CN110483297A - 1,5-二烯型巴豆烷二萜及其在制备抗艾滋病毒药物中的用途 - Google Patents

1,5-二烯型巴豆烷二萜及其在制备抗艾滋病毒药物中的用途 Download PDF

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CN110483297A
CN110483297A CN201810461388.3A CN201810461388A CN110483297A CN 110483297 A CN110483297 A CN 110483297A CN 201810461388 A CN201810461388 A CN 201810461388A CN 110483297 A CN110483297 A CN 110483297A
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卢燕
陈道峰
黄雅思
李国雄
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Abstract

本发明属中药制药领域，涉及1,5‑二烯型巴豆烷二萜及其在制备抗艾滋病毒药物中的用途。本发明从大戟科(Euphorbia)石栗属(Aleurites)植物三子油桐(Aleurites trisperma)中分离得到4个在5,6位具有不饱和双键的巴豆烷型二萜类新化合物，经试验证实其具有显著的抗HIV活性，EC50值为0.038～4.03μM，且细胞毒性较小，均大于1.6μM。本发明所述的巴豆烷型二萜化合物可作为活性成分用于制备抗艾滋病毒的药物。

Description

1,5-二烯型巴豆烷二萜及其在制备抗艾滋病毒药物中的用途
技术领域
本发明属中药制药领域，涉及三子油桐(Aleurites trisperma)中的巴豆烷型二萜类新化合物及其在制备抗艾滋病药物中的用途。
背景技术
现有技术公开了艾滋病(AIDS)是由艾滋病毒(HIV)引起的危害极大的传染性疾病，对艾滋病的治疗无疑是当今世界医学界一大难题。由于HIV的变异极快，疫苗研究困难，所以对艾滋病的治疗和预防一直未能取得突破性进展。
目前，采用的治疗艾滋病的有效方法是将HIV逆转录酶抑制剂和蛋白酶抑制剂合用的鸡尾酒疗法。医疗实践显示，尽管鸡尾酒疗法可以将艾滋病患者血液病毒水平降低到检出水平以下，但仍然不能彻底清除这一恶性病毒，研究表明，因为艾滋病毒进入体内后大部分会先进入潜伏期，而处于潜伏期的病毒可以躲过免疫系统和药物的攻击而不受影响，这成为了将艾滋病毒彻底根除的最大障碍，因此开发研制能够作用于潜伏期的HIV病毒的新药向药物化学工作者提出了挑战。在筛选抗HIV新药的过程中，越来越多的药物化学工作者将注意力转向了植物来源丰富、价廉易得、毒副作用小、分子结构复杂多样的天然化合物。
近年来研究发现，巴豆烷型二萜为大戟科(Euphorbia)植物的特征性成分之一，部分化合物可在一定程度上抑制HIV-1引起的MT4细胞病变。三子油桐(Aleuritestrisperma)是大戟科石栗属植物，主要产于印度、东亚等地，但活性成分研究较少。
基于现有技术的现状，本发明拟通过活性导向分离从三子油桐中寻找具有抗HIV活性的新的巴豆烷型二萜类化合物。
发明内容
本发明的目的是基于现有技术的现状，提供巴豆烷型二萜类新化合物及其在制备抗艾滋病毒药物中的用途，具体涉及1,5-二烯型巴豆烷二萜及其在制备抗艾滋病毒药物中的用途。
本发明应用现代药理筛选方法，从大戟科(Euphorbia)石栗属(Aleurites)植物三子油桐(Aleurites trisperma)中提取得到巴豆烷二萜类新化合物，并经实验证实其具有很强的抗艾滋病活性。
本发明所述的巴豆烷二萜类化合物具有如下的化学结构：
其中，R1与R2为如下取代基：
本发明的1,5-二烯型巴豆烷二萜化合物通过下述方法制备：取三子油桐的正丁醇部位浸膏，以抗HIV-1活性为导向，依此通过反复正相硅胶柱色谱、氨基硅胶柱色谱及反相高效液相色谱分离纯化，得到巴豆烷型化合物1～4，经鉴定均为新化合物，结构数据如下：
化合物(1)，C32H48O7(544)，淡黄色油状液体，[α]D 25+6.5°(c 0.14,MeOH)；IR(KBr)νmax:3440,2923,2853,1714,1383,1050cm-1；UV(MeOH)λmax(logε):225(4.1)nm；1H-NMR(600MHz,CDCl3)δH:7.65(1H,brs,H-1),6.89(1H,brs,H-5),4.38&4.26(2H,d,J＝13.9,H-20),3.48(1H,d,J＝5.31,H-8),3.29(1H,m,H-10),2.31(1H,m,H-2′),2.11(1H,m,H-12a),2.05(1H,m,H-11),1.82(3H,brs,H-19),1.62(2H,m,H-3′),1.61(1H,d,J＝5.35,H-14),1.59(1H,m,H-12b),1.17(3H,s,H-16),1.02(3H,s,H-17),0.94(3H,d,J＝6.01,H-18),0.88(3H,t,H-14′).13C-NMR(150MHz,CDCl3)δC:10.5(C-19),14.2(C-12′),15.5(C-17),18.7(C-18),22.6(C-15),22.6(C-4′),22.8(C-11′),23.1(C-16),24.8(C-3′),25.7(C-14),29.2～29.7(C-5′～9′),31.8(C-12),32.0(C-10′),34.7(C-2′),38.4(C-11),55.4(C-8),58.8(C-10),63.4(C-13),63.6(C-20),73.3(C-4),73.6(C-9),135.0(C-2),137.1(C-5),148.5(C-6),160.5(C-1),176.1(C-1′),202.5(C-7),205.5(C-3).
