CN114133424B - 三萜类化合物及其制备方法和应用 - Google Patents
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Abstract
本发明属于医药技术领域,涉及三萜类化合物及其制备方法和应用,具体涉及从雀舌木属植物雀舌木、线叶雀舌木、云南雀舌木、腺缘雀舌木中得到的三萜类化合物及其制备方法和应用,属于医药技术领域。本发明所述的化合物及其盐如式(I)或(II)所示:其中,R1‑R4如权利要求和说明书所述。所述的三萜类化合物具有较好的抗肿瘤活性,能够用于制备抗肿瘤药物。
Description
技术领域
本发明属于医药技术领域,涉及三萜类化合物及其制备方法和应用,具体涉及从雀舌木属植物雀舌木、线叶雀舌木、云南雀舌木、腺缘雀舌木中得到的三萜类化合物及其制备方法和应用,属于医药技术领域。
背景技术
大戟科(Euphorbiaceae)雀舌木属(Leptopus)植物,又名黑钩叶属,在世界范围内约有二十余种,分布于喜马拉雅山北部至亚洲东南部,经马来西亚至澳大利亚。其在我国共有九种,分布在中国南方地区,主要产于四川,广东,广西,云南,贵州,海南等地。线叶雀舌木(Leptopus lolonum(Hand.-Mazz.)Pojark.)、雀舌木、云南雀舌木、腺缘雀舌木等多年生草本植物,生长在海拔2000-2500米山地灌木丛中,在我国分布于四川,贵州,云南等省。雀舌木属植物具有良好的药用价值,中国植物志(1994,44,19)记载:厚叶雀舌木(Leptopuspachyphyllus X.X.Chen)的叶可供药用,可治皮肤溃疡,用于止血等;新华本草纲要(二册,225)记载:雀舌木,即雀儿舌头(Leptopus chinensis(Bunge)Pojark),又名黑钩叶(秦岭植物志),草桂花(昆明),入药部位为根部,可治腹泻。雀儿舌头在河南民间主要用于治疗肺癌,病毒性肝炎,肾炎以及全身瘫痪,雀儿舌头乙醇提取液对Eca-109,PC-3,MGC-803,SK-N-SH等癌细胞株具有较好的抑制作用,而其余八种雀舌木属植物的化学成分及药理活性亦处于空白中,未有文献报道。
发明内容
本发明的首要目的在于揭示雀舌木属植物的药效物质基础及药理活性。
本发明的另一个目的是提供14种三萜类化合物。
本发明的另一目的在于提供了27种三萜类化合物作为制备抗肿瘤药物的用途。
本发明提供了式(I)或(II)所示的化合物及其盐:
其中,母核由A、B、C、D、E五个环骈合而成,A/B、B/C、C/D均为反式骈合,D/E环存在顺式或反式骈合两种方式;
R1、R2、R4为氢、羟基,或羟基与酰基相连形成的酯,酰基的种类主要包括顺、反式的桂皮酰基、咖啡酰基、香豆酰基、阿魏酰基、异阿魏酰基,以及6-10元芳香羧酸基;
R3为C1-C4烷基、-CH2OH、-COOH、-CHO、-OH、-OOH中的任意一个,以及由相应位置的-CH2OH及-COOH衍生的酯类中的一个或多个。
本发明优选具有如下结构的三萜类化合物:
通式(I)中,
R1为羟基与酰基相连形成的酯,酰基的种类主要包括顺、反式的桂皮酰基、咖啡酰基、香豆酰基、阿魏酰基、异阿魏酰基;
R2为氢、羟基;
R3为-CH2OH、-COOH、-CHO、-OH、-OOH、-CH2OAc;
R4为氢、羟基;
通式(II)中,
R1为羟基与酰基相连形成的酯,酰基的种类主要包括顺、反式的桂皮酰基、咖啡酰基、香豆酰基、阿魏酰基、异阿魏酰基;
R2为羟基与酰基相连形成的酯,酰基的种类主要包括顺、反式的桂皮酰基、咖啡酰基、香豆酰基、阿魏酰基、异阿魏酰基;
R3为-COOH;
R4为氢、羟基。
本发明优选具有如下结构的五环三萜类化合物;
羽扇豆烷型,其中C-20-OH或C-20(29)为双键;齐墩果烷型的C-24位为-CH2OH。
本发明优选具有如下结构的羽扇豆烷、羽扇豆烯及齐墩果烷类三萜:
其中,R1、R4为羟基或其中的1个或2个羟基与顺或反式的桂皮酰基、咖啡酰基、香豆酰基、阿魏酰基、异阿魏酰酰基、苯甲酰基相连形成酯。R2为-CH3或-CH2OH,优选选择-CH2OH;
R3为-CH3、-CH2OH、-COOH、-CHO、-OH、-OOH中的任意一个。
本发明所说的对天然来源的三萜类化合物开展的化学反应和结构修饰,是指本领域采用的常规化学方法,包括对天然来源的三萜类化合物纯品或其混合物实施水解,断开糖链,除去原有酯基,得到含有多个羟基的衍生物或将多羟基的衍生物与酸酐、酰卤反应,将游离的羟基酯化,得到半合成三萜类化合物的方法。
本发明所提供了27种三萜类化合物的结构和名称如下,其中标有“*”为新结构。
化合物1-27结构具体见表1,其中1-9、12-16为14个新化合物。
表1化合物1-27结构
化合物1-27谱学数据如下:
化合物1 3β-O-(trans-p-coumaroyl)-lupane-28-al-20-ol
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.86(3H,s,H-23),0.88(3H,s,H-25),0.89(3H,s,H-26),0.90(3H,s,H-24),0.99(3H,s,H-27),1.16(3H,s,H-29),1.27(3H,s,H-30),1.47(3H,s,H-22),4.60(1H,dd,J=10.8,4.8Hz,H-3),6.29(1H,d,J=15.6Hz,H-2'),6.83(2H,d,J=8.4Hz,H-6',8'),7.42(2H,d,J=8.4Hz,H-5',9'),7.62(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.6(C-1),24.0(C-2),81.0(C-3),38.2(C-4),55.5(C-5),18.4(C-6),34.8(C-7),41.5(C-8),50.5(C-9),37.2(C-10),21.5(C-11),28.4(C-12),38.4(C-13),43.7(C-14),29.4(C-15),29.7(C-16),61.8(C-17),47.2(C-18),49.6(C-19),73.8(C-20),29.3(C-21),33.2(C-22),28.2(C-23),16.9(C-24),16.5(C-25),16.4(C-26),14.7(C-27),207.2(C-28),25.1(C-29),31.4(C-30),167.5(C-1'),115.1(C-2'),144.3(C-3'),127.5(C-4'),130.1(C-5',9'),116.1(C-6',8'),158.0(C-7').
化合物2 3β-O-(trans-p-coumaroyl)-20-ol-betulinic acid
白色粉末(甲醇),1H-NMR(600MHz,DMSO)δH:0.83(3H,s,H-23),0.85(3H,s,H-25),0.88(3H,s,H-24),0.89(3H,s,H-26),0.97(3H,s,H-27),1.00(3H,s,H-29),1.09(3H,s,H-30),4.50(1H,dd,J=11.4,4.8Hz,H-3),6.36(1H,d,J=16.2Hz,H-2'),6.79(2H,d,J=9.0Hz,H-6',8'),7.53(1H,d,J=15.6Hz,H-3'),7.54(2H,d,J=8.4Hz,H-5',9')。13C-NMR(150MHz,DMSO)δC:38.4(C-1),24.0(C-2),80.3(C-3),37.1(C-4),55.1(C-5),18.3(C-6),34.6(C-7),41.2(C-8),50.2(C-9),36.7(C-10),21.6(C-11),26.8(C-12),38.1(C-13),43.3(C-14),28.9(C-15),30.1(C-16),58.4(C-17),46.3(C-18),49.3(C-19),71.7(C-20),28.7(C-21),32.4(C-22),28.2(C-23),17.0(C-24),16.5(C-25),16.0(C-26),15.2(C-27),178.2(C-28),26.8(C-29),31.4(C-30),166.9(C-1'),115.1(C-2'),144.9(C-3'),125.6(C-4'),130.8(C-5',9'),116.2(C-6',8'),160.2(C-7').
