CN109734759B - 一种梓醇衍生物及其应用 - Google Patents
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Abstract
本发明属于医药及化工的技术领域，公开了一类天然梓醇衍生物和一类来源于梓苷和胡黄连苷II修饰的新梓醇衍生物，本发明同时提供上述衍生物的制备方法以及在作为制备抗炎药物上的应用。本发明中涉及到的天然梓醇衍生物的结构如式(I)或式(II)所示，来源于梓苷和胡黄连苷II修饰的新梓醇衍生物的结构如式(III)或式(IV)所示。实验证明本发明所述的式(I)、式(II)、式(III)和式(IV)化合物或其水合物、药学上可接受的盐、互变异构体、立体异构体、前体化合物对8‑羟基鸟嘌呤DNA糖基化酶1(8‑hydroxytridine DNA glycosylase 1,OGG1)具有显著的抑制抑制，在制备抗炎药物和抗肿瘤药物上有着广阔的应用空间。
Description
技术领域
本发明属于医药领域，涉及一类对8-羟基鸟嘌呤DNA糖基化酶1(8-hydroxytridine DNA glycosylase 1,OGG1)具有抑制活性的化合物，具体来说是基于OGG1抑制剂的一种天然或者修饰的梓醇衍生物及其应用。
背景技术
氧化应激(ROS)会导致各种细胞内生物大分子(包括蛋白质、脂质及核酸)的氧化。ROS在DNA上造成的氧化性碱基的主要类型是8-羟基鸟嘌呤(8-oxoG)。8-羟基鸟嘌呤DNA糖基化酶1(OGG1)是特异性修复8-oxoG的修复蛋白，通过OGG1起始的碱基切除修复途径(OGG1-BER)将8-oxoG识别出来并更正为正确的碱基。出乎意料的是，基因组上异常过量的8-oxoG并不影响胚胎发育、癌前病变或小鼠的寿命[Arai等，Toxicology 2006,221:179–186；Leopoldo等，Free Radical Bio.Med.2015,8:1107–118]，而且OGG1-/-的小鼠对炎症没有明显的反应，表现为细胞内促炎因子的表达降低和炎症细胞浸润不足[Mabley等，FASEBJ.2005,19:290–292]。进一步的机制研究表明OGG1识别启动子区氧化损伤的产物8-oxoG时能够激活鸟苷三磷酸酶(GTPases)，进而通过丝裂原活化蛋白(MAP)激酶和磷脂酰肌醇3(PI3)激酶介导的KRAS-GTP信号转导和有丝分裂原应激相关激酶-1(MSK1)加速核因子-κB(NF-κB)与DNA的结合，促进炎症因子的释放和疾病的产生，而其他DNA糖基化酶则无此作用[Ba等,Int.J.Mol.Sci.2014,15:16975-16997；Aguilera-Aguirre等,J Immunol.2014,193(9):4643-53；pan等,J.Bio.Chem.2016,291(49):25553-25566]。
同时，越来越多的证据表明OGG1抑制剂不仅具有提高某些癌症治疗疗效的潜力，而且具有主动抑制潜在耐药机制的潜力[Preston等,Mol.Cancer Ther.2009,8:2015-2026；Noren等,J.Biol.Chem.2011,286:44679-44690]。此外，OGG1的过表达逆转了ratsarcoma viral oncogene homolog(RAS)诱导的生长停滞，表明一些RAS诱导的肿瘤可能依赖于OGG1活性来维持其肿瘤表型，并且OGG1抑制剂可用于治疗这些癌症[Ramdzan等,PLoSBiol.2014,12:e1001807；Nathan等，ACS Chem.Biol.2015,10,2334-2343]。因此，选择性OGG1抑制剂可以作为单药治疗或与DNA损伤剂联合治疗癌症。
目前，报道的小分子OGG1抑制剂都是来源于化学合成[Noren等,J.Biol.Chem.2011,286:44679-44690；Visnes等,Science 2018,362(6416):834-839]。尚无来自于天然产物及其衍生物关于抑制OGG1活性的报道，受到传统清热中药的启发，梓醇衍生物特别是梓醇6位非极性取代的衍生物对OGG1具有显著的抑制活性。因此，梓醇衍生物有希望成为由ROS引起的OGG1活化导致的各种炎性疾病、自身免疫性疾病的治疗药物。
梓醇衍生物主要分布于14个科50个属中的150种植物，被报道的天然梓醇类衍生物总共有146个，主要分为6位酯化梓醇衍生物和6位鼠李糖苷化梓醇衍生物两种类型，梓醇衍生物的药理活性同样非常广泛，主要有抗炎、抗氧化和抗肿瘤等药理活性，其中抗炎报道占到了37％。与此形成鲜明对比的是，在2013年报道的梓醇系统性综述中(Liu等,CurrBioactCompd,2013,9:306-323.)，梓醇抗炎报道只占到了药理研究的11％。由于梓醇属于多羟基类环烯醚萜苷，通过常规的苷化或酯化选择性的在6位醇羟基上引入相应的基团是不现实的。通过文献调研，我们发现梓实和胡黄连中的6位酯化梓醇衍生物更加丰富。同时梓实和胡黄连中可用于结构修饰的梓苷(含量约为0.3％)和胡黄连苷II(含量大于6％)含量更高。在碱性条件下，梓苷和胡黄连苷II6位的酚羟基转变为芳氧负离子，增加了亲核能力，可以选择性地与卤代烃发生亲核取代反应，而结构中的醇羟基则不会发生此反应。反应在弱碱性条件下进行，既可避免了苷键的水解，也可减少酯键的断裂而减少副产物。从而保证了梓苷和胡黄连苷II衍生物的顺利进行。
发明内容
本发明的目的是为了提供一种天然梓醇衍生物或结构修饰新梓醇衍生物对新药物靶点OGG1抑制活性，为制备预防、缓解和/或治疗由OGG1活化所引起的疾病筛选新的药物。
本发明所述的具有OGG1抑制活性的天然梓醇衍生物是具有式I和式II所示化学结构或/和其可药用衍生物：
其中，式I和式II中的R1、R2、R3、R4、R5各自独立选自氢、烷基或酰基。所述的烷基选自C1～C4的烷基；所述的酰基选自C1～C4的酰基或选自肉桂酰基、苯环取代型肉桂酰基、苯甲酰基、苯环取代型苯甲酰基。
式I中的R1、R2、R3为氢、肉桂酰基、对羟基肉桂酰基、咖啡酸酰基、阿魏酸酰基、异阿魏酸酰基、3,4-二甲氧基肉桂酰基、苯甲酰基、对羟基苯甲酰基、香草酰基、藜芦酰基、异香草酰基、3,4-二羟基苯甲酰基，乙酰基的任意一种；式II中的R4、R5为氢、肉桂酰基、对羟基肉桂酰基、咖啡酸酰基、阿魏酸酰基、异阿魏酸酰基、3,4-二甲氧基肉桂酰基、苯甲酰基、对羟基苯甲酰基、香草酰基、藜芦酰基、异香草酰基、3,4-二羟基苯甲酰基，乙酰基的任意一种。
作为更进一步优选方案，所述式I化合物具有如下结构式：
I-1:R1＝乙酰基,R2＝乙酰基,R3＝3,4-二甲氧基肉桂酰基
I-2:R1＝乙酰基,R2＝肉桂酰基,R3＝乙酰基
I-3:R1＝乙酰基,R2＝肉桂酰基,R3＝肉桂酰基
I-4:R1＝肉桂酰基,R2＝乙酰基,R3＝氢
I-5:R1＝氢,R2＝氢,R3＝肉桂酰基
I-6:R1＝氢,R2＝氢,R3＝对羟基肉桂酰基
I-7:R1＝氢,R2＝氢,R3＝阿魏酰基
I-8:R1＝阿魏酰基,R2＝氢,R3＝氢。
作为更进一步优选方案，所述式II化合物具有如下结构式：
II-1:R4＝4-羟基-3,5-二甲氧基苯甲酰基,R5＝氢
II-2:R4＝氢,R5＝肉桂酰基
II-3:R4＝4-羟基-3-甲氧基苯甲酰基,R5＝氢
II-4:R4＝氢,R5＝阿魏酰基
II-5:R4＝阿魏酰基,R5＝氢
II-6:R4＝异阿魏酰基,R5＝氢
II-7:R4＝4-羟基苯甲酰基,R5＝氢
II-8:R4＝4-羟基肉桂酰基,R5＝氢
II-9:R4＝咖啡酰基,R5＝氢。
式I所示化合物可来源于天然提取物，其中的式I-1～I-8化合物可来源于齿叶玄参(Scrophularia dentata Royle ex Benth.)提取物，式II-1～II-10化合物可来源于梓(Catalpa ovata G.Don)或胡黄连(Picrorhiza scrophulariiflora.Pennell)或水蔓青[Veronica linariifolia Pall.Cx Link.sub.Dilatata(Nakai et Kitagawa)Hong.]提取物。
本发明所述的具有OGG1抑制活性的修饰的梓醇衍生物是具有式III和式IV所示化学结构或/和其可药用衍生物：
式III和式IV中的R为：
具有1-12个碳原子的烷基，其为支链或非支链的，且未被取代或被以下基团取代一次或次：卤素、羟基、氰基、C1-4烷氧基、氧或它们的组合，且其中任选一个或多个-CH2CH2-基团在这种情况下被-CH＝CH-或-C≡C-取代；
或者具有3-10个碳原子的环烷基，其未被取代或被以下基团取代一次或多次：卤素、羟基、氧、氰基、具有1-4个碳原子的烷基、具有1-4个碳原子的烷氧基，或它们的组合；
