CN115947707A - 愈创木烷型倍半萜类化合物及其制备方法与应用 - Google Patents
愈创木烷型倍半萜类化合物及其制备方法与应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药研究技术领域,具体涉及一种愈创木烷型倍半萜类化合物及其制备方法与应用。
背景技术
这里的陈述仅提供与本发明相关的背景技术,而不必然地构成现有技术。
艾Artemisia argyi Lévl.et.Vant.为菊科蒿属植物,主要分布于朝鲜半岛、日本、蒙古以及我国。蕲艾是来源于湖北省蕲春县的艾叶,是著名道地药材。研究发现蕲艾含有多种化学成分,包括萜类、黄酮类、酚酸类、多糖类及香豆素类等。其中萜类化合物具有重要的生理活性和药用价值,如抗疟疾药物青蒿素、抗肿瘤药物紫杉醇等。
萜类化合物是一类碳氢骨架以异戊烯为基本结构单元组成的天然产物,其中以三个异戊烯构成的为倍半萜,倍半萜内酯则是基本骨架为三个异戊烯单元构成的内酯化合物。目前,已经从艾叶中分离得到倍半萜类化合物近百种,中国专利CN112159378A公开了一种从腺梗豨莶中制备的吉马烷型倍半萜内酯类化合物,对于RANKL诱导的破骨细胞具有明显的抑制分化效果,绝大多数化合物的IC50均在10μM以下,且在10μM下不显示细胞毒性,可用于预防骨质疏松药物领域;中国专利CN114671837A公开了一种从豚草中制备的桉叶烷型倍半萜类化合物,对常见杂草有明显的抑制生长作用,在浓度为100μM时对狗尾草的生长抑制率达到了73.40±8.54%,对马唐的生长抑制率达到了51.23±4.12%,对藜的生长抑制率达到了69.88±8.09%,有望成为具有植物源除草剂应用前景的先导活性物质;中国专利CN114292253A公开了一种从伊犁绢蒿中制备的倍半萜类化合物,具有显著的体外促黑色素生成活性,和促进细胞内酪氨酸酶活性的作用,有望可以用于制备抗白癜风药物的先导化合物。
黑色素瘤起源于皮肤中的黑色素细胞,是皮肤癌中较为常见的类型,发病机理是皮肤中黑色素细胞发生超常增生。至今尚没有治疗痊愈的药物,给人类医学带来了难题。
发明内容
针对现有技术存在的不足,本发明的目的是提供一种愈创木烷型倍半萜类化合物及其制备方法与应用。
为了实现上述目的,本发明是通过如下的技术方案来实现:
第一方面,本发明提供一种愈创木烷型倍半萜类化合物,其选自具有以下结构式的化合物:
第二方面,本发明提供所述愈创木烷型倍半萜类化合物的制备方法,包括如下步骤:
将艾叶清洗、干燥后,采用50%-80%乙醇加热浸提,将提取液浓缩得粗提物;
将粗提物悬浮于水中,采用乙酸乙酯萃取或依次采用石油醚、乙酸乙酯萃取,乙酸乙酯萃取液浓缩得粗馏分;
将粗馏分经柱层析和高效液相色谱法制备得到目的化合物,高效液相色谱采用反相C18柱,洗脱体系为甲醇-水或乙腈-水。
经过试验发现,采用50%-80%乙醇加热浸提,可以具有较好选择性地将艾叶中的目标化合物提取至乙醇溶液中。再对粗提物进行萃取时,试验了多种溶剂体系,当采用乙酸乙酯作为萃取剂时,对目标化合物具有更好的选择性和提取率。而先采用石油醚进行萃取时,可以对粗提物进行预除杂,降低乙酸乙酯中的杂质含量,减轻后续分离过程中对目标化合物的杂质干扰。
在一些实施例中,所述加热浸提的温度为55-65℃,加热提取的时间为8-12h。
优选的,加热浸提的次数为2-4次。
在一些实施例中,所述柱层析包括正相硅胶柱层析、ODS反相柱层析和凝胶柱层析中的一种或两种。
优选的,柱层析的洗脱体系为甲醇、二氯甲烷-甲醇、石油醚-乙酸乙酯或甲醇-水。
优选的,柱层析的方法具体为:首先将乙酸乙酯萃取部分流经正相硅胶柱层析,采用二氯甲烷-甲醇洗脱体系按100:0→0:100梯度洗脱,得7个馏分,分别为Fr.1、Fr.2、Fr.3、Fr.4、Fr.5、Fr.6、Fr.7;
然后将Fr.2经ODS反相柱层析,采用二氯甲烷-甲醇洗脱体系按100:0→0:100洗脱,得5个馏分,分别为Fr.2-1、Fr.2-2、Fr.2-3、Fr.2-4、Fr.2-5;将Fr.2-1经凝胶柱层析,采用甲醇或二氯甲烷-甲醇洗脱体系洗脱;再采用高效液相色谱纯化,得化合物1。