化合物3 3β-O-(trans-p-coumaroyl)-lupane-28-O-acetyl-20-ol
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.88(3H,s,H-26),0.89(3H,s,H-23),0.91(3H,s,H-24),0.99(3H,s,H-25),1.07(3H,s,H-27),1.14(3H,s,H-29),1.24(3H,s,H-30),2.07(3H,s,H-32),3.83(1H,d,J=10.8Hz,H-28),4.34(1H,d,J=10.8Hz,H-28),4.60(1H,dd,J=10.8,4.2Hz,H-3),6.29(1H,d,J=15.6Hz,H-2'),6.83(2H,d,J=8.4Hz,H-6',8'),7.43(2H,d,J=9.0Hz,H-5',9'),7.60(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.6(C-1),24.0(C-2),81.0(C-3),38.3(C-4),55.0(C-5),18.4(C-6),34.6(C-7),41.7(C-8),50.3(C-9),36.8(C-10),21.5(C-11),27.4(C-12),37.2(C-13),43.6(C-14),29.2(C-15),30.5(C-16),48.1(C-17),49.0(C-18),49.8(C-19),73.7(C-20),28.5(C-21),34.2(C-22),28.2(C-23),16.9(C-24),16.4(C-25),16.4(C-26),15.2(C-27),63.1(C-28),24.9(C-29),31.9(C-30),171.9(C-31),21.3(C-32),167.4(C-1'),116.7(C-2'),144.0(C-3'),127.7(C-4'),130.1(C-5',9'),116.0(C-6',8'),157.6(C-7').
化合物4 3β-O-(trans-caffeoyl)-lupane-28-al-20-ol
白色粉末(甲醇),1H-NMR(600MHz,DMSO)δH:0.81(3H,s,H-23),0.82(3H,s,H-25),0.83(3H,s,H-26),0.86(3H,s,H-24),0.96(3H,s,H-27),1.03(3H,s,H-29),1.10(3H,s,H-30),4.49(1H,dd,J=11.4,4.8Hz,H-3),6.23(1H,d,J=16.2Hz,H-2'),6.75(1H,d,J=8.4Hz,H-8'),6.98(1H,d,J=8.4,1.8Hz,H-9'),6.99(1H,d,J=1.8Hz,H-5'),7.45(1H,d,J=15.6Hz,H-3'),9.59(1H,s,CHO)。13C-NMR(150MHz,DMSO)δC:38.1(C-1),23.5(C-2),79.8(C-3),37.6(C-4),54.5(C-5),17.8(C-6),34.0(C-7)40.8(C-8),49.6(C-9)36.6(C-10),20.9(C-11),27.3(C-12),37.9(C-13),43.1(C-14),28.8(C-15),29.0(C-16),60.7(C-17),46.3(C-18),48.9(C-19),71.2(C-20)28.3(C-21),32.9(C-22),27.7(C-23),16.5(C-24),15.8(C-25),16.0(C-26),14.4(C-27),207.7(C-28),26.1(C-29),30.9(C-30),166.3(C-1'),114.4(C-2'),144.8(C-3'),125.5(C-4'),114.8(C-5'),145.6(C-6'),148.3(C-7'),121.3(C-8'),115.7(C-9').
化合物5 3β-O-(trans-p-coumaroyl)-lupane-20,28-diol
白色粉末(甲醇),1H-NMR(600MHz,DMSO)δH:0.83(3H,s,H-23),0.85(3H,s,H-25),0.88(3H,s,H-24),0.96(3H,s,H-27),0.98(3H,s,H-29),1.01(3H,s,H-26),1.09(3H,s,H-30),3.04(1H,dd,J=10.2,4.8Hz,H-28),3.57(1H,dd,J=10.2,4.8Hz,H-28),4.50(1H,dd,J=11.4,4.8Hz,H-3),6.37(1H,d,J=16.2Hz,H-2'),6.78(2H,d,J=8.4Hz,H-6',8'),7.53(1H,d,J=15.6Hz,H-3'),7.54(2H,d,J=8.4Hz,H-5',9')。13C-NMR(150MHz,DMSO)δC:38.4(C-1),24.0(C-2),80.3(C-3),37.0(C-4),55.1(C-5),18.3(C-6),34.4(C-7),41.5(C-8),50.2(C-9),36.4(C-10),21.4(C-11),27.4(C-12),38.1(C-13),43.4(C-14),28.2(C-15),28.4(C-16),49.0(C-17),48.7(C-18),49.0(C-19),71.8(C-20),30.1(C-21),33.5(C-22),28.2(C-23),17.0(C-24),16.5(C-25),16.0(C-26),15.4(C-27),58.9(C-28),25.4(C-29),32.2(C-30),166.8(C-1'),115.1(C-2'),144.9(C-3'),125.6(C-4'),130.8(C-5',9'),116.2(C-6',8'),160.2(C-7').
化合物6 3β-O-(trans-p-coumaroyl)-lupane-20,28-diol
白色粉末(甲醇),1H-NMR(600MHz,DMSO)δH:0.82(3H,s,H-23),0.85(3H,s,H-25),0.88(3H,s,H-24),0.95(3H,s,H-27),0.98(3H,s,H-29),1.02(3H,s,H-26),1.09(3H,s,H-30),3.04(1H,dd,J=10.2,4.8Hz,H-28),3.57(1H,dd,J=10.2,4.8Hz,H-28),4.49(1H,dd,J=11.4,5.4Hz,H-3),5.80(1H,d,J=13.2Hz,H-2'),6.75(1H,d,J=8.4,1.8Hz,H-6'),6.88(1H,d,J=13.6Hz,H-3'),6.99(1H,d,J=8.4Hz,H-5'),7.03(1H,d,J=1.8Hz,H-5')。13C-NMR(150MHz,DMSO)δC:38.3(C-1),24.0(C-2),80.3(C-3),37.0(C-4),55.0(C-5),18.3(C-6),34.4(C-7),41.5(C-8),50.1(C-9),36.4(C-10),21.4(C-11),27.4(C-12),38.1(C-13),43.4(C-14),28.2(C-15),28.4(C-16),49.0(C-17),48.7(C-18),49.0(C-19),71.9(C-20),30.1(C-21),33.5(C-22),27.9(C-23),17.1(C-24),16.3(C-25),16.4(C-26),15.5(C-27),58.9(C-28),25.4(C-29),32.2(C-30),166.8(C-1'),114.9(C-2'),145.3(C-3'),126.0(C-4'),121.8(C-5'),116.2(C-6'),148.8(C-7'),146.0(C-8'),115.3(C-9')。
化合物7 3β-O-(trans-p-coumaroyl)-lupane-20,28-diol
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.90(3H,s,H-23),0.90(3H,s,H-25),0.92(3H,s,H-24),0.95(3H,s,H-26),0.98(3H,s,H-27),1.21(3H,s,H-29),1.28(3H,s,H-30),4.62(1H,dd,J=11.4,4.8Hz,H-3),6.30(1H,d,J=15.6Hz,H-2'),6.84(2H,d,J=8.4Hz,H-6',8'),7.43(2H,d,J=8.4Hz,H-5',9'),7.53(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.8(C-1),24.0(C-2),80.9(C-3),38.3(C-4),55.8(C-5),18.4(C-6),34.2(C-7),41.4(C-8),51.2(C-9),36.8(C-10),21.8(C-11),27.5(C-12),37.4(C-13),42.8(C-14),28.3(C-15),31.1(C-16),80.4(C-17),49.7(C-18),54.0(C-19),72.4(C-20),23.5(C-21),40.7(C-22),28.2(C-23),16.9(C-24),16.9(C-25),15.8(C-26),14.5(C-27),29.2(C-29),31.2(C-30),167.4(C-1'),116.5(C-2'),144.2(C-3'),127.6(C-4'),130.1(C-5',9'),116.1(C-6',8'),157.9(C-7').
