52(d,J=4.0Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.5,157.9,155.2,145.0,134.6,134.4,133.6,133.4,128.7,128.0(d,J=4.6Hz),127.3(d,J=3.7Hz),127.0(d,J=3.1Hz),124.1(d,J=3.6Hz),126.4,125.8,115.8,115.6,112.5,111.8,68.6,40.9.HRMS(ESI):m/zcaclcdforC24H16O5F[(M-H+)-],403.0982;found,403.0983.
2-(4-(3-氟苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3i
收率79%;mp172-174oC;1HNMR(400MHz,CDCl3)δ13.48(s,1H),12.90(s,1H),8.33-8.35(m,2H),7.83-7.85(m,2H),7.50(s,1H),7.23-7.25(m,1H),7.05-7.13(m,2H),6.89-6.94(m,1H),6.50(d,J=15.6Hz,1H),6.30(dt,J=15.6,7.6Hz,1H),5.20(dt,J=8.0,4.0Hz,1H),2.87-2.93(m,1H),2.53-2.67(m,2H).13CNMR(100MHz,CDCl3)δ187.4,186.5,164.3,157.9,155.2,144.9,139.3(d,J=7.7Hz),134.6,134.4,133.6,133.4,132.8(d,J=2.5Hz),130.0,127.0(d,J=2.1Hz),126.8,125.8,122.1(d,J=2.6Hz),114.4,114.1,112.8,111.9,68.6,40.4.HRMS(ESI):m/zcaclcdforC24H16O5F[(M-H+)-],403.0982;found,403.0990.
2-(4-(4-氟苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3j
收率67%;mp176-178oC;1HNMR(400MHz,CDCl3)δ13.50(s,1H),12.93(s,1H),8.35-8.37(m,2H),7.84-7.86(m,2H),7.52(s,1H),7.31-7.35(m,2H),6.97-7.02(m,2H),6.51(d,J=16.0Hz,1H),6.20(dt,J=16.0,7.2Hz,1H),5.20(dt,J=8.0,4.0Hz,1H),2.88-2.92(m,1H),2.60-2.65(m,1H),2.48(d,J=4.0Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.5,157.9,155.2,145.0,134.6,134.4,133.6,133.4,133.1(d,J=3.4Hz),132.9,127.7(d,J=7.9Hz),127.1(d,J=2.1Hz),125.8,124.9,115.6,115.3,112.5,111.8,68.6,40.5.HRMS(ESI):m/zcaclcdforC24H16O5F[(M-H+)-],403.0982;found,403.0985.
2-(4-(2-氯苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3k
收率60%;mp128-130oC;1HNMR(400MHz,CDCl3)δ13.50(s,1H),12.91(s,1H),8.34-8.36(m,2H),7.83-7.85(m,2H),7.52(s,1H),7.32-7.34(m,1H),7.16-7.21(m,2H),6.90(d,J=16.0Hz,1H),6.27(dt,J=15.6,7.6Hz,1H),5.22(s,1H),2.92-2.98(m,1H),2.67-2.74(m,1H),2.54(s,1H).13CNMR(100MHz,CDCl3)δ187.4,186.5,157.9,155.2,144.9,135.1,134.6,134.4,133.6,133.4,132.7,130.2,129.6,128.5,128.2,127.1,127.0,126.8,125.9,112.6,111.9,68.6,40.6.HRMS(ESI):m/zcaclcdforC24H16O5Cl[(M-H+)-],419.0686;found,419.0683.
2-(4-(3-氯苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3l
收率90%;mp171-173oC;1HNMR(400MHz,CDCl3)δ13.50(s,1H),12.92(s,1H),8.35-8.37(m,2H),7.84-7.86(m,2H),7.51(s,1H),7.35(s,1H),7.19-7.24(m,3H),6.48(d,J=16.0Hz,1H),6.32(dt,J=15.6,7.6Hz,1H),5.20(dt,J=8.0,4.4Hz,1H),2.88-2.94(m,1H),2.60-2.67(m,1H),2.48(d,J=4.8Hz,1H).13CNMR(100MHz,CDCl3)δ187.5,186.5,157.9,155.2,144.9,138.9,134.6,134.4,133.6,133.4,132.6,132.6,129.8,127.4,127.4,127.1,127.0,126.2,125.8,124.4,112.6,111.9,68.7,40.5.HRMS(ESI):m/zcaclcdforC24H16O5Cl[(M-H+)-],419.0686;found,419.0702.
2-(4-(4-氯苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3m
收率85%;mp117-119oC;1HNMR(400MHz,CDCl3)δ13.50(s,1H),12.92(s,1H),8.35-8.37(m,2H),7.84-7.86(m,2H),7.51(s,1H),7.27-7.30(m,3H),6.49(d,J=16.0Hz,1H),6.26(dt,J=15.6,7.6Hz,1H),5.20(dt,J=8.0,4.4Hz,1H),2.87-2.93(m,1H),2.59-2.66(m,1H),2.48(d,J=4.8Hz,1H).13CNMR(100MHz,CDCl3)δ187.5,186.5,157.9,155.2,145.0,135.0,134.6,134.4,133.6,133.4,133.1,132.7,128.7,127.4,127.1,126.0,125.8,112.6,111.9,68.6,40.5.HRMS(ESI):m/zcaclcdforC24H16O5Cl[(M-H+)-],419.0686;found,419.0679.