或者具有4-16个碳原子的烷氧基，其未被取代或在环烷基部分和/或烷基部分被以下基团取代一次或多次：卤素、氧、氰基、羟基、C1-4-烷基、C1-4-烷氧基，或它们的组合；
或者具有6-14个碳原子的芳基，其未被取代或被以下基团取代一次或多次：卤素、CF3、OCF3、烷基、羟基、烷氧基、硝基、亚甲二氧基、亚乙二氧基、氰基，或它们的组合；
或者芳基烷基，其中芳基部分具有6-14个碳原子，而烷基部分为支链或非支链的，并具有1-5个碳原子，所述芳基烷基未被取代或在芳基部分被以下基团取代一次或多次：卤素、CF3、OCF3、烷基、羟基、烷氧基、硝基、亚甲二氧基、亚乙二氧基、氰基，或它们的组合，且其中在烷基部分中，一个或多个-CH2CH2-基团各自任选被-CH＝CH-或-C≡C-取代，且一个或多个-CH2-基团各自任选被-O-或-NH-取代，和/或烷基部分任选被卤素、氧、羟基、氰基，或它们的组合取代；
或者具有5-14个碳原子的部分不饱和碳环基团，其未被取代或被以下基团取代一次或多次：卤素、烷基、烷氧基、羟基、硝基、氰基、氧，或它们的组合；
或者杂环基，其为饱和、部分饱和或不饱和的，具有5-10个环原子，其中至少一个环原子为N、O或S原子，其未被取代或被以下基团取代一次或多次：卤素、羟基、芳基、烷基、烷氧基、氰基、三氟甲基、硝基、氧，或它们的组合；
或者杂环烷基，其中杂环部分为饱和、部分饱和或不饱和的，并具有5-10个环原子，其中至少一个环原子为N、O或S原子，且烷基部分为支链或非支链的，并具有1-5个碳原子，所述杂环烷基未被取代或在杂环部分被以下基团取代一次或多次：卤素、OCF3、羟基、芳基、烷基、烷氧基、氰基、CF3、硝基、氧，或它们的组合，其中在烷基部分中，一个或多个-CH2CH2-基团各自任选被-CH＝CH-或-C≡C-取代，且一个或多个-CH2-基团各自任选被-O-或-NH-取代，和/或烷基部分任选被卤素、氧、羟基、氰基，或它们的组合取代。
作为一种优选方案，式III和式IV的R为：烷基、苄基、取代苄基、联苯苄基、蒽甲基、喹啉甲基、吖啶甲基或二苯甲基。
作为更进一步优选方案，所述式III和式IV化合物具有如下结构式：
所述的可药用梓醇衍生物优选为药学上可接受的盐或溶剂化物。
本发明所述的梓醇衍生物，以梓苷和胡黄连苷II6位选择性修饰新梓醇衍生物或/和其可药用衍生物作为活性成分用于制备预防、缓解和/或治疗由OGG1活化所引起的疾病的药物和保健食品。
进一步说，本发明所述的疾病包括但不限于：炎症疾病、自身免疫性疾病、病毒感染性疾病、肿瘤和/或它们的并发症。
本发明所述的药物可以各种给药途径给予患者，包括但不限于口服、透皮、肌肉、皮下和静脉注射。
本发明提供的梓醇衍生物对OGG1具有显著的抑制作用，在制备新型的抗炎药物方面具有良好的应用前景。本发明所公开的基于梓苷和胡黄连苷II结构修饰的梓醇衍生物的制备方法，为首次合成，与从植物中寻找显著抑制OGG1活性的梓醇衍生物相比，更加快捷高效。
本发明和已有技术相比，其技术进步是显著的。实验证明本发明所述的式(I)、式(II)、式(III)和式(IV)化合物或其水合物、药学上可接受的盐、互变异构体、立体异构体、前体化合物对8-羟基鸟嘌呤DNA糖基化酶1(8-hydroxytridine DNA glycosylase 1,OGG1)具有显著的抑制抑制，在制备抗炎药物和抗肿瘤药物上有着广阔的应用空间。
具体实施方式
下面结合实施例对本发明作进一步详细、完整地说明，但并不因此限制本发明；本领域的技术人员根据下述内容所作的一些非本质的改进或替换均属于本发明的保护范围。
下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。
实施例1：式I天然梓醇衍生物的制备
将4.1kg齿叶玄参药材用体积分数为95％的乙醇水溶液回流提取3次，每次回流2小时，每次用乙醇水溶液40L，合并提取液，减压浓缩得浸膏(约570g)；向该浸膏中加约3倍量(1500mL)水混悬后，依次用石油醚(1500mL×3)、乙酸乙酯(1500mL×3)萃取，收集乙酸乙酯萃取液；减压回收乙酸乙酯后进行硅胶柱层析，依次用石油醚和乙酸乙酯进行梯度洗脱(10:1～0:1)；将所得流分用硅胶柱层析：先用石油醚-乙醇混合溶剂进行梯度洗脱(体积比由10:1至3:1)，然后用反向柱层析：用甲醇水溶液进行梯度洗脱(甲醇的体积分数由50％至70％)，最后用Sephadex LH-20分离纯化(洗脱剂为甲醇)，即得化合物I-1至I-8，均为白色固体粉末。
化合物I-1
1H NMR(400MHz,CD3OD)：δH 6.40(1H,dd,J＝1.5/5.9Hz,3-H)，2.49(1H,m,5-H)，4.07(1H,d,J＝8.1Hz,6-H)，3.67(1H,br s,7-H)，2.59(1H,dd,J＝7.7/9.6Hz,9-H)，4.16(1H,d,J＝13.1Hz,10β-H)，3.82(1H,d,J＝13.1Hz,10α-H)，4.77(1H,d,J＝7.9Hz,1′-H)，3.40(1H,t,J＝9.0Hz,3′-H)，3.92(1H,dd,J＝1.9/11.9Hz,6′β-H)，3.62(1H,dd,J＝6.6/11.9Hz,6′α-H)，5.31(1H,dd,J＝3.4/1.7Hz,2″-H)，5.36(1H,dd,J＝3.4/10.0Hz,3″-H)，5.17(1H,t,J＝10.0Hz,4″-H)，4.07(1H,dd,J＝6.2/10.0Hz,5″-H)，1.22(3H,d,J＝6.2Hz,6″-H)，7.67(1H,d,J＝15.9Hz,7″′-H)，6.42(1H,d,J＝15.9Hz,8″′-H)，7.24(1H,d,J＝1.9Hz,H-2″′)，6.98(1H,d,J＝8.4Hz,H-5″′)，7.19(1H,dd,J＝1.9/8.4Hz,H-6″′)，2.17(3H,s,COMe)，1.93(3H,s,COMe)，3.87(3H,s,OMe)，3.87(3H,s,OMe′)；13C-NMR(100MHz,CD3OD)：δC 95.3(C-1)，142.7(C-3)，103.3(C-4)，37.3(C-5)，85.0(C-6)，59.6(C-7)，66.7(C-8)，43.4(C-9)，61.6(C-l0)，99.9(C-l′)，75.0(C-2′)，77.8(C-3′)，72.0(C-4′)，78.8(C-5′)，63.1(C-6′)，97.9(C-1")，71.4(C-2")，70.8(C-3")，72.1(C-4")，68.4(C-5")，17.9(C-6")，128.7(C-l′")，111.7(C-2"′)，151.0(C-3"′)，153.3(C-4"′)，112.7(C-5"′)，124.5(6′")，147.8(C-7),115.5(C-8)，168.1(s,CO)，171.8&171.8(COMe×2)，20.8(COMe×2)，56.6(OMe)，56.7(OMe′)。
ESI-MS(pos.)：805[M+Na]+，ESI-MS(neg.)：827[M+HCOO-]-。
上述数据分析结果与文献(Fitoterapia,2014,98:84–90)中报道的scrodentoside A一致。
化合物I-2
ESI-MS(pos.)：745[M+Na]+，761[M+K]+，ESI-MS(neg.)：767[M+HCOO-]-，1443[2M-H]-。1H NMR(400MHz,CD3OD)：δH 6.40(1H,dd,J＝1.3/6.0Hz,3-H)，2.50(1H,m,5-H)，4.07(1H,d,J＝7.6Hz,6-H)，3.68(1H,br s,7-H)，2.59(1H,dd,J＝6.0/9.5Hz,9-H)，4.15(1H,d,J＝13.1Hz,10β-H)，3.82(1H,d,J＝13.1Hz,10α-H)，4.78(1H,d,J＝8.0Hz,1′-H)，3.40(1H,t,J＝9.0Hz,3′-H)，3.92(1H,dd,J＝1.7/11.9Hz,6′β-H)，3.63(1H,dd,J＝6.6/11.9Hz,6′α-H)，5.39(1H,dd,J＝3.5/9.9Hz,3″-H)，5.15(1H,t,J＝9.9Hz,4″-H)，4.04(1H,dd,J＝6.2/9.9Hz,5″-H)，1.22(3H,d,J＝6.2Hz,6″-H)，7.65(1H,d,J＝16.1Hz,7″′-H)，6.44(1H,d,J＝16.1Hz,8″′-H)，7.60(2H,m,H-2″′,6″′)，7.41(3H,m,H-3″′,H-4″′,H-5″′)，2.04(3H,s,COMe)，2.16(3H,s,COMe)；13C-NMR(100MHz,CD3OD)：δC 95.2(C-1)，142.6(C-3)，103.3(C-4)，37.3(C-5)，85.0(C-6)，59.5(C-7)，66.7(C-8)，43.4(C-9)，61.5(C-l0)，99.7(C-l′)，74.9(C-2′)，77.8(C-3′)，72.4(C-4′)，78.8(C-5′)，63.1(C-6′)，97.8(C-1")，71.4(C-2")，70.9(C-3")，71.9(C-4")，68.2(C-5")，17.9(C-6")，135.6(C-l′")，130.2(C-2"′,6′")，129.5(C-3",C-5")，131.9(C-4")，147.5(C-7),118.0(C-8)，167.3(s,CO)，171.7&171.9(COMe×2)，20.9(COMe×2)；