化合物8 3β-O-(cis-caffeoyl)-norlupane-17β,20-diol
白色粉末(甲醇),1H-NMR(600MHz,DMSO)δH:0.76(3H,s,H-25),0.80(3H,s,H-23),0.82(3H,s,H-24),0.90(3H,s,H-26),0.91(3H,s,H-27),1.05(3H,s,H-29),1.07(3H,s,H-30),4.62(1H,dd,J=11.4,5.4Hz,H-3),5.77(1H,d,J=12.6Hz,H-2'),6.74(2H,d,J=8.4Hz,H-6',8'),6.84(1H,d,J=13.2Hz,H-3'),7.62(2H,d,J=8.4Hz,H-5',9')。13C-NMR(150MHz,DMSO)δC:38.4(C-1),23.8(C-2),80.4(C-3),37.9(C-4),55.3(C-5),18.2(C-6),34.0(C-7),41.2(C-8),50.7(C-9),36.5(C-10),21.6(C-11),27.2(C-12),37.1(C-13),42.3(C-14),28.2(C-15),31.1(C-16),78.7(C-17),49.7(C-18),54.0(C-19),70.8(C-20),23.4(C-21),40.5(C-22),28.1(C-23),16.9(C-24),16.8(C-25),15.8(C-26),14.5(C-27),29.1(C-29),31.3(C-30),166.3(C-1'),116.5(C-2'),143.4(C-3'),126.0(C-4'),132.9(C-5',9'),115.3(C-6',8'),159.2(C-7').
化合物9 3β-O-(trans-p-coumaroyl)-norlupane-17β-hydroperoxide-20-ol
白色粉末(甲醇),1H-NMR(600MHz,DMSO)δH:0.83(3H,s,H-23),0.85(3H,s,H-25),0.88(3H,s,H-24),0.94(3H,s,H-27),1.00(3H,s,H-26),1.01(3H,s,H-29),1.23(3H,s,H-30),4.62(1H,dd,J=12.0,4.8Hz,H-3),6.37(1H,d,J=15.6Hz,H-2'),6.78(2H,d,J=8.4Hz,H-6',8'),7.53(1H,d,J=15.6Hz,H-3'),7.55(2H,d,J=8.4Hz,H-5',9')。13C-NMR(150MHz,DMSO)δC:38.4(C-1),24.0(C-2),80.3(C-3),37.1(C-4),55.1(C-5),18.3(C-6),34.6(C-7),41.3(C-8),50.3(C-9),35.3(C-10),21.6(C-11),27.5(C-12),38.1(C-13),42.8(C-14),28.2(C-15),29.2(C-16),90.6(C-17),49.3(C-18),48.3(C-19),71.8(C-20),29.4(C-21),32.9(C-22),28.0(C-23),17.1(C-24),16.7(C-25),16.4(C-26),14.6(C-27),27.0(C-29),31.0(C-30),166.9(C-1'),115.3(C-2'),144.9(C-3'),125.5(C-4'),130.7(C-5',9'),116.2(C-6',8'),156.3(C-7').
化合物10Lupane-3,20,28-triol
白色粉末(甲醇),1H-NMR(600MHz,DMSO)δH:0.82(3H,s,H-23),0.86(3H,s,H-25),0.88(3H,s,H-24),0.95(3H,s,H-27),0.97(3H,s,H-29),1.01(3H,s,H-26),1.09(3H,s,H-30),3.05(1H,dd,J=10.2,4.8Hz,H-28),3.58(1H,dd,J=10.2,4.8Hz,H-28),4.49(1H,dd,J=11.4,5.4Hz,H-3),6.23(1H,d,J=15.6Hz,H-2'),6.75(1H,d,J=8.4,1.8Hz,H-6'),6.99(1H,d,J=8.4Hz,H-5'),7.03(1H,d,J=1.8Hz,H-5'),7.45(1H,d,J=16.2Hz,H-3')。13C-NMR(150MHz,DMSO)δC:38.3(C-1),24.0(C-2),80.3(C-3),37.0(C-4),55.0(C-5),18.3(C-6),34.4(C-7),41.5(C-8),50.1(C-9),36.4(C-10),21.4(C-11),27.4(C-12),38.1(C-13),43.4(C-14),28.2(C-15),28.4(C-16),49.0(C-17),48.7(C-18),49.0(C-19),71.9(C-20),30.1(C-21),33.5(C-22),27.9(C-23),17.1(C-24),16.3(C-25),16.4(C-26),15.5(C-27),58.9(C-28),25.4(C-29),32.2(C-30),166.8(C-1'),114.9(C-2'),145.3(C-3'),126.0(C-4'),121.8(C-5'),116.2(C-6'),148.8(C-7'),146.0(C-8'),115.3(C-9')。
化合物11Monogynol A
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.80(3H,s,H-23),0.87(3H,s,H-25),0.92(3H,s,H-24),0.94(3H,s,H-27),1.00(3H,s,H-29),1.04(3H,s,H-26),1.10(3H,s,H-30),3.45(1H,dd,J=12.0,4.8Hz,H-3)。13C-NMR(150MHz,CDCl3)δC:38.7(C-1),27.6(C-2),79.0(C-3),38.8(C-4),55.2(C-5),18.6(C-6),34.6(C-7),41.4(C-8),50.3(C-9),37.5(C-10),21.6(C-11),29.1(C-12),37.1(C-13),43.5(C-14),27.4(C-15),35.6(C-16),44.7(C-17),48.3(C-18),49.9(C-19),73.6(C-20),29.7(C-21),40.2(C-22),28.0(C-23),16.4(C-24),15.7(C-25),15.7(C-26),15.1(C-27),19.5(C-28),24.8(C-29),31.9(C-30).
化合物12 24-O-(trans-p-coumaroyl)-hederagenin
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.72(3H,s,H-26),0.92(3H,s,H-29),0.95(3H,s,H-30),1.06(3H,s,H-25),1.14(3H,s,H-27),1.24(3H,s,H-22),3.44(1H,dd,J=12.0,4.8Hz,H-3),4.25(1H,d,J=11.4Hz,H-24),4.63(1H,d,J=11.4Hz,H-24),5.30(1H,brs,H-12),5.91(1H,d,J=16.2Hz,H-2'),6.66(2H,d,J=8.4Hz,H-6',8'),7.01(2H,d,J=7.8Hz,H-5',9'),7.46(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.7(C-1),22.9(C-2),80.6(C-3),42.5(C-4),56.4(C-5),18.9(C-6),33.3(C-7),39.4(C-8),47.6(C-9),37.3(C-10),23.8(C-11),123.0(C-12),143.7(C-13),41.2(C-14),27.2(C-15),27.9(C-16),46.7(C-17),41.5(C-18),45.9(C-19),30.9(C-20),33.9(C-21),32.7(C-22),22.7(C-23),66.3(C-24),15.9(C-25),17.6(C-26),26.2(C-27),184.4(C-28),32.8(C-29),23.8(C-30),167.4(C-1'),114.5(C-2'),145.2(C-3'),126.2(C-4'),130.3(C-5',9'),116.1(C-6',8'),159.2(C-7').