进一步优选的,将馏分Fr.3经硅胶柱色谱,采用石油醚-乙酸乙酯洗脱体系按7:1→0:1进行梯度洗脱,得5个馏分,分别为Fr.3-1、Fr.3-2、Fr.3-3、Fr.3-4、Fr.3-5,Fr.3-1经HPLC制备色谱纯化,得到化合物2-4;
或,将馏分Fr.4经过凝胶柱层析,采用二氯甲烷-甲醇洗脱,得6个馏分,分别为Fr.4-1、Fr.4-2、Fr.4-3、Fr.4-4、Fr.4-5、Fr.4-6,Fr.4-3经HPLC制备色谱纯化,得到化合物5-6。
进一步优选的,将馏分Fr.5经过凝胶柱层析,采用二氯甲烷-甲醇洗脱,分离得到5个馏分,分别为Fr.5-1、Fr.5-2、Fr.5-3、Fr.5-4、Fr.5-5;将Fr.5-2经硅胶柱层析,采用二氯甲烷-甲醇梯度洗脱,得到6个馏分,分别为Fr.5-2-1、Fr.5-2-2、Fr.5-2-3、Fr.5-2-4、Fr.5-2-5、Fr.5-2-6;
Fr.5-2-3经HPLC制备色谱纯化,得到化合物7;
或,Fr.5-4经ODS柱层析,甲醇-水梯度洗脱,分离得到5个馏分,分别为Fr.5-4-1、Fr.5-4-2、Fr.5-4-3、Fr.5-4-4、Fr.5-4-5,Fr.5-4-1采用重结晶,得到化合物8。
第三方面,本发明提供所述愈创木烷型倍半萜类化合物1-8在制备黑色素瘤治疗药物或在化妆品中的应用。
上述本发明的一种或多种实施例取得的有益效果如下:
本发明提供的愈创木烷倍半萜内酯类化合物moxartenolide、dehydroleucodin、arteglasin A、artemdubolide C、arteglasin-B、dehydromatricarin、seco-tanapartholide C、3β-ethoxytanapartholide均具有良好的抗黑色素瘤活性,其中化合物moxartenolide对黑色素瘤细胞的IC50值达到0.832μM,本发明为研究和开发抗黑色素瘤药物提供了新的先导化合物,可应用于医药和化妆品领域,具有良好的运用前景。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为化合物1的抗黑色素瘤抑制曲线图;
图2为化合物2的抗黑色素瘤抑制曲线图;
图3为化合物3的抗黑色素瘤抑制曲线图;
图4为化合物4的抗黑色素瘤抑制曲线图;
图5为化合物5的抗黑色素瘤抑制曲线图;
图6为化合物6的抗黑色素瘤抑制曲线图;
图7为化合物7的抗黑色素瘤抑制曲线图;
图8为化合物8的抗黑色素瘤抑制曲线图。
图9为化合物1的1H-NMR谱图。
图10为化合物1的13C-NMR谱图。
图11为化合物2的1H-NMR谱图。
图12为化合物2的13C-NMR谱图。
图13为化合物3的1H-NMR谱图。
图14为化合物3的13C-NMR谱图。
图15为化合物4的1H-NMR谱图。
图16为化合物4的13C-NMR谱图。
图17为化合物5的1H-NMR谱图。
图18为化合物5的13C-NMR谱图。
图19为化合物6的1H-NMR谱图。
图20为化合物6的13C-NMR谱图。
图21为化合物7的1H-NMR谱图。
图22为化合物7的13C-NMR谱图。
图23为化合物8的1H-NMR谱图。
图24为化合物8的13C-NMR谱图。
具体实施方式
应该指出,以下详细说明都是例示性的,旨在对本发明提供进一步的说明。除非另有指明,本发明使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
以下实施例对本发明做进一步的描述,但该实施例并非用于限制本发明的保护范围。
实施例1化合物的制备
(1)取新鲜蕲艾艾叶干燥后,加入60%乙醇浸没后加热至60℃浸泡10h后提取两次,合并提取液浓缩得到粗提物。
(2)将粗提物悬浮于水中,依次采用石油醚和乙酸乙酯萃取6-8次,分别合并萃取液,浓缩得到2个粗馏分。
(3)取乙酸乙酯萃取的粗馏分,采用正相硅胶(200-300目)柱层析,以二氯甲烷-甲醇系统进行梯度洗脱,洗脱梯度为100:0、100:1、80:1、70:1、50:1、30:1、20:1、5:1、0:100,经TLC薄层色谱分析,划分为7个馏分(Fr.1~7)。