上述数据分析结果与文献(J.Nat.Prod.,1993,56:606-609.)中报道的scropolioside D一致。
化合物I-3
ESI-MS(pos.)：833[M+Na]+；ESI-MS(neg.)：855[M+HCOO-]-。1H NMR(400MHz，CD3OD)：δH 6.41(1H,dd,J＝1.5/5.9Hz,3-H)，2.53(1H,m,5-H)，4.10(1H,d,J＝8.2Hz,6-H)，3.70(1H,br s,7-H)，2.61(1H,dd,J＝7.8/9.6Hz,9-H)，4.18(1H,d,J＝13.1Hz,10β-H)，3.84(1H,d,J＝13.1Hz,10α-H)，4.79(1H,d,J＝7.9Hz,1′-H)，3.41(1H,dd,J＝8.9Hz,3′-H)，3.93(1H,dd,J＝1.8/11.9Hz,6′β-H)，3.64(1H,dd,J＝6.6/11.9Hz,6′α-H),5.41(1H,dd,J＝1.7/3.4Hz,2″-H)，5.51(1H,dd,J＝3.4/10.2Hz,3″-H)，5.30(1H,t,J＝10.2Hz,4″-H)，4.15(1H,dd,J＝6.2/10.2Hz,5″-H)，1.26(3H,d,J＝6.2Hz,6″-H)，7.61(1H,d,J＝16.0Hz,7″′-H)，6.40(1H,d,J＝16.0Hz,8″′-H)，7.54(2H,m,H-2″′,6″′)，7.41(6H,m,H-3″′,3″″,H-4″′,4″″,H-5″′,5″″)，7.70(1H,d,J＝16.0Hz,7″″-H)，6.50(1H,d,J＝16.0Hz,8″″-H)，7.51(2H,m,H-2″″,6″″)，2.18(3H,s,COMe)；13C NMR(100MHz,CD3OD)：δC 95.2(C-1)，142.6(C-3)，103.4(C-4)，37.3(C-5)，85.1(C-6)，59.6(C-7)，66.7(C-8)，43.5(C-9)，61.6(C-l0)，99.9(C-l′)，75.0(C-2′)，7.8(C-3′)，72.6(d,C-4′)，78.8(C-5′)，63.1(C-6′)，97.9(C-1")，71.6(C-2")，70.9(C-3")，71.9(C-4")，68.4(C-5")，18.0(C-6")，135.6(C-l′",1″″)，130.1(C-2"′,2″″and C-6′",6″″)，129.5(C-3"′,3″″和C-5"′,5″″)，131.9(d,C-4"′,4″″)，147.5(C-7″′or7″″)，147.8(C-7″′or7″″)，118.0(C-8″′,8″″)，167.4(C-9″′或9″″)，167.8(C-9″′或9″″)，171.8(COMe)，20.9(COMe)。
上述数据分析结果与文献(Planta Medica,1988,54(2):168-170.)中报道的scropolioside B一致。
化合物I-4
ESI-MS(pos.)：703[M+Na]+；ESI-MS(neg.)：725[M+HCOO-]-。1H NMR(400MHz，CD3OD)：δH 6.39(1H,dd,J＝6.0/1.5Hz,H-3)，2.49(1H,m,H-5)，4.06(1H,d,J＝8.2Hz,H-6)，2.58(1H,dd,J＝9.5/7.6Hz,H-9)，4.15(1H,d,J＝13.1Hz,H-10a)，3.82(1H,d,J＝13.1Hz,H-10b)，4.78(1H,d,J＝7.9Hz,H-1′)，3.42(1H,t,J＝8.9Hz,H-3′)，3.92(1H,J＝12.1/2.0Hz,H-6′b)，5.03(1H,br s,H-1″)，5.32(1H,dd,J＝3.4/1.7Hz,H-2″)，5.23(1H,dd,J＝9.9/3.4Hz,H-3″)，1.33(3H,d,J＝6.2Hz,H-6″)，7.61(2H,m,H-2″′,6″′)，7.41(3H,m,H-3″′,4″′,5″′)，7.71(1H,d,J＝16.0Hz,H-7″′)，6.52(1H,d,J＝16.0Hz,H-8″′)，2.12(COMe,s)，5.03-5.13(3H,m,H-1,4,1″)，3.60-3.67(3H,m,H-7,6′a,5″)，3.23-3.31(4H,m,H-2′,4′,5′,4″)。
上述数据分析结果与文献(Phytochemistry,1995,40(5):1569-1571.)中报道的scorodioside一致。
化合物I-5
ESI-MS(pos.)：661[M+Na]+；ESI-MS(neg.)：683[M+HCOO-]-。1H NMR(400MHz,CD3OD)：δH 6.39(1H,dd,J＝1.6/6.2Hz,H-3)，2.43(1H,m,H-5)，4.04(1H,d,J＝7.7Hz,H-6)，3.66(1H,br s,H-7)，2.57(1H,dd,J＝8.1/9.5Hz,H-9)，4.15(1H,d,J＝13.2Hz,H-10a)，3.82(1H,d,J＝13.2Hz,H-10b)，4.77(1H,d,J＝8.1Hz,H-1′)，3.40(1H,t,J＝9.1Hz,H-3′)，3.62(1H,dd,J＝6.4/12.1Hz,H-6′α)，5.00(1H,brs,H-1″)，1.18(3H,d,J＝6.2,H-6″)，7.62(2H,m,H-2″′,6″′)，7.41(3H,m,H-3″′,4″′,5″′)，7.74(1H,d,J＝16.0Hz,H-7″′)，6.58(1H,d,J＝16.0Hz,H-8″′)，5.05-5.12(3H,m,H-1,H-4,H-4″)，3.20-3.31(4H,H-2′,4′,5′,3″)，3.89-3.94(4H,H-6′β,2″,5″)。
上述数据分析结果与文献(Phytochemistry,1999,50:619-627.)中报道的6-O-α-L-(4″-O-trans-cinnamoyl)rhamnopyranosylcatalpol一致。
化合物I-6
ESI-MS(pos.)：721[M+Na]+；ESI-MS(neg.)：743[M+HCOO-]-。1H NMR(400MHz，CD3OD)：δH 6.39(1H,dd,J＝1.6/6.0Hz,H-3)，2.42(1H,m,H-5)，4.04(1H,d,J＝8.3Hz,H-6)，3.66(1H,br s,H-7)，2.59(1H,dd,J＝7.8/9.6Hz,H-9)，4.16(1H,d,J＝13.1Hz,H-10β)，3.82(1H,d,J＝13.1Hz,H-10α)，4.77(1H,d,J＝7.9Hz,H-1′)，3.40(1H,t,J＝9.0Hz,H-3′)，3.62(1H,dd,J＝6.6/12.0Hz,H-6′α)，5.00(1H,d,J＝1.0Hz,H-1″)，1.18(3H,d,J＝6.3Hz,H-6″)，7.68(1H,d,J＝16.0Hz,H-7″′)，6.47(1H,d,J＝16.0Hz,H-8″′)，7.24(1H,d,J＝1.8Hz,H-2″′)，6.98(1H,d,J＝8.3Hz,H-5″′)，7.20(1H,dd,J＝1.8/8.3Hz,H-6″′)，3.87(6H,s,OMe×2)，5.05-5.11(3H,H-1,H-4,H-4″)，3.23-3.31(3H,H-2′,4′,5′)，3.89-3.94(4H,H-6′β,2”,3″,5″)。
上述数据分析结果与文献(Phytochemistry,1999,50:619-627.)中报道的Lagotisoside D一致。
化合物I-7