化合物13 24-O-(trans-feruloyl)-hederagenin
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.75(3H,s,H-26),0.90(3H,s,H-29),0.93(3H,s,H-30),0.96(3H,s,H-25),1.13(3H,s,H-27),1.21(3H,s,H-22),3.33(1H,dd,J=12.0,4.8Hz,H-3),3.88(3H,s,OCH3)4.27(1H,d,J=11.4Hz,H-24),4.47(1H,d,J=11.4Hz,H-24),5.28(1H,brs,H-12),6.20(1H,d,J=16.2Hz,H-2'),6.87(1H,d,J=7.8Hz,H-6'),6.95(1H,d,J=1.8Hz,H-9'),7.01(1H,d,J=7.8,1.8Hz,H-5'),7.55(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.7(C-1),23.0(C-2),79.8(C-3),42.7(C-4),56.4(C-5),19.0(C-6),33.3(C-7),39.5(C-8),47.9(C-9),37.2(C-10),23.8(C-11),122.7(C-12),143.7(C-13),41.2(C-14),27.5(C-15),27.9(C-16),46.7(C-17),41.8(C-18),46.0(C-19),30.9(C-20),34.0(C-21),32.6(C-22),22.5(C-23),65.8(C-24),15.9(C-25),17.2(C-26),26.1(C-27),183.3(C-28),33.1(C-29),23.8(C-30),167.4(C-1'),115.4(C-2'),145.4(C-3'),127.0(C-4'),123.5(C-5'),114.8(C-6'),148.2(C-7'),146.9(C-8'),109.4(C-9'),56.1(OCH3).
化合物14 24-O-(cis-feruloyl)-hederagenin
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.74(3H,s,H-26),0.91(3H,s,H-29),0.92(3H,s,H-30),0.93(3H,s,H-25),1.12(3H,s,H-27),1.13(3H,s,H-22),3.28(1H,dd,J=12.0,4.8Hz,H-3),3.92(3H,s,OCH3)4.18(1H,d,J=11.4Hz,H-24),4.37(1H,d,J=11.4Hz,H-24),5.28(1H,brs,H-12),5.78(1H,d,J=13.2Hz,H-2'),6.80(1H,d,J=13.2Hz,H-3'),6.88(1H,d,J=8.4Hz,H-6'),7.12(1H,d,J=8.4,1.2Hz,H-5'),7.69(1H,d,J=1.2Hz,H-9')。13C-NMR(150MHz,CDCl3)δC:38.5(C-1),23.0(C-2),79.4(C-3),42.2(C-4),56.1(C-5),18.9(C-6),33.0(C-7),39.2(C-8),47.7(C-9),36.9(C-10),23.5(C-11),122.5(C-12),143.5(C-13),41.1(C-14),27.1(C-15),27.6(C-16),46.5(C-17),41.6(C-18),45.9(C-19),30.7(C-20),33.8(C-21),32.4(C-22),22.4(C-23),65.4(C-24),15.6(C-25),16.8(C-26),25.8(C-27),181.6(C-28),32.9(C-29),23.5(C-30),166.4(C-1'),116.4(C-2'),144.5(C-3'),127.1(C-4'),125.5(C-5'),113.9(C-6'),147.1(C-7'),146.0(C-8'),112.8(C-9'),56.0(OCH3).
化合物15 24-Hydroxyl-scaphopetalumate
白色粉末(甲醇),1H-NMR(600MHz,CDCl3):0.77(3H,s,H-26),0.91(3H,s,H-29),0.93(3H,s,H-30),0.95(3H,s,H-25),1.14(3H,s,H-27),1.21(3H,s,H-23),3.32(1H,dd,10.9,5.4Hz,H-3),3.90(3H,s,6′-OCH3),4.26(1H,d,11.7Hz,H-24β),4.47(1H,d,11.7Hz,H-24α),5.30(1H,brt,3.2Hz,H-12),6.24(1H,d,15.9Hz,H-2′),6.90(1H,d,8.2Hz,H-8′),6.98(1H,d,1.7Hz,H-5′),7.04(1H,dd,8.2,1.7Hz,H-9′),7.56(1H,d,15.9Hz,H-3′)。13C-NMR(150MHz,CDCl3):32.5(C-1),27.3(C-2),79.6(C-3),42.6(C-4),56.3(C-5),19.0(C-6),38.7(C-7),39.4(C-8),47.9(C-9),37.1(C-10),27.8(C-11),122.7(C-12),143.6(C-13),41.8(C-14),27.4(C-15),23.1(C-16),46.6(C-17),41.3(C-18),46.0(C-19),30.8(C-20),33.9(C-21),33.2(C-22),22.5(C-23),65.7(C-24),15.8(C-25),17.0(C-26),26.0(C-27),181.2(C-28),33.1(C-29),23.7(C-30),167.4(C-1′),115.3(C-2′),145.4(C-3′),127.0(C-4′),109.4(C-5′),146.9(C-6′),148.2(C-7′),114.8(C-8′),123.4(C-9′).
化合物16 24-O-(trans-feruloyl)-2α,3β-dihydroxy-olean-12-en-28-oicacid
白色粉末(甲醇),1H-NMR(600MHz,DMSO-d6):0.70(3H,s,H-26),0.88(3H,s,H-29),0.88(3H,s,H-30),0.92(3H,s,H-25),1.04(3H,s,H-23),1.11(3H,s,H-27),3.50(1H,dd-like,H-3),3.77(1H,m,H-2),3.82(3H,s,6′-OCH3),3.96(1H,d,11.4Hz,H-24β),4.26(1H,d,11.4Hz,H-24α),5.18(1H,brt,3.2Hz,H-12),6.45(1H,d,15.9Hz,H-2′),6.79(1H,d,8.2Hz,H-8′),7.11(1H,dd,8.2,1.7Hz,H-9′),7.31(1H,d,1.7Hz,H-5′),7.52(1H,d,15.9Hz,H-3′)。13C-NMR(150MHz,DMSO-d6):41.4(C-1),64.4(C-2),72.7(C-3),42.5(C-4),48.2(C-5),17.9(C-6),32.6(C-7),39.0(C-8),47.1(C-9),37.6(C-10),23.1(C-11),121.4(C-12),143.9(C-13),41.3(C-14),27.1(C-15),22.6(C-16),45.4(C-17),40.7(C-18),45.7(C-19),30.4(C-20),33.3(C-21),32.1(C-22),22.9(C-23),66.4(C-24),16.4(C-25),16.7(C-26),25.7(C-27),178.6(C-28),32.8(C-29),23.4(C-30),166.7(C-1′),114.5(C-2′),145.0(C-3′),125.5(C-4′),111.2(C-5′),148.0(C-6′),149.4(C-7′),115.5(C-8′),123.2(C-9′).
化合物17 3β-O-(E)-isoferuloyl oleanolic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3):0.78(3H,s,H-26),0.92(3H,s,H-29),0.94(3H,s,H-30),0.95(3H,s,H-25),1.10(3H,s,H-27),1.20(3H,s,H-23),3.34(1H,dd,10.9,5.4Hz,H-3),3.93(3H,s,7′-OCH3),5.31(1H,brt,3.2Hz,H-12),6.23(1H,d,15.9Hz,H-2′),6.92(1H,d,8.0Hz,H-8′),7.00(1H,d,1.8Hz,H-5′),7.12(1H,dd,8.0,1.8Hz,H-9′),7.56(1H,d,15.9Hz,H-3′)。13C-NMR(150MHz,CDCl3):32.3(C-1),27.1(C-2),79.5(C-3),42.5(C-4),56.6(C-5),19.8(C-6),38.2(C-7),39.3(C-8),47.4(C-9),37.0(C-10),25.8(C-11),122.0(C-12),143.7(C-13),41.7(C-14),27.7(C-15),23.8(C-16),46.3(C-17),41.0(C-18),46.0(C-19),30.3(C-20),33.5(C-21),33.0(C-22),28.2(C-23),16.4(C-24),15.9(C-25),17.0(C-26),26.1(C-27),181.4(C-28),33.0(C-29),23.6(C-30),167.2(C-1′),115.0(C-2′),145.3(C-3′),127.4(C-4′),112.4(C-5′),151.2(C-6′),148.2(C-7′),116.8(C-8′),122.4(C-9′).