取馏分Fr.2经硅胶柱色谱(200~300目),二氯甲烷-甲醇(100:0→0:100)梯度洗脱得到5个馏分Fr.2-1~Fr.2-5。Fr2-1经凝胶柱色谱(二氯甲烷:甲醇=1:1)分离,再采用HPLC制备色谱(甲醇:水=55:45)纯化得到化合物1。
取馏分Fr.3经硅胶柱色谱(300-400目),石油醚-乙酸乙酯(7:1→1:1)梯度洗脱得到5个馏分Fr.3-1~Fr.3-5。Fr.3-1经HPLC制备色谱(甲醇:水=65:35)纯化,得到化合物2-4。
取馏分Fr.4经过凝胶柱色谱(二氯甲烷:甲醇=1:1)分离得到6个馏分Fr.4-1~Fr.4-6。Fr.4-3经HPLC制备色谱(甲醇:水=55:45)纯化,得到化合物5-6;
取馏分Fr.5经过凝胶柱色谱(二氯甲烷:甲醇1:1)分离得到5个馏分Fr.5-1~Fr.5-5。Fr.5-2经硅胶柱色谱(200-300目),二氯甲烷:甲醇(100:0→0:100)梯度洗脱后得到6个馏分Fr.5-2-1~Fr.5-2-6,Fr.5-2-3经HPLC制备色谱(乙腈:水=55:45)纯化,得到化合物7;Fr.5-4经ODS柱色谱,甲醇-水(20%→100%)梯度洗脱分离得到5个馏分Fr.5-4-1~Fr.5-4-5,Fr.5-4-1采用重结晶得到化合物8。
实施例2化合物结构鉴定
所有化合物经核磁鉴定后,所得化合物的性状和波谱数据如下:
化合物1:dehydroleucodin,无色油状物,分子式为C15H16O3。1H-NMR(600MHz,CDCl3)δ:6.18(1H,d,J=3.1Hz,H-13b),6.17(1H,m,H-3),5.46(1H,d,J=3.1Hz,H-13a),3.61(1H,t,J=10.1Hz,H-6),3.51(1H,d,J=10.0Hz,H-5),2.90(1H,m,H-7),2.44(3H,s,H-10),2.32(3H,s,H-4);13C-NMR(126MHz,CDCl3)δ:195.9(C-2),169.6(C-4),169.3(C-12),152.0(C-10),138.6(C-11),135.8(C-3),132.0(C-1),119.0(C-13),84.4(C-6),53.1(C-5),53.0(C-5),37.3(C-9),24.5(C-8),21.9(C-14),19.9(C-15)。以上数据与文献对照,故鉴定化合物1为dehydroleucodin。
化合物2:arteglasin A,无色油状物,分子式为C17H20O5。1H-NMR(600MHz,CD3OD)δ:6.07(1H,d,J=3.0Hz,H-13a),5.61(1H,d,J=3.0Hz,H-13b),4.75(1H,ddd,J=2.2,10.6,21.1Hz,H-8),3.84(1H,t,J=10.4Hz,H-6),3.43(1H,s,H-3),3.26(1H,m,H-7),3.12(1H,d,J=10.8Hz,H-5),2.61(1H,d,J=18.3Hz,H-2a),2.54(1H,dd,J=2.0,12.8Hz,H-9a),2.52(1H,s,H-2b),2.21(1H,dd,J=2.0,12.8Hz,H-9b),2.09(1H,s,H-2′)1.71(3H,s,H-15),1.61(3H,s,H-14);13C-NMR(126MHz,CD3OD)δ:171.6(C-1′),170.7(C-11),138.9(C-12),138.1(C-1),129.0(C-10),120.7(C-12),79.4(C-6),71.8(C-8),68.2(C-4),65.0(C-3),57.1(C-7),52.3(C-5),41.9(C-9),34.1(C-2),21.9(C-15),21.0(C-2′),19.2(C-14)。以上数据与文献对照,故鉴定化合物2为arteglasin A。