ESI-MS(pos.):707[M+Na]+,ESI-MS(neg.):683[M-H]-.1H NMR(400MHz,CD3OD):δH6.38(1H,br d,J＝5.7Hz,H-3),2.42(1H,m,H-5),4.03(1H,d,J＝8.1Hz,H-6),3.66(1H,brs,H-7),2.57(1H,dd,J＝8.0/9.0Hz,H-9),4.16(1H,d,J＝13.1Hz,H-10a),3.82(1H,d,J＝13.1Hz,H-10b),4.78(1H,d,J＝7.9Hz,H-1′),3.41(1H,t,J＝9.0Hz,H-3′),3.63(1H,dd,J＝6.6/11.8Hz,H-6′a),4.99(1H,br s,H-1″),1.18(3H,d,J＝6.2Hz,H-6″),7.21(1H,s,H-2″′),6.82(1H,d,J＝8.0Hz,H-5″′),7.10(1H,d,J＝8.0Hz,H-6″′),7.65(1H,d,J＝15.9Hz,H-7″′),6.41(1H,d,J＝15.9Hz,H-8″′),5.05-5.10(3H,m,H-1,H-4,H-4″),3.20-3.35(4H,H-2′,4′,5′,3″),3.86-3.94(4H,H-6′b 2″,5″).13C NMR(100MHz,CD3OD):δC 95.3(C-1),142.5(C-3),103.6(C-4),37.4(C-5),84.2(C-6),59.6(C-7),66.7(C-8),43.4(C-9),61.6(C-l0),99.8(C-l′),74.9(C-2′),77.8(C-3′),71.9(C-4′),78.7(C-5′),63.1(C-6′),100.6(C-1"),72.6(C-2"),70.4(C-3"),75.4(C-4"),68.4(C-5"),18.0(C-6"),127.9(C-1″′),111.9(C-2″′),150.8(C-3″′),149.5(C-4″′),115.6(C-5″′),124.3(C-6″′),147.3(C-7″′),116.6(C-8″′),169.0(C-9″′),56.6(OMe).
上述数据分析结果与文献(Phytochemistry,1991,30(6):1917-1920.)中报道的6-O-α-L-(4”-O-feruloyl)rhamnopyranosylcatalpol一致。
化合物I-8
ESI-MS(pos.):707[M+Na]+,ESI-MS(neg.):683[M-H]-.1H NMR(400MHz,CD3OD):δH6.39(1H,dd,J＝6.0/1.7Hz,H-3),2.45(1H,m,H-5),4.04(1H,d,J＝8.2Hz,H-6),3.67(1H,br s,H-7),2.59(1H,dd,J＝7.8/8.9Hz,H-9),4.17(1H,d,J＝13.1Hz,H-10a),3.82(1H,d,J＝13.1Hz,H-10b),4.79(1H,d,J＝7.9Hz,H-1′),3.42(1H,t,J＝9.0Hz,H-3′),3.64(1H,dd,J＝6.7/11.9Hz,H-6′a),5.05(1H,d,J＝1.3Hz,H-1″),5.17(1H,dd,J＝3.4/1.3Hz,H-2″),3.95(1H,dd,J＝3.4/9.6Hz,H-3″),3.51(1H,t,J＝9.6Hz,H-4″),3.77(1H,dd,J＝9.6/6.2Hz,H-5″),1.33(3H,d,J＝6.2Hz,H-6″),7.24(1H,d,J＝1.5Hz,H-2″′),6.84(1H,d,J＝8.3Hz,H-5″′),7.11(1H,dd,J＝8.3/1.5Hz,H-6″′),7.68(1H,d,J＝15.9Hz,H-7″′),6.46(1H,d,J＝15.9Hz,H-8″′),3.92(3H,s,OMe)；13C NMR(100MHz,CD3OD):δC 95.3(C-1),142.4(C-3),103.6(C-4),37.4(C-5),84.5(C-6),59.6(C-7),66.7(C-8),43.4(C-9),61.6(C-l0),99.8(C-l′),75.0(C-2′),77.8(C-3′),71.9(C-4′),78.7(C-5′),63.1(C-6′),97.8(C-1"),74.4(C-2"),70.7(C-3"),74.3(C-4"),70.4(C-5"),18.2(C-6"),127.9(C-1″′),111.8(C-2″′),150.9(C-3″′),149.5(C-4″′),115.4(C-5″′),124.5(C-6″′),147.6(C-7″′),116.6(C-8″′),168.8(C-9″′),56.6(OMe).
上述数据分析结果与文献(Journal of Natural Products.1990,53:107-111)中报道的6-O-α-L-(2”-O-feruloyl)rhamnopyranosylcatalpol一致。
实施例2：式II天然梓醇衍生物的制备
胡黄连根茎1kg，粉碎为粗粉，用10倍量甲醇加热回流提取3次，浓缩后加200-300目硅胶拌样，用300-400目硅胶柱层析，经氯仿-甲醇(1:20-1:5)梯度洗脱，得到2个流份。其中流份2用反相ODS柱层析，经甲醇-水(10％-30％)梯度洗脱，所得胡黄连苷II流份进行sephadex LH-20柱纯化(50％甲醇)，分离得到II-1～II-6，均为白色粉末。
梓实10kg，粉碎为粗粉，用10倍量75％乙醇加热回流提取3次，每次2h，提取液经减压回收乙醇至无醇味，用等量二氯甲烷萃取3次脱脂。剩余水层浓缩至一定体积后，通过D101大孔树脂柱进行初步分离，分别收集水、20％乙醇、40％乙醇、60％乙醇、80％乙醇、95％乙醇洗脱流份，40％和60％乙醇洗脱流份分别通过硅胶柱色谱、MCI柱色谱、SephadexLH-20柱色谱、ODS柱色谱共分离得到II-5，II-7，II-8，II-9，均为白色粉末。
将15kg水蔓菁药材用体积分数为95％的乙醇水溶液回流提取3次，每次回流2小时，每次用乙醇水溶液75L，合并提取液，减压浓缩得浸膏(约5.6kg)；向该浸膏中加约5倍量(30L)水混悬后，用二氯甲烷(20L×3)萃取，得水层于二氯甲烷层。将水层浓缩至10L上大孔树脂梯度洗脱，梯度为水，20％乙醇，40％乙醇，60％乙醇，80％乙醇，95％乙醇，每个梯度75L。对40％乙醇洗脱部位(约795g)进行分离，减压回收40％乙醇洗脱部位后进行硅胶柱层析，依次用二氯甲烷和甲醇进行梯度洗脱(20:1～0:1)；将所得流分用反相层析：先用MCI层析(甲醇体积分数30％,35％,40％)，后用ODS柱层析(甲醇体积分数25％,27.5％，30％,32.5％,35％)，最后用Sephadex LH-20纯化，(洗脱剂为甲醇-水＝1：1)，即得化合物1，2，3，4，5；对水洗脱部位(约1265g)进行分离，减压回收部分水洗脱部位后进行硅胶柱层析，依次用乙酸乙酯和甲醇进行梯度洗脱(50:1～0:1)；将所得流分用反相层析：先用MCI层析(甲醇体积分数0％,5％,10％)，后用Sephadex LH-20纯化，(洗脱剂为甲醇-水或二氯甲烷-甲醇＝1：1)，即得化合物II-3，II-5，II-8，II-9，II-10，均为白色粉末。
化合物II-1
ESI-MS(pos.):565[M+Na]+,ESI-MS(neg.):541[M-H-]-.Molecular formula:C24H30O14,Molecular weight:542。1H NMR(500MHz,CD3OD)：δH 5.11(1H,d,J＝9.6Hz,H-1),6.43(1H,brd,J＝5.9Hz,H-3),4.98(1H,dd,J＝5.9/5.0Hz,H-4),2.60(1H,m,H-5),5.07(1H,brd,J＝8.1Hz,H-6),3.71(1H,brs,H-7),2.47(1H,m,H-9),3.92(1H,d,J＝13.2Hz,H-10a),3.74(1H,m,H-10b),4.62(1H,d,J＝7.8Hz,H-1′),3.43(1H,dd,J＝6.9/11.7Hz,H-6′a),7.25(1H,s,H-2″,6″),3.82(6H,OMe×2).13C NMR(125MHz,CD3OD):δC 93.0(C-1),141.1(C-3),101.9(C-4),35.2(C-5),79.9(C-6),58.3(C-7),65.9(C-8),41.8(C-9),58.5(C-l0),97.9(C-l′),73.5(C-2′),76.4(C-3′),70.3(C-4′),77.5(C-5′),61.4(C-6′),118.6(C-1″),107.1(C-2″,6″),147.7(C-3″,5″),141.3(C-4″),165.7(C-7″),56.1(OMe×2).