化合物18 3β-O-(Z)-isoferuloyl-2β-hydroxyolean-12-en-28-oic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3):0.78(3H,s,H-26),0.80(3H,s,H-23),0.92(3H,s,H-24),0.92(3H,s,H-29),0.94(3H,s,H-30),0.95(3H,s,H-25),1.10(3H,s,H-27),3.34(1H,dd,10.9,5.4Hz,H-3),3.77(1H,m,H-2),3.93(3H,s,7′-OCH3),5.31(1H,brt,3.2Hz,H-12),5.80(1H,d,13.0Hz,H-2′),6.82(1H,d,13.0Hz,H-3′),6.92(1H,d,8.0Hz,H-8′),7.00(1H,d,1.8Hz,H-5′),7.12(1H,dd,8.0,1.8Hz,H-9′)。13C-NMR(150MHz,CDCl3):41.5(C-1),65.9(C-2),72.5(C-3),42.4(C-4),56.5(C-5),19.2(C-6),38.0(C-7),39.1(C-8),47.2(C-9),37.1(C-10),25.2(C-11),122.3(C-12),143.4(C-13),41.2(C-14),27.9(C-15),23.2(C-16),46.1(C-17),41.4(C-18),46.8(C-19),30.6(C-20),33.3(C-21),33.0(C-22),28.1(C-23),16.2(C-24),16.0(C-25),17.1(C-26),26.0(C-27),181.2(C-28),33.1(C-29),23.2(C-30),167.0(C-1′),115.2(C-2′),145.1(C-3′),126.4(C-4′),112.3(C-5′),151.5(C-6′),148.2(C-7′),116.5(C-8′),122.3(C-9′).
化合物19 3β-O-(trans-feruloyl)-olean-12-en-28-oic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3):0.78(3H,s,H-26),0.91(3H,s,H-25),0.94(3H,s,H-24),0.94(3H,s,H-30),0.97(3H,s,H-29),1.15(3H,s,H-23),1.25(3H,s,H-27),3.93(3H,s,6′-OCH3),4.64(1H,dd,9.8,6.6Hz,H-3),5.30(1H,brt,3.6Hz,H-12),6.29(1H,d,15.9Hz,H-2′),6.91(1H,d,8.2Hz,H-8′),7.04(1H,d,1.7Hz,H-5′),7.08(1H,dd,8.2,1.7Hz,H-9′),7.59(1H,d,15.9Hz,H-3′)。13C-NMR(150MHz,CDCl3):38.3(C-1),27.8(C-2),80.9(C-3),38.1(C-4),55.5(C-5),18.4(C-6),32.6(C-7),39.4(C-8),47.7(C-9),37.1(C-10),23.7(C-11),122.8(C-12),143.7(C-13),41.8(C-14),28.2(C-15),23.8(C-16),46.6(C-17),41.3(C-18),46.0(C-19),30.8(C-20),33.8(C-21),32.2(C-22),29.8(C-23),17.0(C-24),15.6(C-25),17.2(C-26),26.0(C-27),181.5(C-28),33.9(C-29),23.6(C-30),167.3(C-1′),109.4(C-2′),144.5(C-3′),127.3(C-4′),114.8(C-5′),148.0(C-6′),146.9(C-7′),116.4(C-8′),123.2(C-9′).
化合物20 3β-O-(trans-p-coumaroyl)maslinic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.87(3H,s,H-26),0.89(3H,s,H-29),0.96(3H,s,H-30),0.99(3H,s,H-25),1.12(3H,s,H-27),1.17(3H,s,H-22),3.92(1H,dd,J=12.0,6.0Hz,H-2),4.65(1H,s,H-3),6.22(1H,d,J=15.6Hz,H-2'),6.85(2H,d,J=8.4Hz,H-6',8'),7.42(2H,d,J=8.4Hz,H-5',9'),7.60(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.7(C-1),67.7(C-2),81.0(C-3),39.7(C-4),55.0(C-5),18.5(C-6),32.5(C-7),39.2(C-8),49.0(C-9),37.5(C-10),24.2(C-11),123.7(C-12),142.5(C-13),44.2(C-14),28.9(C-15),27.7(C-16),46.2(C-17),42.0(C-18),45.2(C-19),31.2(C-20),34.5(C-21),32.4(C-22),18.1(C-23),29.1(C-24),18.0(C-25),16.8(C-26),15.2(C-27),178.2(C-28),33.0(C-29),23.1(C-30),166.3(C-1'),116.4(C-2'),144.3(C-3'),127.4(C-4'),130.0(C-5',9'),116.2(C-6',8'),158.0(C-7').
化合物21Maslinic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.80(3H,s,H-26),0.85(3H,s,H-29),0.93(3H,s,H-30),0.97(3H,s,H-25),1.16(3H,s,H-27),1.14(3H,s,H-22),2.12(3H,s,H-31),4.52(1H,J=11.4,4.8Hz,H-3)。13C-NMR(150MHz,CDCl3)δC:46.1(C-1),68.2(C-2),83.1(C-3),38.9(C-4),55.1(C-5),18.5(C-6),32.3(C-7),39.1(C-8),47.4(C-9),37.9(C-10),23.2(C-11),121.9(C-12),143.8(C-13),41.5(C-14),27.5(C-15),22.7(C-16),46.2(C-17),41.0(C-18),45.8(C-19),30.4(C-20),33.6(C-21),32.3(C-22),28.2(C-23),16.4(C-24),16.3(C-25),16.6(C-26),27.4(C-27),180.6(C-28),32.7(C-29),23.1(C-30),26.3(C-31).
化合物22 3-O-(trans-p-coumaroyl)-alphitolic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.90(3H,s,H-26),0.95(3H,s,H-27),0.99(3H,s,H-24),1.00(3H,s,H-23),1.16(3H,s,H-25),1.73(3H,s,H-30),4.75,4.65(2H,s,H-29),3.92(1H,dd,J=12.0,6.0Hz,H-2),4.65(1H,s,H-3),6.22(1H,d,J=15.6Hz,H-2'),6.85(2H,d,J=8.4Hz,H-6',8'),7.42(2H,d,J=8.4Hz,H-5',9'),7.60(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:42.1(C-1),67.7(C-2),82.0(C-3),39.5(C-4),50.0(C-5),35.2(C-6),33.5(C-7),39.2(C-8),52.0(C-9),41.0(C-10),19.7(C-11),25.7(C-12),37.9(C-13),44.2(C-14),30.9(C-15),33.0(C-16),58.6(C-17),57.0(C-18),49.0(C-19),151.0(C-20),31.6(C-21),38.0(C-22),18.1(C-23),29.1(C-24),18.0(C-25),16.8(C-26),15.2(C-27),178.2(C-28),110.2(C-29),19.2(C-30),166.0(C-1'),116.5(C-2'),144.1(C-3'),127.8(C-4'),130.2(C-5',9'),116.1(C-6',8'),158.2(C-7').
化合物23 3β-O-(trans-p-coumaroyl)-lup-20(29)-en-28-oic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.87(3H,s,H-26),0.90(3H,s,H-27),0.94(3H,s,H-24),0.98(3H,s,H-23),1.16(3H,s,H-25),1.51(3H,s,H-30),4.61,4.72(2H,s,H-29),4.62(1H,dd,J=11.4,4.8Hz,H-3),6.21(1H,d,J=16.2Hz,H-2'),6.83(2H,d,J=8.4Hz,H-6',8'),7.40(2H,d,J=8.4Hz,H-5',9'),7.45(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.8(C-1),23.1(C-2),80.4(C-3),38.1(C-4),55.5(C-5),18.2(C-6),33.6(C-7),41.0(C-8),49.5(C-9),37.1(C-10),22.3(C-11),26.1(C-12),37.1(C-13),42.0(C-14),27.0(C-15),29.8(C-16),48.9(C-17),47.2(C-18),46.4(C-19),150.1(C-20),29.2(C-21),34.3(C-22),28.4(C-23),16.8(C-24),16.4(C-25),16.3(C-26),14.4(C-27),60.1(C-28),110.0(C-29),19.3(C-30),166.3(C-1'),115.8(C-2'),144.2(C-3'),126.9(C-4'),130.0(C-5',9'),116.1(C-6',8'),158.7(C-7').