化合物(2)，C34H52O7(572)，淡黄色油状液体，[α]D 25+11.4(c 0.30,MeOH)；IR(KBr)νmax:3388,2921,2850,1712,1646cm-1；UV(MeOH)λmax(logε):225(4.0)nm；1H-NMR(600MHz,CDCl3)δH:7.66(1H,brs,H-1),6.87(1H,brs,H-5),4.38&4.26(2H,d,J＝13.9,H-20),3.46(1H,d,J＝5.38,H-8),3.31(1H,m,H-10),2.31(1H,m,H-2′),2.10(1H,t,H-12a),2.05(1H,m,H-11),1.83(3H,brs,H-19),1.62(2H,m,H-3′),1.62(1H,d,J＝5.53,H-14),1.59(1H,m,H-12b),1.17(3H,s,H-16),1.02(3H,s,H-17),0.94(3H,d,J＝6.35,H-18),0.88(3H,t,H-16′).13C-NMR(150MHz,CDCl3)δC:10.5(C-19),14.3(C-14′),15.5(C-17),18.6(C-18),22.6(C-15),22.6(C-4′),22.8(C-13′),23.1(C-16),24.8(C-3′),25.7(C-14),29.3～29.8(C-5′～11′),31.8(C-12),32.1(C-12′),34.7(C-2′),38.4(C-11),55.5(C-8),58.8(C-10),63.4(C-13),63.9(C-20),73.3(C-4),73.6(C-9),135.0(C-2),137.3(C-5),148.5(C-6),160.3(C-1),176.1(C-1′),202.7(C-7),205.5(C-3).
化合物(3)，C36H56O7(600)，淡黄色油状液体，[α]D 25+10.3°(c 0.185,MeOH)；IR(KBr)νmax:3387,2922,2852,1713,1672cm-1；UV(MeOH)λmax(logε):225(4.0)nm；1H-NMR(600MHz,CDCl3)δH:7.66(1H,brs,H-1),6.88(1H,brs,H-5),4.38&4.27(2H,d,J＝13.9,H-20),3.47(1H,d,J＝5.39,H-8),2.31(1H,t,H-2′),3.30(1H,m,H-10),2.11(1H,m,H-12a),2.04(1H,m,H-11),1.83(3H,brs,H-19),1.62(2H,m,H-3′),1.62(1H,d,J＝5.51,H-14),1.59(1H,m,H-12b),1.17(3H,s,H-16),1.02(3H,s,H-17),0.94(3H,d,J＝6.31,H-18),0.87(3H,t,H-16′).13C-NMR(150MHz,CDCl3)δC:10.5(C-19),14.3(C-14′),15.5(C-17),18.6(C-18),22.6(C-15),22.6(C-4′),22.8(C-13′),23.1(C-16),24.8(C-3′),25.7(C-14),29.3～29.8(C-5′～11′),31.8(C-12),32.1(C-12′),34.7(C-2′),38.4(C-11),55.5(C-8),58.8(C-10),63.4(C-13),63.9(C-20),73.3(C-4),73.6(C-9),135.0(C-2),137.3(C-5),148.5(C-6),160.3(C-1),176.1(C-1′),202.7(C-7),205.5(C-3).
化合物(4)，C32H50O7(546)，淡黄色油状液体，[α]D 25+23.3°(c 0.18,MeOH)；IR(KBr)νmax:3406,2923,2853,1707,1383,1049cm-1；UV(MeOH)λmax(logε):248(3.87)nm；H-NMR(600MHz,CDCl3)δH:6.14(1H,d,J＝5.0,H-7),5.60(1H,s,H-1),5.34(1H,s H-5),4.41(1H,dd,J＝5.6,10.6,H-8),3.94&1.60(2H,m,H-20),3.71(1H,s,H-3),2.62(1H,m,H-11),2.35(2H,m,H-3′),2.31&2.11(2H,ABq,H-12),2.31(2H,m,H-2′),1.77(3H,s,H-19),1.71(2H,m,H-3′),1.23(1H,m,H-4′-15′),1.18(3H,s,H-17),1.01(1H,m,H-16),0.99(3H,s,H-14),0.97(3H,d,J＝6.4,H-18),0.85(3H,m,H-14′),0.68(1H,m,H-13).13C-NMR(150MHz,CDCl3)δC:14.2(C-14′),14.7(C-17),15.6(C-19),19.2(C-18),22.8(C-15′),23.1(C-14),23.6(C-13),25.0(C-15),25.0(C-3′),28.7(C-16),29.2(C-13′),29.4(C-11′),29.4(C-12′),29.6(C-9′),29.6(C-10′),29.7(C-5′),29.7(C-6′),32.0(C-12),32.6(C-14'),34.4(C-2′),37.1(C-11),43.9(C-8),65.4(C-20),75.1(C-5),75.5(C-10),78.3(C-3),85.7(C-4),126.4(C-1),130.6(C-7),138.9(C-6),140.0(C-2),174.0(C-1′),208.5(C-9).。
本发明所述的巴豆烷型二萜类化合物经药理试验证明，均显示有显著的抗HIV作用，EC50值为0.038～4.03μM，且细胞毒性较小，均大于1.6μM(详见表1)。
本发明所述的巴豆烷型二萜类化合物可进一步作为活性成分用于制备治疗艾滋病毒的药物。
附图说明
图1是三子油桐中巴豆烷型二萜类成分提取分离流程图。
具体实施方式
实施例1制备三子油桐中的巴豆烷型二萜
取三子油桐乙醇提取物浸膏330g，分散于温水中，分别用石油醚、乙酸乙酯、正丁醇萃取，取正丁醇部位(101g)干法上样，进行硅胶柱色谱，以二氯甲烷-甲烷系统(95:5)等度洗脱，将正丁醇部位分成4个流分(Fr1～Fr4)，减压回收溶剂后，取Fr.2(11.5g)进行硅胶柱色谱，用石油醚-乙酸乙酯系统(100:0～0:100)进行梯度洗脱，将Fr2分成5个流份(Fr2.1～Fr2.5)，减压回收溶剂后，取Fr.2.3(2.7g)进行氨基硅胶柱色谱分离，用二氯甲烷-甲醇体系(100:0～0～100)洗脱，将Fr2.3分成5个流份(Fr2.3.1～Fr2.3.5)，减压收集溶剂，将Fr2.3.2与Fr2.2.3合并，并将该组分用反相高效液相色谱纯化，以乙腈-水(80:20～100:0)梯度洗脱，分离得到巴豆烷型二萜类化合物1～4。
实施例2体外抗HIV实验
应用HIV-1NL4-3病毒株感染MT4细胞(感染倍数＝0.001)，同时加入不同浓度的药物，感染48小时后加入含适宜浓度药物的新鲜基质以维持细胞的正常生长，4天后采用P24ELISA试剂盒分析病毒的复制情况；实验以齐多夫定(AZT)为阳性药物；化合物的EC50指药物抑制HIV-1P24抗原产生降低至50％时的药物浓度，采用线性回归法求得EC50(Biosoftsoftware)，结果如表1所示：
表1.化合物1～4抗HIV活性测定结果