上述数据分析结果与文献(中华中医药杂志,2017,32(5):2070-2074.)中报道的胡黄连苷Ⅵ一致。
化合物II-2
ESI-MS(pos.):510[M+NH4]+,ESI-MS(neg.):551[M+CH3COO-]-.1H NMR(600MHz,CD3OD):δH 4.88(1H,m,H-1),6.32(1H,dd,J＝1.4/6.0Hz,H-3),5.02(1H,dd,J＝6.0/5.0Hz,H-4),2.24(1H,m,H-5),3.79(1H,brd,J＝8.0Hz,H-6),3.41(1H,br s,H-7),2.54(1H,dd,J＝9.6/7.9Hz,H-9),4.16(1H,d,J＝13.0Hz,H-10a),3.66(1H,d,J＝13.0Hz,H-10b),4.79(1H,d,J＝7.9Hz,H-1′),3.29(1H,m,H-2′),3.43(2H,m,H-3′,4′),3.56(1H,m,H-5′),4.45(1H,dd,J＝5.6/11.9Hz,H-6′a),4.53(1H,dd,J＝11.9/2.0Hz,H-6′b),7.62(2H,m,H-2″,6″),7.41(3H,m,H-3″,4″,5″),7.71(1H,d,J＝16.0Hz,H-7″),6.56(1H,d,J＝16.0Hz,H-8″).13C NMR(150MHz,CD3OD):δC 95.4(C-1),141.9(C-3),104.2(C-4),39.2(C-5),79.8(C-6),62.5(C-7),66.2(C-8),43.5(C-9),62.0(C-l0),99.9(C-l′),74.9(C-2′),77.6(C-3′),71.7(C-4′),76.0(C-5′),64.3(C-6′),135.7(C-1″),130.2(C-2″,6″),129.5(C-3″,5″),131.8(C-4″),146.8(C-7″),118.8(C-8″),168.5(C-9″)。
上述数据分析结果与文献(中国天然产物,2006,4(1):36-39.)中报道的胡黄连苷I一致。
化合物II-3
ESI-MS(pos.):530[M+NH4]+,ESI-MS(neg.):511[M-H-]-.1H NMR(600MHz,CD3OD)：δH 5.20(1H,d,J＝9.2Hz,H-1),6.38(1H,dd,J＝1.2/5.9Hz,H-3),5.01(1H,dd,J＝5.9/4.2Hz,H-4),2.59(1H,m,H-5),5.13(1H,br d,J＝7.1Hz,H-6),3.75(1H,br s,H-7),2.63(1H,m,H-9),4.19(1H,d,J＝13.2Hz,H-10a),3.85(1H,d,J＝13.2Hz,H-10b),4.80(1H,d,J＝7.9Hz,H-1′),3.27(2H,m,H-2′,4′),3.33(1H,m,H-5′),3.41(1H,t,J＝9.0Hz,H-3′),3.65(1H,dd,J＝6.8/12.0Hz,H-6′a),3.95(1H,dd,J＝1.9/12.0Hz,H-6′b),7.57(1H,d,J＝1.8Hz,H-2″),6.86(1H,d,J＝8.3Hz,H-5″),7.60(1H,dd,J＝8.3/1.8Hz,H-6″),3.91(3H,s,OCH3).13C NMR(150MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),81.9(C-6),60.4(C-7),67.0(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),122.2(C-1″),113.7(C-2″),153.2(C-3″),149.0(C-4″),116.1(C-5″),125.5(C-6″),168.0(C-7″),56.6(OCH3)。
上述数据分析结果与文献(中国医药工业杂志,2007,38(3):221-226)中报道的胡黄连苷II一致。
化合物II-4
ESI-MS(pos.):556[M+NH4]+,ESI-MS(neg.):537[M-H-]-.1H NMR(600MHz,CD3OD):δH 4.86(1H,m,H-1),6.32(1H,dd,J＝1.7/6.0Hz,H-3),5.02(1H,dd,J＝6.0/4.8Hz,H-4),2.23(1H,m,H-5),3.79(1H,br d,J＝8.1Hz,H-6),3.41(1H,br s,H-7),2.54(1H,dd,J＝9.7/7.7Hz,H-9),4.16(1H,d,J＝13.0Hz,H-10a),3.66(1H,d,J＝13.0Hz,H-10b),4.78(1H,d,J＝7.9Hz,H-1′),3.29(1H,m,H-2′),3.42(2H,m,H-3′,4′),3.55(1H,ddd,J＝8.2/5.6/2.3Hz,H-5′),4.45(1H,dd,J＝5.6/11.9Hz,H-6′a),4.50(1H,dd,J＝11.9/2.3Hz,H-6′b),7.20(1H,d,J＝1.8Hz,H-2″),7.08(1H,dd,J＝8.2/1.8Hz,H-5″),6.82(1H,d,J＝8.2Hz,H-6″),7.62(1H,d,J＝15.9Hz,H-7″′),6.39(1H,d,J＝15.9Hz,H-8″),3.90(3H,s,OCH3).13CNMR(150MHz,CD3OD):δC 95.5(C-1),141.9(C-3),104.2(C-4),39.3(C-5),79.8(C-6),62.6(C-7),66.3(C-8),43.5(C-9),62.0(C-l0),99.9(C-l′),74.9(C-2′),77.6(C-3′),71.7(C-4′),76.1(C-5′),64.1(C-6′),127.7(C-1″),111.8(C-2″),149.6(C-3″),150.9(C-4″),116.7(C-5″),124.4(C-6″),147.3(C-7″),115.4(C-8″),169.1(C-9″),56.6(OCH3).