化合物24 3β-O-(cis-p-coumaroyl)-lup-20(29)-en-28-oic acid
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.81(3H,s,H-23),0.82(3H,s,H-25),0.85(3H,s,H-26),0.90(3H,s,H-24),0.99(3H,s,H-27),1.50(3H,s,H-29),4.61,4.72(2H,s,H-30),4.59(1H,dd,J=11.4,4.8Hz,H-3),5.82(1H,d,J=13.2Hz,H-2'),6.81(1H,d,J=13.2Hz,H-3'),6.82(2H,d,J=8.4Hz,H-6',8'),7.43(2H,d,J=8.4Hz,H-5',9')。13C-NMR(150MHz,CDCl3)δC:38.8(C-1),23.3(C-2),80.0(C-3),38.1(C-4),55.5(C-5),18.3(C-6),33.7(C-7),41.0(C-8),49.5(C-9),37.0(C-10),22.3(C-11),26.1(C-12),37.1(C-13),42.0(C-14),27.0(C-15),29.7(C-16),48.9(C-17),47.0(C-18),46.5(C-19),150.0(C-20),29.1(C-21),34.2(C-22),28.4(C-23),16.8(C-24),16.4(C-25),16.3(C-26),14.4(C-27),60.1(C-28),110.0(C-29),19.3(C-30),166.3(C-1'),115.5(C-2'),144.1(C-3'),126.8(C-4'),130.0(C-5',9'),116.1(C-6',8'),158.6(C-7').
化合物25 3β-O-(trans-caffeoyl)-lup-20(29)-en-28-oic acid
白色粉末(甲醇),1H-NMR(600MHz,DMSO-d6):0.81(3H,s,H-26),0.83(3H,s,H-25),0.87(3H,s,H-23),0.88(3H,s,H-24),0.95(3H,s,H-27),1.65(3H,s,H-30),4.48(1H,dd,11.5,4.7Hz,H-3),4.56(1H,d,1.6Hz,H-29β),4.69(1H,d,1.6Hz,H-29α),6.23(1H,d,15.8Hz,H-2′),6.75(1H,d,8.2Hz,H-8′),6.99(1H,dd,8.2,1.8Hz,H-9′),7.03(1H,d,1.8Hz,H-5′),7.44(1H,d,15.8Hz,H-3′)。13C-NMR(150MHz,DMSO-d6):37.8(C-1),23.5(C-2),79.8(C-3),37.6(C-4),55.4(C-5),17.8(C-6),33.7(C-7),40.3(C-8),49.7(C-9),36.3(C-10),20.5(C-11),25.1(C-12),37.6(C-13),42.0(C-14),29.2(C-15),31.7(C-16),48.5(C-17),54.7(C-18),46.6(C-19),150.4(C-20),30.1(C-21),36.7(C-22),27.7(C-23),16.6(C-24),15.9(C-25),15.7(C-26),14.4(C-27),177.3(C-28),109.7(C-29),19.0(C-30),166.3(C-1′),114.4(C-2′),144.8(C-3′),125.5(C-4′),114.8(C-5′),145.6(C-6′),148.3(C-7′),115.7(C-8′),121.3(C-9′).
化合物26 3-(E)-p-coumaroylbetulin
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.90(3H,s,H-26),0.95(3H,s,H-27),0.99(3H,s,H-24),1.00(3H,s,H-23),1.16(3H,s,H-25),1.73(3H,s,H-30),3.06(1H,dd,J=10.2,4.8Hz,H-28),3.60(1H,dd,J=10.2,4.8Hz,H-28),4.75,4.65(2H,s,H-29),4.65(1H,J=11.4,4.8Hz,H-3),6.22(1H,d,J=15.6Hz,H-2'),6.85(2H,d,J=8.4Hz,H-6',8'),7.42(2H,d,J=8.4Hz,H-5',9'),7.60(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.5(C-1),23.4(C-2),80.9(C-3),38.1(C-4),55.6(C-5),18.3(C-6),33.8(C-7),41.0(C-8),50.3(C-9),37.1(C-10),20.8(C-11),25.2(C-12),37.3(C-13),42.7(C-14),27.0(C-15),29.2(C-16),47.9(C-17),48.9(C-18),47.8(C-19),150.4(C-20),29.3(C-21),34.2(C-22),28.0(C-23),16.5(C-24),16.4(C-25),16.2(C-26),14.7(C-27),60.6(C-28),110.3(C-29),19.3(C-30),166.9(C-1'),115.5(C-2'),144.3(C-3'),126.1(C-4'),130.0(C-5',9'),115.1(C-6',8'),158.5(C-7').
化合物27Betulin 3-O-caffeate
白色粉末(甲醇),1H-NMR(600MHz,CDCl3)δH:0.78(3H,s,H-23),0.80(3H,s,H-25),0.84(3H,s,H-26),0.88(3H,s,H-24),0.98(3H,s,H-27),1.72(3H,s,H-29),3.05(1H,dd,J=10.2,4.8Hz,H-28),3.61(1H,dd,J=10.2,4.8Hz,H-28),4.62,4.70(2H,s,H-30),4.52(1H,dd,J=11.4,4.8Hz,H-3),6.22(1H,d,J=16.2Hz,H-2'),6.71(1H,d,J=8.4Hz,H-8'),6.97(1H,d,J=8.4,1.8Hz,H-9'),7.02(1H,d,J=1.8Hz,H-5'),7.43(1H,d,J=15.6Hz,H-3')。13C-NMR(150MHz,CDCl3)δC:38.4(C-1),23.3(C-2),81.0(C-3),38.2(C-4),55.5(C-5),18.2(C-6),33.7(C-7),41.1(C-8),50.0(C-9),37.2(C-10),20.7(C-11),25.1(C-12),37.2(C-13),42.5(C-14),27.1(C-15),29.1(C-16),47.8(C-17),48.8(C-18),47.7(C-19),150.0(C-20),29.0(C-21),34.1(C-22),28.2(C-23),16.6(C-24),16.4(C-25),16.3(C-26),14.6(C-27),60.3(C-28),110.4(C-29),19.1(C-30),166.2(C-1'),116.2(C-2'),144.5(C-3'),125.4(C-4'),115.1(C-5'),145.8(C-6'),148.0(C-7'),121.4(C-8'),116.0(C-9').