化合物3:moxartenolide,无色油状物,分子式为C20H22O5。1H-NMR(600MHz,CD3OD)δ:6.28(1H,m,H-3′),6.19(1H,d,J=1.3Hz,H-3),6.11(1H,d,J=3.2Hz,H-13b),5.61(1H,d,J=3.2Hz,H-13a),5.04(1H,ddd,J=2.2,10.5,21.0Hz,H-8),3.83(1H,dd,J=10.4,20.1Hz,H-6),3.55(1H,m,H-7),2.91(1H,dd,J=10.9,13.7Hz,H-9a),2.49(1H,dd,J=2.2,13.7Hz,H-9b),2.43(3H,s,H-14),2.34(3H,br s,H-15),2.03(3H,dq,J=1.6,7.3Hz,H-4′),1.93(3H,dq,J=1.5,1.7Hz,H-5′);13C-NMR(126MHz,CD3OD)δ:197.5(C-2),173.0(C-4),170.2(C-12),167.7(C-1′),147.1(C-10),141.3(C-3′),138.5(C-3),136.2(C-1),135.0(C-11),128.3(C-2′),121.4(C-13),83.1(C-6),70.3(C-8),55.6(C-7),52.3(C-5),45.0(C-9),21.3(C-14),20.6(C-5′),19.9(C-15),16.1(C-4′)。以上数据与文献对照,故鉴定化合物3为moxartenolide。
化合物4:artemdubolide C,无色油状物,分子式为C20H24O5。1H-NMR(600MHz,CD3OD)δ:6.18(1H,s,H-3),6.12(1H,d,J=3.2Hz,H-13a),5.68(1H,d,J=2.9Hz,H-13b),4.94(1H,m,H-8),3.82(1H,dd,J=9.6,10.2Hz,H-6),3.78(1H,d,J=10.5Hz,H-5),3.48(1H,m,H-7),2.86(1H,dd,J=10.9,13.8Hz,H-9a),2.44(1H,dd,J=2.4,13.8Hz,H-9b),2.42(1H,m,H-2′),2.41(3H,s,H-15),2.33(3H,s,H-14),2.12(1H,m,H-3′a),1.92(1H,m,H-3′b),1.01(3H,d,J=6.6Hz,H-5′),0.99(3H,d,J=6.6Hz,H-4′);13C-NMR(126MHz,CD3OD)δ:197.5(C-2),173.4(C-1′),173.0(C-12),170.3(C-4),147.0(C-10),138.2(C-11),136.2(C-3),135.0(C-1),121.7(C-13),83.0(C-6),70.6(C-8),55.5(C-5),52.3(C-7),45.0(C-9),44.0(C-2′),26.7(C-3′),22.7(C-14),22.7(C-15),21.3(C-5′),19.9(C-4′)。以上数据与文献对照,故鉴定化合物4为artemdubolide C。
化合物5:arteglasin-B,无色油状物,分子式为C17H20O6。1H-NMR(600MHz,CDCl3)δ:6.24(1H,d,3.0Hz,H-13a),5.63(1H,d,J=3.0Hz,H-13b),5.55(1H,s,H-14b),5.01(1H,s,H-14a),4.95(1H,m,H-8),4.04(1H,s,1-OH),3.90(1H,q,J=11.24Hz,H-6),3.58(1H,s,H-3),3.24(1H,m,H-7),2.15(3H,s,H-2′),1.65(3H,s,H-15);13C-NMR(126MHz,CDCl3)δ:170.3(C-1′),168.7(C-12),140.6(C-10),136.5(C-11),122.8(C-13),118.2(C-14),81.9(C-1),75.3(C-6),73.3(C-8),67.5(C-4),64.4(C-3),61.0(C-5),46.4(C-7),40.6(C-2),35.1(C-9),21.3(C-2′),18.7(C-15)。以上数据与文献对照,故鉴定化合物6为arteglasin-B。