Claims (3)

1.具有如下化学结构的1,5-二烯型巴豆烷二萜类化合物，
其中，R1与R2为如下取代基，
2.权利要求1所述的1,5-二烯型巴豆烷二萜类化合物的制备方法，其特征在于你，其包括步骤：取三子油桐的正丁醇部位浸膏，以抗HIV-1活性为导向，依此通过反复正相硅胶柱色谱、氨基硅胶柱色谱及反相高效液相色谱分离纯化，得到巴豆烷型化合物1～4，
所述的化合物(1)：C32H48O7(544)；化合物(2)：C34H52O7(572)；化合物(3)：C36H56O7(600)；化合物(4)：C32H50O7(546)。
3.权利要求1所述的1,5-二烯型巴豆烷二萜化合物在制备抗艾滋病毒药物中的用途。
CN201810461388.3A 2018-05-15 2018-05-15 1,5-二烯型巴豆烷二萜及其在制备抗艾滋病毒药物中的用途 Pending CN110483297A (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112715542A (zh) * 2021-01-20 2021-04-30 沈阳农业大学 巴豆烷二萜类化合物的制备方法及其在制备杀线虫的杀虫剂中的应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130243860A1 (en) * 2007-10-26 2013-09-19 Fundacao Universidade Do Vale Do Itajai Standardized plant extract, process for obtaining the same and uses thereof
CN105198899A (zh) * 2014-06-30 2015-12-30 复旦大学 1-烷基化瑞香烷型二萜及其在制备抗艾滋病毒药物中的用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130243860A1 (en) * 2007-10-26 2013-09-19 Fundacao Universidade Do Vale Do Itajai Standardized plant extract, process for obtaining the same and uses thereof
CN105198899A (zh) * 2014-06-30 2015-12-30 复旦大学 1-烷基化瑞香烷型二萜及其在制备抗艾滋病毒药物中的用途

Cited By (1)

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