2-(4-(2-溴苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3n
收率65%;mp140-142oC;1HNMR(400MHz,CDCl3)δ13.51(s,1H),12.92(s,1H),8.35-8.37(m,2H),7.83-7.86(m,2H),7.48-7.53(m,3H),7.24-7.26(m,1H),7.07-7.11(m,1H),6.84(d,J=15.6Hz,1H),6.20(dt,J=16.0,8.0Hz,1H),5.24(dt,J=7.6,4.4Hz,1H),2.92-2.98(m,1H),2.67-2.74(m,1H),2.54(d,J=4.0Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.5,157.9,155.2,144.9,136.9,134.6,134.4,133.6,133.4,132.9,132.8,128.8,128.4,127.5,127.1,127.1,127.0,125.9,123.3,112.6,111.9,68.6,40.5.HRMS(ESI):m/zcaclcdforC24H16O5Br[(M-H+)-],463.0181;found,463.0197.
2-(4-(3-溴苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3o
收率85%;mp179-181oC;1HNMR(400MHz,CDCl3)δ13.51(s,1H),12.93(s,1H),8.35-8.38(m,2H),7.84-7.86(m,2H),7.51(s,2H),7.35(d,J=8.0Hz,1H),7.29(s,1H),7.15-7.19(m,1H),6.47(d,J=16.0Hz,1H),6.30(dt,J=16.0,8.0Hz,1H),5.21(dt,J=8.0,4.0Hz,1H),2.88-2.94(m,1H),2.60-2.68(m,1H),2.47(d,J=4.8Hz,1H).13CNMR(100MHz,CDCl3)δ187.5,186.5,157.9,155.2,144.9,139.2,134.6,134.4,133.6,133.4,132.5,130.3,130.1,129.1,127.1,127.1,127.0,125.8,124.9,122.8,112.6,111.9,68.6,40.5.HRMS(ESI):m/zcaclcdforC24H16O5Br[(M-H+)-],463.0181;found,463.0172.
2-(4-(4-溴苯基)-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌3p
收率74%;mp180-182oC;1HNMR(400MHz,CDCl3)δ13.49(s,1H),12.91(s,1H),8.34-8.36(m,2H),7.83-7.86(m,2H),7.50(s,1H),7.41-7.43(m,2H),7.21-7.23(m,2H),6.47(d,J=16.0Hz,1H),6.27(dt,J=16.0,8.0Hz,1H),5.20(dt,J=8.0,4.0Hz,1H),2.86-2.92(m,1H),2.60-2.66(m,1H),2.50(d,J=4.0Hz,1H).13CNMR(100MHz,CDCl3)δ187.4,186.5,157.9,155.2,144.9,135.9,134.6,134.4,133.6,133.4,132.8,131.7,127.7,127.1,126.1,125.8,121.2,112.6,111.9,68.6,40.5.HRMS(ESI):m/zcaclcdforC24H16O5Br[(M-H+)-],463.0181;found,463.0170.
实施例2:化合物3a-p的体外细胞活性测试。
测定了本发明的化合物对人宫颈癌细胞HeLa,人乳腺癌细胞MDA-MB-231,人胰腺癌细胞MiaPaca-2,人乳腺癌细胞MCF-7和人正常乳腺上皮细胞MCF10的生长抑制作用。根据目标化合物在不同浓度下对细胞生长的抑制率,计算抑制细胞生长达到50%的化合物的浓度,以紫草素(shikonin)为阳性对照。结果列于表2,以IC50值表示。
表2目标化合物对不同的肿瘤细胞和正常细胞的毒性IC50(μM)
Claims (4)
1.一种基于蒽醌结构的紫草素类似物,其特征在于:其为2-(4-取代苯基-1-羟基-3-丁烯)-1,4-二羟基-9,10-蒽醌衍生物,结构通式如下:
R具体为氢,2-甲基,3-甲基,4-甲基,2-甲氧基,3-甲氧基,4-甲氧基,2-氟,3-氟,4-氟,2-氯,3-氯,4-氯,2-溴,3-溴,4-溴。
2.一种基于蒽醌结构的紫草素类似物的制备方法,其特征在于:以1,4-二羟基蒽醌(醌茜)为原料,与β,γ-不饱和醛经2位羟烷基化反应,再经双氧水氧化得到目标化合物。
3.根据权利要求2所述的一种基于蒽醌结构的紫草素类似物的制备方法,其特征在于:具体步骤如下:
步骤1:1,4-二羟基蒽醌(0.5mmol)溶于甲醇(10ml)中,加入氢氧化钠溶液(1N,2.5ml);
步骤2:氮气保护下,加入溶于水(2mL)的连二亚硫酸钠(1.0mmol);
步骤3:搅拌10分钟后,加入β,γ-不饱和醛(1.0mmol),于0°C下反应3小时;
步骤4:将反应液倒入10mL加有30%双氧水(2mL)的冰水中,搅拌10分钟;
步骤5:加入盐酸溶液(3N,1mL)酸化,二氯甲烷萃取,饱和碳酸氢钠溶液洗,水洗,饱和食盐水洗,无水硫酸镁干燥;
步骤6:柱层析分离,得橙红色固体。
4.一种基于蒽醌结构的紫草素类似物的应用,其特征在于,其应用在制备抗肿瘤药物中。
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CN1374288A (zh) * | 2002-03-19 | 2002-10-16 | 中山大学 | 紫草萘醌类衍生物及其在制备抗癌药物中的应用 |
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