化合物6:dehydromatricarin,无色油状物,分子式为C17H18O5。1H-NMR(600MHz,CDCl3)δ:6.22(1H,d,J=3.0Hz,H-13b),6.18(1H,s,H-3),5.64(2H,d,J=3.0Hz,H-13a),4.90(1H,dt,J=2.3,10.7Hz,H-8),3.7(1H,t,J=10.1Hz,H-6),3.5(1H,d,J=10.6Hz,H-5),3.25(1H,dt,J=2.5,10.5Hz,H-7),2.70(1H,t,J=11.5Hz,H-9a),2.46(1H,t,J=11.5Hz,H-9b),2.43(3H,s,H-15),2.32(3H,s,H-14),2.15(3H,s,H-2′);13C NMR(126MHz,CDCl3)δ:195.0(C-2),169.7(C-1′),169.3(C-4),168.4(C-12),144.7(C-10),136.1(C-3),135.7(C-11),133.6(C-1),121.9(C-13),81.4(C-6),69.3(C-8),55.0(C-7),51.6(C-5),44.4(C-9),21.3(C-15),21.1(C-2′),20.0(C-14)。以上数据与文献对照,故鉴定化合物7为dehydromatricarin。
化合物7:seco-tanapartholide C,无色油状物,分子式为C15H18O4。1H-NMR(600MHz,CDCl3)δ:6.32(1H,d,J=2.7Hz,H-13b),5.64(1H,d,J=2.5Hz,H-13a),4.94(1H,d,J=5.0Hz,H-6),3.16(1H,m,H-7),2.58(2H,m,H-3),2.55(1H,m,H-9),2.53(1H,dd,J=6.0,8.5Hz,H-9),2.38(2H,t,J=5.0Hz,H-2),2.13(3H,s,H-14),2.12(3H,s,H-15),1.95(1H,m,H-8b),1.84(1H,m,H-8a);13C-NMR(126MHz,CDCl3)δ:207.6(C-1),207.2(C-10),175.4(C-4),170.1(C-12),138.6(C-11),136.8(C-5),122.6(C-13),76.5(C-6),42.7(C-7),39.5(C-9),34.4(C-2),32.7(C-3),30.1(C-14),27.4(C-8),17.8(C-15)。以上数据与文献对照,故鉴定化合物10为seco-tanapartholide C。
化合物8:3β-ethoxytanapartholide,无色油状物,分子式为C17H22O5。1H-NMR(600MHz,CDCl3)δ:6.34(1H,d,J=2.6Hz,H-13a),5.65(1H,d,J=2.6Hz,H-13b),4.97(1H,d,J=5.2Hz,H-4),4.36(1H,d,J=6.0Hz,H-6),3.60(1H,m,H-16a),3.54(1H,m,H-16b),3.05(1H,m,H-3),2.70(1H,dd,J=6.0,18.3Hz,H-9a),2.57(2H,m,H-2),2.30(1H,dd,J=6.0Hz,18.3Hz,H-9b),2.14(3H,s,H-15),2.12(3H,s,H-14),1.23(3H,t,J=6.9Hz,H-17),1.96(2H,m,H-8);13C-NMR(126MHz,CDCl3)δ:207.5(C-10),203.0(C-1),171.69(C-4),170.04(C-12),138.55(C-5),138.23(C-11),123.23(C-13),78.32(C-6),76.20(C-3),66.09(C-16),43.39(C-7),41.70(C-2),39.49(C-9),30.17(C-14),27.63(C-8),15.45(C-15),14.58(C-17)。以上数据与文献对照,故鉴定化合物11为3β-ethoxytanapartholide。
实施例3药理活性实验
实验方法:将实施例2中的化合物1~8作为测试样品,用DMSO配制为20mM母液置于-20℃保存,PBS稀释为1mL 500μM测试液置于4℃保存,不含细胞、待测样品为空白组,含细胞不含待测样品的为对照孔,含细胞与待测样品的试验孔。采用CCK8法检测样品对黑色素瘤A2058细胞的抑制率,每个样品浓度均设置3个复孔。