本发明所述的结构通式所示的化合物及其药学上可接受的盐,具有很好的抗肿瘤作用,可以和药学上可接受的载体结合制备临床上可接受的药物,用于治疗肺癌、肝癌、乳腺癌、宫颈癌等癌症。
本发明的另一目的在于提供了所述的三萜类衍生物的制备方法,包括以下操作步骤,采用雀舌木属植物,或具体至雀舌木、线叶雀舌木、云南雀舌木、腺缘雀舌木为原料,用有机溶剂或含水醇、盐溶液制备提取物,再进行对化合物的分离。
方法一:
(1)取选定的药材粗粉(雀舌木属植物等中药饮片或植物),利用溶剂加热、超声、浸渍提取法,采用3~15倍量水煎煮或30%~100%醇回流提取,减压回收水或有机溶剂,残渣挥至无醇味或醇度低于10%后,以水溶解后离心取上清液。
(2)上清液用大孔树脂处理,用水-醇溶液梯度洗脱,富集30%~100%醇洗脱部分,得到三萜粗提物;所述的大孔树脂包括极性、非极性大孔树脂D-101、DM-301、HPD-100、AB-8等;
(3)上述粗提取物经硅胶柱色谱进行分离,采用石油醚、环己烷、正己烷、乙醚、乙酸乙酯、二氯甲烷、三氯甲烷、正丁醇、丙酮、甲醇等组成的不同溶剂系统进行梯度洗脱,结合中低压制备分离色谱、高效液相色谱进行制备分离,以乙腈/水系统、甲醇/水系统进行分离,获得三萜类化合物。
方法二:
(1)取选定的药材粗粉(雀数木属等中药饮片或植物),利用超声或溶剂加热提取法,采用3~15倍量水煎煮或20%~100%醇回流提取,减压回收水或醇溶剂,残渣挥至无醇味或醇度低于10%后,以水溶解,得混悬液。
(2)混悬液依此用乙醚或二氯甲烷或三氯甲烷、乙酸乙酯、正丁醇进行萃取,萃取次数1-5次,萃取体积(1:1-1:8)获得各萃取部位,分别回收溶剂得浸膏,其中乙醚或二氯甲烷或三氯甲烷、乙酸乙酯层浸膏为三萜苷元组分;正丁醇层为总苷类。
(3)粗三萜苷元或粗三萜苷都可经硅胶柱色谱、凝胶柱色谱进行分离,采用石油醚、环己烷、正己烷、乙醚、乙酸乙酯、二氯甲烷、三氯甲烷、丙酮、甲醇等组成的不同溶剂系统进行梯度洗脱,结合中低压制备分离色谱、高效液相色谱进行制备分离,以乙腈/水系统、甲醇/水系统,辅以甲酸、乙酸、氟乙酸、氯乙酸、磷酸等作为防拖尾调节剂,进行分离,则获得三萜类化合物。
方法三:
(1)粉碎药材,采用超声、浸渍或加热回流提取法,以3~15倍量的有机溶剂提取,减压回收有机溶剂,用水混悬后离心取上清液上大孔吸附树脂,或直接取有机溶剂提取浸膏。
(2)上清液用非极性大孔树脂(如D101,HPD400,HPD100等)处理,以水-醇系统洗脱4-8个保留体积,收集30%~90%醇洗脱部分,各洗脱部分分别用TLC或HPLC筛选富含三萜的有效部分,即得三萜粗提物;
(3)上述步骤(2)中粗提物经硅胶柱色谱进行分离,采用石油醚-乙酸乙酯;二氯甲烷-甲醇;氯仿-甲醇三种溶剂系统进行洗脱;
(4)上述步骤(3)中所得含有三萜类化合物流份和(1)中有机溶剂提取物的再次经凝胶、ODS反相柱色谱分离后,用制备型、半制备型或分析型HPLC色谱分离,以甲醇/水或乙腈/水系统进行梯度洗脱,得到三萜类化合物。
本发明提供的三萜类化合物的制备方法(一)方法(二)中提到的醇为甲醇或乙醇,浓度为10%-100%。
本发明提供的三萜类化合物的制备方法(一)中,所提到的大孔树脂包括极性、非极性大孔树脂D-101、DM-301、HPD-100、AB-8等。
本发明提供的三萜类化合物经硅胶柱色谱制备单体成分方法,所提到的有机溶剂为石油醚、环己烷、正己烷、乙醚、二氯甲烷、三氯甲烷、丙酮、乙酸乙酯、乙醇、甲醇中的一种、二种或防拖尾调节剂等多种混合溶剂。
本发明提供的三萜粗提物经中低压、高效液相色谱制备单体成分的方法,流动相为甲醇/水、或乙腈/水、或乙醇/水,混合比例为1:10-90:10,或甲醇/乙腈/水,混合比例为1:1:10-40:40:20。
具体实施方式
为了使本发明的目的及优点更加清楚明白,以下结合实施例对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明
实施例1
取线叶雀舌木干燥全草18.0kg,粉碎后用75%乙醇加热回流提取3次,料液比为1:8,每次2h,减压回收溶剂,浸膏用蒸馏水分散,依次用等体积的石油醚、氯仿、乙酸乙酯和正丁醇萃取3次,得石油醚层萃取物126.4g(提取物1),氯仿层萃取物26.7g(提取物2),乙酸乙酯层萃取物36.1g(提取物3),正丁醇层萃取物162.3g(提取物4)。
所得的氯仿层萃取物26.7g,采用正相硅胶柱色谱进行分离,流动相选用石油醚:乙酸乙酯(100:0-1:1)及二氯甲烷:甲醇(50:1-1:1)梯度洗脱,所得组分经硅胶薄层色谱分析,合并相同组分后得到15份洗脱物。
对石油醚:乙酸乙酯=50:1组分2.8g进行分离。采用硅胶柱色谱法,用石油醚:正己烷;丙酮梯度洗脱,在10:10:1处,对白色固体粉末采用半制备型HPLC分离,得化合物1,2,4,9,10;在石油醚:丙酮10:1处,对黄色固体粉末进行Sephadex LH-20分离,随后采用HPLC分离,重结晶得化合物3,5,6,7,8,11,12。对石油醚:乙酸乙酯=25:1组分2.1g进行分离,采用硅胶柱色谱法,用石油醚:乙酸乙酯梯度洗脱,在5:1处,对黄色固体采用HPLC分离,得化合物13-16。对石油醚:丙酮=15:1组分1.6g进行分离,采用硅胶柱色谱法,用二氯甲烷:甲醇梯度洗脱,在50:1处,对黄色固体采用Sephadex LH-20分离,随后采用HPLC分离,重结晶得化合物18,20;在20:1处,对黄色固体采用HPLC分离,得化合物19,21。
实施例2
取干燥缘腺雀舌木(Leptopus clarkei(Hook.f.)Pojark.)27.1kg,粉碎后用二氯甲烷加热回流提取3次,料液比为1:8,每次1.5h,减压回收溶剂,浸膏用氯仿、丙酮、甲醇分别溶解。取氯仿层浸膏37.3g,采用硅胶柱色谱进行分离,以石油醚-乙酸乙酯、石油醚-丙酮组成的溶剂系统进行洗脱,辅以1-2滴冰乙酸,得到流份12份,对石油醚:乙酸乙酯=50:1组分1.7g进行反复硅胶柱色谱法分离,对黄色固体粉末采用制备型HPLC分离,得化合物3,4,13,14;在8:1处,对黄色固体粉末采用半制备型HPLC分离,得化合物5,9,16,18,24。对石油醚:乙酸乙酯=25:1组分2.3g进行分离。采用硅胶柱色谱法,用石油醚:丙酮梯度洗脱,在5:1处,对黄色固体粉末采用制备型HPLC分离,得化合物12,21,23。
实施例3
雀儿舌头(Leptopus chinensis(Bunge)Pojark)干燥全草19.2kg,粉碎后用60%乙醇加热回流提取3次,料液比为1:8,每次1.5h,减压回收溶剂,浸膏用蒸馏水分散后离心取上清液,上清液用非极性大孔树脂D101处理后,依次用水和醇梯度洗脱,收集30%~100%醇洗脱部分,各洗脱部分利用薄层色谱或HPLC(210nm)筛选,筛选富含三萜类化合物的有效部位,即得三萜粗提物;所得的三萜粗提物35.7g,采用正相硅胶柱色谱进行分离,以正己烷-二氯甲烷、二氯甲烷-乙酸乙酯、二氯甲烷-甲醇组成的溶剂系统进行梯度洗脱,所得组分经硅胶薄层色谱分析,合并相同组分后得到13份洗脱物。正己烷:二氯甲烷=25:1组分2.5g经快速中低压反相色谱,以甲醇/水或乙醇/水梯度洗脱,所得黄色固体粉末采用制备型HPLC分离,得化合物3,4,13,14,15;在10:1处,对黄色固体粉末采用半制备型HPLC分离,得化合物22,26,27。