上述数据分析结果与文献(Journal of Natural Products,1980,43(6):649-707)中报道的胡黄连苷III一致。
化合物II-5
ESI-MS(pos.):556[M+NH4]+,ESI-MS(neg.):537[M-H-]-.1H NMR(600MHz,CD3OD)：δH 5.17(1H,d,J＝9.1Hz,H-1),6.38(1H,dd,J＝1.2/5.9Hz,H-3),4.99(1H,dd,J＝5.9/4.4Hz,H-4),2.61(2H,m,H-5,9),5.03(1H,br d,J＝7.8Hz,H-6),3.71(1H,br s,H-7),4.17(1H,d,J＝13.2Hz,H-10a),3.84(1H,d,J＝13.2Hz,H-10b),4.80(1H,d,J＝7.9Hz,H-1′),3.27(2H,m,H-2′,4′),3.31(1H,m,H-5′),3.41(1H,t,J＝9.1Hz,H-3′),3.65(1H,dd,J＝6.8/12.0Hz,H-6′a),3.93(1H,dd,J＝1.8/12.0Hz,H-6′b),7.22(1H,d,J＝1.6Hz,H-2″),6.82(1H,d,J＝8.1Hz,H-5″),7.10(1H,dd,J＝8.1/1.6Hz,H-6″),7.67(1H,d,J＝15.9Hz,H-7″),6.43(1H,d,J＝15.9Hz,H-8″),3.90(3H,s,OCH3).13C NMR(150MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),81.5(C-6),60.4(C-7),67.0(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),127.8(C-1″),111.9(C-2″),149.5(C-3″),151.0(C-4″),116.6(C-5″),124.5(C-6″),147.6(C-7″),115.0(C-8″),169.1(C-9″),56.6(OCH3)。
上述数据分析结果与文献(Planta Medica,1989,55(5):467-469)中报道的6-O-E-feruloylcatalpol一致。
化合物II-6
ESI-MS(pos.):556[M+NH4]+,ESI-MS(neg.):537[M-H-]-.1H NMR(600MHz,CD3OD)：δH 5.17(1H,d,J＝9.2Hz,H-1),6.38(1H,dd,J＝1.6/5.8Hz,H-3),4.99(1H,dd,J＝5.8/4.2Hz,H-4),2.60(1H,m,H-5),5.04(1H,dd,J＝7.9/1.1Hz,H-6),3.71(1H,d,J＝1.1Hz,H-7),2.63(1H,dd,J＝9.2/7.7Hz,H-9),4.17(1H,d,J＝13.2Hz,H-10a),3.84(1H,d,J＝13.2Hz,H-10b),4.80(1H,d,J＝7.9Hz,H-1′),3.27(2H,m,H-2′,4′),3.34(1H,m,H-5′),3.41(1H,t,J＝9.0Hz,H-3′),3.65(1H,dd,J＝6.7/12.0Hz,H-6′a),3.93(1H,dd,J＝2.1/12.0Hz,H-6′b),7.09(1H,d,J＝2.1Hz,H-2″),6.94(1H,d,J＝8.4Hz,H-5″),7.05(1H,dd,J＝8.4/2.1Hz,H-6″),7.63(1H,d,J＝15.9Hz,H-7″′),6.37(1H,d,J＝15.9Hz,H-8″),3.89(3H,s,OCH3).13C NMR(150MHz,CD3OD):δC 95.2(C-1),142.5(C-3),103.1(C-4),36.9(C-5),81.5(C-6),60.4(C-7),67.0(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),128.9(C-1″),115.1(C-2″),148.9(C-3″),152.1(C-4″),112.6(C-5″),115.5(C-6″),147.5(C-7″),122.8(C-8″),169.0(C-9″),56.5(OCH3)。
上述数据分析结果与文献(Helvetica Chimica Acta,1979,62(2):535-539.)中报道的米内苷(minecoside)一致。
化合物II-7
ESI-MS(pos.):500[M+NH4]+,ESI-MS(neg.):481[M-H-]-.Molecular formula:C22H26O12,Molecular weight:482。1H NMR(600MHz,CD3OD)：δH 5.15(1H,d,J＝9.1Hz,H-1),6.34(1H,dd,J＝1.2/6.0Hz,H-3),4.96(1H,dd,J＝6.0/4.1Hz,H-4),2.63(1H,m,H-5),5.07(1H,brd,J＝6.9Hz,H-6),3.71(1H,brs,H-7),2.59(1H,m,H-9),4.15(1H,d,J＝13.2Hz,H-10a),3.81(1H,d,J＝13.2Hz,H-10b),4.77(1H,d,J＝7.9Hz,H-1′),3.26(2H,m,H-2′,4′),3.30(1H,m,H-5′),3.39(1H,t,J＝9.1Hz,H-3′),3.62(1H,dd,J＝6.6/12.0Hz,H-6′a),3.90(1H,dd,J＝1.8/12.0Hz,H-6′b),7.87(2H,d,J＝8.8Hz,H-2″,6″),6.81(2H,d,J＝8.8Hz,H-3″,5″).13C NMR(150MHz,CD3OD):δC 95.2(C-1),142.5(C-3),103.1(C-4),36.8(C-5),81.7(C-6),60.4(C-7),67.0(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),74.9(C-2′),78.7(C-3′),71.8(C-4′),77.8(C-5′),63.0(C-6′),121.8(C-1″),133.1(C-2″,6″),116.4(C-3″,5″),163.9(C-4″),168.0(C-7″).
上述数据分析结果与文献(中成药,2012,34(12):2381-2384.)中报道的梓苷一致。
化合物II-8
ESI-MS(pos.):526[M+NH4]+,ESI-MS(neg.):507[M-H-]-.Molecular formula:C24H28O12，Molecular weight:508。1H NMR(600MHz,C5D5N):δH 5.57(1H,m,H-1),6.47(1H,dd,J＝5.7Hz,H-3),5.12(1H,dd,J＝5.9/3.6Hz,H-4),2.93(2H,m,H-5,9),5.29(1H,d,J＝6.7Hz,H-6),3.99(1H,br s,H-7),4.57(1H,d,J＝13.3Hz,H-10a),4.46(1H,d,J＝13.3Hz,H-10b),5.57(1H,d,J＝7.8Hz,H-1′),4.18(1H,dd,J＝7.8,9.0Hz,H-2′),4.34(1H,t,J＝9.1Hz,H-3′),4.27(1H,t,J＝9.0Hz,H-4′),4.06(1H,m,H-5′),4.39(1H,dd,J＝11.9/5.4Hz,H-6′a),4.55(1H,dd,J＝11.9/2.0Hz,H-6′b),7.63(2H,d,J＝8.5Hz,H-2″,6″),7.19(2H,d,J＝8.5Hz,
H-3″,5″),8.00(1H,d,J＝15.9Hz,H-7″,),6.61(1H,d,J＝15.9Hz,H-8″).13C NMR(150MHz,C5D5N):δC 95.0(C-1),141.9(C-3),102.8(C-4),36.7(C-5),80.7(C-6),59.8(C-7),67.3(C-8),43.5(C-9),60.5(C-l0),100.5(C-l′),75.4(C-2′),79.5(C-3′),71.8(C-4′),78.7(C-5′),62.9(C-6′),126.3(C-1″),131.2(C-2″,6″),117.2(C-3″,5″),162.0(C-4″),146.3(C-7″),114.8(C-8″),167.7(C-9″).
以上述数据分析结果与文献(中草药,1994,25(5):227-228.)中报道的specioside一致。
化合物II-9
ESI-MS(pos.):525[M+H]+,ESI-MS(neg.):1047[2M-H-]-.Molecular formula:C24H28O13，Molecular weight:524.1H NMR(400MHz,CD3OD),δH 5.17(1H,d,J＝9.2Hz,H-1),6.37(1H,brd,J＝6.0Hz,H-3),4.98(1H,dd,J＝6.0/4.2Hz,H-4),2.62(2H,m,H-5,9),5.03(1H,brd,J＝7.5Hz,H-6),3.70(1H,brs,H-7),4.17(1H,d,J＝13.2Hz,H-10a),3.83(1H,d,J＝13.2Hz,H-10b),4.80(1H,d,J＝7.8Hz,H-1′),3.27(2H,m,H-2′,4′),3.42(1H,t,J＝8.9Hz,H-3′),3.65(1H,dd,J＝6.5/12.0Hz,H-6′a),3.93(1H,brd,J＝12.0Hz,H-6′b),7.07(1H,d,J＝1.2Hz,H-2″),6.79(1H,d,J＝8.1Hz,H-5″),6.97(1H,dd,J＝8.1/1.2Hz,H-6″),7.60(1H,d,J＝15.9Hz,H-7″′),6.32(1H,d,J＝15.9Hz,H-8″).13C NMR(100MHz,CD3OD),δC95.2(C-1),142.5(C-3),103.1(C-4),36.9(C-5),81.4(C-6),60.4(C-7),67.0(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),75.0(C-2′),78.7(C-3′),71.9(C-4′),77.8(C-5′),63.0(C-6′),127.8(C-1″),114.6(C-2″),146.9(C-3″),149.9(C-4″),116.7(C-5″),123.3(C-6″),147.8(C-7″),115.3(C-8″),169.1(C-9″).