具体实验步骤:人黑色素瘤A2058细胞(购自武汉普诺赛公司)用RPMI 1640完全培养基(10% FBS,1%青霉素,1%链霉素),置于37℃、5% CO2的恒温培养箱中培养。将培养至对数生长期的A2058细胞按每孔3×103的100μL细胞悬液均匀铺至96孔板中,培养24h至细胞贴壁生长后,将测试样品分别配置为(0.625、1.25、2.5、5、10μM)的200μL含药培养基,换液给药。给药72h后,弃上清液,每孔加入含10% CCK8的培养基100μL。培养箱培养2h后,酶标仪中测定在450nm处的吸光度。
按上述方法得到的结果如表1所示
表1为化合物1~8对人黑色素瘤细胞A2058的抑制活性结果,IC50表示细胞半数抑制浓度
表1
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
2.权利要求1所述愈创木烷型倍半萜类化合物的制备方法,其特征在于:包括如下步骤:
将艾叶清洗、干燥后,采用50%-80%乙醇加热浸提,将提取液浓缩得粗提物;
将粗提物悬浮于水中,采用乙酸乙酯萃取或依次采用石油醚、乙酸乙酯萃取,乙酸乙酯萃取液浓缩得粗馏分;
将粗馏分经柱层析和高效液相色谱法制备得到目的化合物,高效液相色谱采用反相C18柱,洗脱体系为甲醇-水或乙腈-水。
3.跟据权利要求2所述的愈创木烷型倍半萜类化合物的制备方法,其特征在于:所述加热浸提的温度为55-65℃,加热提取的时间为8-12h。
4.跟据权利要求3所述的愈创木烷型倍半萜类化合物的制备方法,其特征在于:加热浸提的次数为2-4次。
5.跟据权利要求2所述的愈创木烷型倍半萜类化合物的制备方法,其特征在于:所述柱层析包括正相硅胶柱层析、ODS反相柱层析和凝胶柱层析中的一种或两种。
6.跟据权利要求5所述的愈创木烷型倍半萜类化合物的制备方法,其特征在于:柱层析的洗脱体系为甲醇、二氯甲烷-甲醇、石油醚-乙酸乙酯或甲醇-水。
7.跟据权利要求6所述的愈创木烷型倍半萜类化合物的制备方法,其特征在于:柱层析的方法具体为:首先将乙酸乙酯萃取部分流经正相硅胶柱层析,采用二氯甲烷-甲醇洗脱体系按100:0→0:100梯度洗脱,得7个馏分,分别为Fr.1、Fr.2、Fr.3、Fr.4、Fr.5、Fr.6、Fr.7;
然后将Fr.2经ODS反相柱层析,采用二氯甲烷-甲醇洗脱体系按100:0→0:100洗脱,得5个馏分,分别为Fr.2-1、Fr.2-2、Fr.2-3、Fr.2-4、Fr.2-5;将Fr.2-1经凝胶柱层析,采用甲醇或二氯甲烷-甲醇洗脱体系洗脱;再采用高效液相色谱纯化,得化合物1。
8.跟据权利要求7所述的愈创木烷型倍半萜类化合物的制备方法,其特征在于:将馏分Fr.3经硅胶柱色谱,采用石油醚-乙酸乙酯洗脱体系按7:1→0:1进行梯度洗脱,得5个馏分,分别为Fr.3-1、Fr.3-2、Fr.3-3、Fr.3-4、Fr.3-5,Fr.3-1经HPLC制备色谱纯化,得到化合物2-4;
或,将馏分Fr.4经过凝胶柱层析,采用二氯甲烷-甲醇洗脱,得6个馏分,分别为Fr.4-1、Fr.4-2、Fr.4-3、Fr.4-4、Fr.4-5、Fr.4-6,Fr.4-3经HPLC制备色谱纯化,得到化合物5-6。
9.跟据权利要求7所述的愈创木烷型倍半萜类化合物的制备方法,其特征在于:将馏分Fr.5经过凝胶柱层析,采用二氯甲烷-甲醇洗脱,分离得到5个馏分,分别为Fr.5-1、Fr.5-2、Fr.5-3、Fr.5-4、Fr.5-5;将Fr.5-2经硅胶柱层析,采用二氯甲烷-甲醇梯度洗脱,得到6个馏分,分别为Fr.5-2-1、Fr.5-2-2、Fr.5-2-3、Fr.5-2-4、Fr.5-2-5、Fr.5-2-6;
Fr.5-2-3经HPLC制备色谱纯化,得到化合物7;
或,Fr.5-4经ODS柱层析,甲醇-水梯度洗脱,分离得到5个馏分,分别为Fr.5-4-1、Fr.5-4-2、Fr.5-4-3、Fr.5-4-4、Fr.5-4-5,Fr.5-4-1采用重结晶,得到化合物8。
10.权利要求1所述愈创木烷型倍半萜类化合物1-8在制备黑色素瘤治疗药物或在化妆品中的应用。
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