实施例4
云南雀舌木(Leptopus yunnanensis P.T.Li)干燥全草12.0kg,粉碎后用二氯甲烷加热回流提取3次,料液比为1:8,每次1.5h,减压回收溶剂,浸膏分别用氯仿、丙酮、甲醇溶解。取氯仿层浸膏29.3g,采用正相硅胶柱色谱进行分离,流动相选用环己烷-二氯甲烷,石油醚-乙酸乙酯组成的溶剂系统进行梯度洗脱,所得组分经硅胶薄层色谱分析及HPLC筛选合并后得到13份洗脱物。对环己烷:二氯甲烷=5:1组分2.2g进行分离。采用快速中低压反相色谱,以甲醇/水或乙醇/水梯度洗脱,所得白色固体粉末采用半制备型HPLC分离,得化合物7,10,15,19,23;在石油醚:丙酮20:1处,对黄色固体粉末进行Sephadex LH-20分离,随后采用HPLC分离,得化合物5,8,16,17,24,27。
实施例5对雀舌木提取物与三萜类化合物的体外抗肿瘤活性评价
采用MTT法,对提取物与27个三萜类化合物的体外抑制人非小细胞性肺癌(A549)、人肝癌细胞(HepG-2)、人乳腺癌细胞(MCF-7)、人宫颈癌细胞(Hela)的活性进行测定。
(1)细胞培养
将细胞培养至对数生长期,计数,用内含10%胎牛血清及1%双抗的DMEM完全培养基稀释细胞至5×104个/mL,接种至96孔板,每孔接种100μL细胞悬液,置于37℃,饱和湿度,5%CO2培养箱中孵育24小时。
(2)添加试药
样品用DMSO溶解后,以DMEM完全培养基稀释至不同浓度,将含药的培养液加入96孔板,放置于上一步相同条件的培养箱中培养48h。
(3)结果测定
药物处理48h后,以5mg/mL的MTT对细胞进行染色2-4小时后,除去上清液,加DMSO溶解甲臜,于酶标仪570nm下测OD值。
(4)细胞生长抑制率的计算
细胞生长抑制率=[(给药组OD值-0.04)/(对照组OD值-0.04)]×100%。
(5)数据处理
采用Graphpad Prism软件计算出药物半数抑制浓度(IC50)。
实验结果如表2、3所示。
表2四种线叶雀舌木提取物对四种癌细胞株的抑制活性(μg/mL)
表2说明,提取物对4种细胞株均表现出了不同程度的抑制活性。
表3 27种三萜衍生物对四种癌细胞株的抑制活性(IC50,μmol/L)
表3显示,化合物1-27对四种癌细胞株均表现出了不同程度的抑制活性,另外,化合物7可显著抑制HepG-2以及MCF-7癌细胞株,提示以上化合物在抗癌方面具有一定的研究价值。
Claims (6)
1.如下所述的三萜类化合物及其盐在制备抗肿瘤药物中的应用,所述的肿瘤为肺癌、肝癌、乳腺癌或宫颈癌,当三萜类化合物为化合物4时,所述的肿瘤不为肺癌;当三萜类化合物为化合物5时,所述肿瘤不为宫颈癌:
。
2.三萜类化合物的制备方法,其特征在于:
取线叶雀舌木干燥全草18.0 kg,粉碎后用75%乙醇加热回流提取3次,料液比为1:8,每次2 h,减压回收溶剂,浸膏用蒸馏水分散,依次用等体积的石油醚、氯仿、乙酸乙酯和正丁醇萃取3次,得石油醚层萃取物-提取物1 126.4 g,氯仿层萃取物-提取物2 26.7 g,乙酸乙酯层萃取物-提取物3 36.1 g,正丁醇层萃取物-提取物4 162.3 g;
所得的氯仿层萃取物26.7 g,采用正相硅胶柱色谱进行分离,流动相选用石油醚:乙酸乙酯100:0-1:1及二氯甲烷:甲醇50:1-1:1梯度洗脱,所得组分经硅胶薄层色谱分析,合并相同组分后得到15份洗脱物;
对石油醚:乙酸乙酯=50:1组分2.8 g进行分离,采用硅胶柱色谱法,用石油醚:正己烷;丙酮梯度洗脱,在10:10:1处,对白色固体粉末采用半制备型HPLC分离,得化合物1,2,4,9;在石油醚:丙酮10:1处,对黄色固体粉末进行Sephadex LH-20分离,随后采用HPLC分离,重结晶得化合物3,5,6,7,8;对石油醚:乙酸乙酯=25:1组分2.1 g进行分离,采用硅胶柱色谱法,用石油醚:乙酸乙酯梯度洗脱,在5:1处,对黄色固体采用HPLC分离,得化合物13-15;对石油醚:丙酮=15:1组分1.6 g进行分离,采用硅胶柱色谱法,用二氯甲烷:甲醇梯度洗脱,在50:1处,对黄色固体采用Sephadex LH-20分离,随后采用HPLC分离,重结晶得化合物18;在20:1处,对黄色固体采用HPLC分离,得化合物19;
。
3.三萜类化合物的制备方法,其特征在于:
取干燥缘腺雀舌木(Leptopus clarkei (Hook.f.) Pojark.)27.1 kg,粉碎后用二氯甲烷加热回流提取3次,料液比为1:8,每次1.5 h,减压回收溶剂,浸膏用氯仿、丙酮、甲醇分别溶解;取氯仿层浸膏37.3 g,采用硅胶柱色谱进行分离,以石油醚-乙酸乙酯、石油醚-丙酮组成的溶剂系统进行洗脱,辅以1-2滴冰乙酸,得到流份12份,对石油醚:乙酸乙酯=50:1组分1.7 g进行反复硅胶柱色谱法分离,对黄色固体粉末采用制备型HPLC分离,得化合物3,4,13,14;在8:1处,对黄色固体粉末采用半制备型HPLC分离,得化合物5,9,18,24,对石油醚:乙酸乙酯=25:1组分2.3 g进行分离,采用硅胶柱色谱法,用石油醚:丙酮梯度洗脱,在5:1处,对黄色固体粉末采用制备型HPLC分离,得化合物23;
。
4.三萜类化合物的制备方法,其特征在于:
雀儿舌头(Leptopus chinensis (Bunge) Pojark)干燥全草19.2 kg,粉碎后用60%乙醇加热回流提取3次,料液比为1:8,每次1.5 h,减压回收溶剂,浸膏用蒸馏水分散后离心取上清液,上清液用非极性大孔树脂D101处理后,依次用水和醇梯度洗脱,收集30%~100%醇洗脱部分,各洗脱部分利用薄层色谱或HPLC 210 nm筛选,筛选富含三萜类化合物的有效部位,即得三萜粗提物;所得的三萜粗提物35.7 g,采用正相硅胶柱色谱进行分离,以正己烷-二氯甲烷、二氯甲烷-乙酸乙酯、二氯甲烷-甲醇组成的溶剂系统进行梯度洗脱,所得组分经硅胶薄层色谱分析,合并相同组分后得到13份洗脱物;正己烷:二氯甲烷=25:1组分2.5 g经快速中低压反相色谱,以甲醇/水或乙醇/水梯度洗脱,所得黄色固体粉末采用制备型HPLC分离,得化合物3,4,13,14,15;在10:1处,对黄色固体粉末采用半制备型HPLC分离,得化合物26,27;
。
5.三萜类化合物的制备方法,其特征在于:南雀舌木(Leptopus yunnanensis P. T.Li)干燥全草12.0 kg,粉碎后用二氯甲烷加热回流提取3次,料液比为1:8,每次1.5 h,减压回收溶剂,浸膏分别用氯仿、丙酮、甲醇溶解。取氯仿层浸膏29.3 g,采用正相硅胶柱色谱进行分离,流动相选用环己烷-二氯甲烷,石油醚-乙酸乙酯组成的溶剂系统进行梯度洗脱,所得组分经硅胶薄层色谱分析及HPLC筛选合并后得到13份洗脱物;对环己烷:二氯甲烷=5:1组分2.2 g进行分离,采用快速中低压反相色谱,以甲醇/水或乙醇/水梯度洗脱,所得白色固体粉末采用半制备型HPLC分离,得化合物7,15,19,23;在石油醚:丙酮20:1处,对黄色固体粉末进行Sephadex LH-20分离,随后采用HPLC分离,得化合物5,8,17,24,27;
。
6.根据权利要求1所述的应用,其特征在于,所述的三萜类化合物及其盐与药学上可接受的载体或赋形剂制备成药物组合物。
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