上述数据分析结果与文献(Journal of natural products.1980,43(6):649-707.)中报道的6-O-咖啡酰基梓醇(nudifloside/verminoside)一致。
ESI-MS(pos.)：516[M+NH4]+；ESI-MS(neg.)：497[M-H-]-。1H NMR(600MHz，CD3OD):δH 5.19(1H,d,J＝9.2Hz,H-1),6.38(1H,d,J＝5.7Hz,H-3),5.00(1H,dd,J＝3.7/5.9Hz,H-4),2.65(1H,d,J＝2.1Hz,H-5),5.09(1H,d,J＝6.9Hz,H-6),3.74(1H,d,J＝1.0Hz,H-7),2.62(1H,d,J＝7.5Hz,H-9),4.18(1H,d,J＝13.2Hz,H-10a),3.84(1H,d,J＝13.2Hz,H-10b),4.80(1H,d,J＝7.9Hz,H-1’),3.25～3.46(4H,m,H-2’,3’,4’,5’),3.93(1H,dd,J＝1.9/11.9Hz,H-6’a),3.65(1H,dd,J＝6.6/12.0Hz,H-6’b),7.47(1H,m,H-2”),6.82(1H,d,J＝8.8Hz,H-5”),7.46(1H,m,H-6”)；13C NMR(150MHz，CD3OD):δC 95.1(C-1),142.4(C-3),103.0(C-4),36.8(C-5),81.6(C-6),60.3(C-7),66.8(C-8),43.2(C-9),61.3(C-10),99.7(C-1’),74.8(C-2’),78.7(C-3’),71.8(C-4’),77.7(C-5’),62.9(C-6’),122.0(C-1”),116.0(C-2”),146.3(C-3”),152.2(C-4”),117.5(C-5”),123.9(C-6”),168.0(C-7”).
上述数据分析结果与文献(Archives of Pharmacal Research,2009,32(2):207-213)中报道的verproside一致。
实施例3梓苷经结构修饰获得梓醇衍生物的制备
在反应瓶中加入梓苷24mg(0.05mmol)和3mL N,N-二甲基甲酰胺(DMF)，室温搅拌下加入R1X(0.10mmol)(表1)和无水K2CO3(21mg,0.15mmol)，于30℃反应至终点(TLC跟踪)。加入适量100-200目硅胶拌样，减压回收溶剂至呈流沙状，经硅胶和MCI柱层析分离得到相应的式III类化合物，收率在50％-98％之间。
表1制备新梓醇衍生物的底物试剂
III-1：1H NMR(600 MHz,C5D5N)：δH 5.53(1H,d,J＝9.1 Hz,H-1),6.43(1H,dd,J＝1.4/5.9 Hz,H-3),5.06(1H,dd,J＝5.9/4.1 Hz,H-4),2.91(1H,m,H-5),5.28(1H,brd,J＝7.6 Hz,H-6),3.97(1H,brs,H-7),2.88(1H,m,H-9),4.50(1H,d,J＝13.3Hz,H-10a),4.42(1H,d,J＝13.3 Hz,H-10b),5.51(1H,d,J＝7.9 Hz,H-1′),4.13(1H,dd,J＝7.9/8.9 Hz,H-2′),4.28(1H,t,J＝8.9 Hz,H-3′),4.21(1H,t,J＝8.9 Hz,H-4′),3.99(1H,m,H-5′),4.32(1H,dd,J＝11.9/5.5 Hz,H-6′a),4.50(1H,m,H-6′b),8.13(2H,d,J＝8.9 Hz,H-2″,6″),7.19(2H,d,J＝8.9 Hz,H-3″,5″),8.11(2H,d,J＝7.9 Hz,H-2″′,6″′),7.43(2H,t,J＝7.9Hz,H-3″′,5″′),7.54(1H,m,H-4″′),5.74(2H,s,H-8″′).13C NMR(150MHz,C5D5N):δC95.0(C-1),141.9(C-3),102.7(C-4),36.7(C-5),81.3(C-6),59.7(C-7),67.4(C-8),43.5(C-9),60.4(C-l0),100.5(C-l′),75.4(C-2′),79.4(C-3′),71.8(C-4′),78.7(C-5′),62.9(C-6′),123.5(C-1″),132.6(C-2″,6″),115.4(C-3″,5″),163.2(C-4″),166.5(C-7″),135.4(C-1″′),129.6(C-2″′,6″′),128.7(C-3″′,5″′),134.5(C-4″′),194.3(C-7″′),71.3(C-8″′).HRESIMS:calcd for C30H32NaO13[M+Na]+623.1735,found:623.1752.
III-2：1H NMR(600 MHz,CD3OD)：δH 5.20(1H,d,J＝9.2 Hz,H-1),6.38(1H,dd,J＝1.2/6.0 Hz,H-3),5.00(1H,dd,J＝6.0/4.2 Hz,H-4),2.68(1H,m,H-5),5.14(1H,brd,J＝7.2 Hz,H-6),3.77(1H,brs,H-7),2.65(1H,m,H-9),4.18(1H,d,J＝13.2 Hz,H-10a),3.86(1H,d,J＝13.2 Hz,H-10b),4.81(1H,d,J＝7.9 Hz,H-1′),3.28(2H,m,H-2′,4′),3.42(1H,t,J＝9.1 Hz,H-3′),3.34(1H,m,H-5′),3.66(1H,dd,J＝6.7/12.0 Hz,H-6′a),3.90(1H,dd,J＝12.0/1.7 Hz,H-6′b),8.04(2H,d,J＝8.9 Hz,H-2″,6″),7.09(2H,d,J＝8.9 Hz,H-3″,5″),4.60(2H,s,H-2″′).13C NMR(150 MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.0(C-4),36.9(C-5),82.0(C-6),60.4(C-7),67.1(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),124.3(C-1″),133.0(C-2″,6″),115.9(C-3″,5″),163.4(C-4″),167.6(C-7″),173.4(C-l″′),68.0(C-2″′)。HRESIMS:calcd for C24H29NNaO13[M+Na]+562.1531,found:562.1542.
III-3：1H NMR(600 MHz,CD3OD)：δH 5.20(1H,d,J＝9.4 Hz,H-1),6.39(1H,dd,J＝6.0/1.7 Hz,H-3),5.01(1H,dd,J＝6.0/4.3 Hz,H-4),2.69(1H,m,H-5),5.15(1H,dd,J＝8.0/1.0 Hz,H-6),3.77(1H,d,J＝1.0 Hz,H-7),2.66(1H,m,H-9),4.19(1H,d,J＝13.2 Hz,H-10a),3.86(1H,d,J＝13.2 Hz,H-10b),4.80(1H,d,J＝7.9Hz,H-1′),3.27(2H,m,H-2′,4′),3.42(1H,t,J＝9.0 Hz,H-3′),3.33(1H,m,H-5′),3.65(1H,dd,J＝12.0/6.7 Hz,H-6′a),3.94(1H,dd,J＝12.0/2.0 Hz,H-6′b),8.07(2H,d,J＝9.0 Hz,H-2″,6″),7.18(2H,d,J＝9.0 Hz,H-3″,5″),7.10(3H,m,H-3″′,4″′,5″′),4.85(2H,s,H-8″′),2.18(6H,CH3×2).13C NMR(150 MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.0(C-4),36.9(C-5),82.0(C-6),60.4(C-7),67.1(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),124.5(C-1″),133.0(C-2″,6″),116.0(C-3″,5″),163.5(C-4″),167.6(C-7″),134.8(C-l″′),137.2(C-2″′,6″′),129.3(C-3″′,5″′),128.8(C-4″′),169.6(C-7″′),68.4(C-8″′),18.5(CH3×2)。HRESIMS:calcd forC32H37NNaO13[M+Na]+666.2157,found:666.2162.
III-4：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.6 Hz,H-1),6.43(1H,dd,J＝1.7/5.9 Hz,H-3),4.97(1H,dd,J＝5.9/4.5 Hz,H-4),2.58(1H,m,H-5),5.09(1H,dd,J＝8.1/1.0 Hz,H-6),3.69(1H,brs,H-7),2.46(1H,dd,J＝9.6/7.9 Hz,H-9),3.92(1H,dd,J＝13.2/4.5 Hz,H-10a),3.74(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.95(2H,d,J＝8.9 Hz,H-2″,6″),7.12(2H,d,J＝8.9 Hz,H-3″,5″),8.12(2H,dd,J＝8.9/5.5 Hz,H-2″′,6″′),7.43(2H,t,J＝8.9 Hz,H-3″′,5″′),5.72(2H,s,H-8″′),4.35(1H,m,10-OH),4.57(1H,brs,6′-OH).13CNMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.8(C-1″),131.4(C-2″,6″),114.8(C-3″,5″),162.1(C-4″),165.3(C-7″),166.4(C-1″′),131.4(C-2″′or6″′),131.1(C-2″′or6″′),116.1(C-3″′or5″′),115.9(C-3″′or5″′),164.4(C-4″′),192.6(C-7″′),70.2(C-8″′).HRESIMS:calcd for C30H31FNaO13[M+Na]+641.1641,found:641.1654.
III-5：1H NMR(600 MHz,CD3OD)：δH 5.20(1H,d,J＝9.0 Hz,H-1),6.38(1H,brd,J＝6.0 Hz,H-3),5.00(1H,dd,J＝6.0/4.6 Hz,H-4),2.68(1H,m,H-5),5.14(1H,brd,J＝7.6Hz,H-6),3.76(1H,brs,H-7),2.65(1H,m,H-9),4.18(1H,d,J＝13.2Hz,H-10a),3.86(1H,d,J＝13.2 Hz,H-10b),4.81(1H,d,J＝7.9 Hz,H-1′),3.28(2H,m,H-2′,4′),3.43(5H,m,H-3′,CH2,CH2′),3.34(1H,m,H-5′),3.65(1H,dd,J＝11.9/6.6 Hz,H-6′a),3.94(1H,brd,J＝11.9 Hz,H-6′b),8.02(2H,d,J＝8.5 Hz,H-2″,6″),7.04(2H,d,J＝8.5 Hz,H-3″,5″),4.89(2H,s,H-2″′),1.26(3H,t,J＝7.0 Hz,CH3),1.15(3H,t,J＝7.1 Hz,CH3′).13C NMR(150MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.0(C-4),36.9(C-5),82.0(C-6),60.4(C-7),67.0(C-8),43.3(C-9),61.4(C-l0),99.8(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),124.0(C-1″),132.9(C-2″,6″),115.8(C-3″,5″),164.0(C-4″),169.0(C-l″′),67.5(C-2″′),42.7(CH2),41.8(CH2′),14.5(CH3),13.2(CH3′)。HRESIMS:calcd forC28H36NO13[M-H]-594.2192,found:594.2179.
III-6：1H NMR(500 MHz,DMSO-d6)：δH 5.12(1H,d,J＝9.6 Hz,H-1),6.43(1H,dd,J＝1.7/5.9 Hz,H-3),4.98(1H,dd,J＝5.9/4.5 Hz,H-4),2.58(1H,m,H-5),5.09(1H,dd,J＝8.1/1.1 Hz,H-6),3.72(1H,brs,H-7),2.48(1H,m,H-9),3.93(1H,dd,J＝13.3/4.8 Hz,H-10a),3.72(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.05(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.98(2H,d,J＝9.0 Hz,H-2″,6″),7.15(2H,d,J＝9.0Hz,H-3″,5″),5.50(2H,s,Ar-O-CH2-),7.86(1H,d,J＝8.3 Hz,H-3″′),7.72(1H,dd,J＝8.3/2.0 Hz,H-4″′),7.86(1H,d,J＝2.0 Hz,H-6″′),3.81(3H,s,OCH3).13C NMR(125MHz,DMSO-d6):δC 93.0(C-1),141.2(C-3),101.8(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.5(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),122.0(C-1″),131.7(C-2″,6″),114.9(C-3″,5″),162.1(C-4″),165.3(C-7″),67.2(Ar-CH2-O-),140.0(C-1″′),127.7(C-2″′),132.4(C-3″′),130.8(C-4″′),126.4(C-5″′),131.1(C-6″′),166.1(C-7″′),52.4(OCH3″′).HRESIMS:calcdforC31H33BrClO14[M+Cl]-743.0748,found:743.0761.
III-7：1H NMR(500 MHz,DMSO-d6)：δH 5.12(1H,d,J＝9.6 Hz,H-1),6.43(1H,dd,J＝1.7/5.9 Hz,H-3),4.97(1H,dd,J＝5.9/4.5 Hz,H-4),2.58(1H,m,H-5),5.09(1H,dd,J＝8.1/1.0 Hz,H-6),3.72(1H,brs,H-7),2.48(1H,m,H-9),3.92(1H,brd,J＝12.7 Hz,H-10a),3.74(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.96(2H,d,J＝9.0 Hz,H-2″,6″),7.14(2H,d,J＝9.0Hz,H-3″,5″),5.76(2H,s,Ar-O-CH2-),8.12(2H,d,J＝8.4 Hz,H-2″′,6″′),7.89(2H,d,J＝8.4 Hz,H-3″′,5″′),7.78(2H,brd,J＝7.3 Hz,H-2″″,6″″),7.52(2H,brt,J＝7.3 Hz,H-3″″,5″″),7.45(1H,brt,J＝7.3 Hz,H-4″″).13C NMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.8(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.8(C-1″),131.4(C-2″,6″),114.8(C-3″,5″),162.2(C-4″),165.3(C-7″),70.3(Ar-O-CH2-),133.0(C-1″′),129.2(C-2″′,6″′),127.0(C-3″′,5″′),145.3(C-6″′),193.5(C-7″′),138.8(C-1″″),127.1(C-2″″,6″″),128.7(C-3″″,5″″),128.6(C-6″″).HRESIMS:calcd for C36H35O13[M-H]-675.2083,found:675.2088.
III-8：1H NMR(500 MHz,CD3OD)：δH 5.20(1H,d,J＝9.2 Hz,H-1),6.38(1H,dd,J＝1.4/6.0 Hz,H-3),5.00(1H,dd,J＝6.0/4.1 Hz,H-4),2.69(1H,m,H-5),5.13(1H,dd,J＝7.8/1.0 Hz,H-6),3.75(1H,brs,H-7),2.67(1H,m,H-9),4.18(1H,d,J＝13.2 Hz,H-10a),3.85(1H,d,J＝13.2 Hz,H-10b),4.80(1H,d,J＝7.9 Hz,H-1′),3.27(2H,m,H-2′,4′),3.41(1H,t,J＝9.1 Hz,H-3′),3.34(1H,m,H-5′),3.65(1H,dd,J＝6.7/12.0 Hz,H-6′a),3.94(1H,dd,J＝12.0/2.1 Hz,H-6′b),7.98(2H,brd,J＝9.0 Hz,H-2″,6″),6.96(2H,brd,J＝9.0 Hz,H-3″,5″),4.90(1H,m,H-1″′),2.00(2H,m,H-2″′,5″′),1.80(4H,m,H-2″′,3″′,4″′,5″′),1.67(2H,m,H-3″′,4″′).13C NMR(125 MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),81.8(C-6),60.4(C-7),67.0(C-8),43.4(C-9),61.5(C-l0),99.9(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.9(C-5′),63.1(C-6′),122.7(C-1″),132.9(C-2″,6″),116.4(C-3″,5″),164.1(C-4″),167.9(C-7″),81.1(C-l″′),33.9(C-2″′,5″′),25.1(C-3″′,4″′)。HRESIMS:calcd for C27H33O12[M-H]+549.1978,found:549.1975.
III-9：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.8 Hz,H-1),6.43(1H,dd,J＝5.9/1.4 Hz,H-3),4.98(1H,dd,J＝5.9/4.9 Hz,H-4),2.58(1H,m,H-5),5.08(1H,d,J＝8.1 Hz,H-6),3.71(1H,brs,H-7),2.47(1H,m,H-9),3.92(1H,dd,J＝13.2/5.0 Hz,H-10a),3.72(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.05(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.96(2H,d,J＝8.8 Hz,H-2″,6″),7.14(2H,d,J＝8.8 Hz,H-3″,5″),5.16(2H,s,-CH2-O-),7.28(2H,d,J＝8.2 Hz,H-2″′,6″′),7.41(2H,d,J＝8.2 Hz,H-3″′,5″′),2.47(3H,s,SCH3).13C NMR(125 MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.8(C-6),58.2(C-7),65.8(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.6(C-1″),131.5(C-2″,6″),115.0(C-3″,5″),162.4(C-4″),165.3(C-7″),69.2(-CH2-O-),132.9(C-1″′),125.9(C-2″′,6″′),128.6(C-3″′,5″′),138.1(C-4″′),14.6(SCH3″′).HRESIMS:calcd for C30H33O12S[M-H]-617.1698,found:617.1684.
III-10：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.8 Hz,H-1),6.42(1H,dd,J＝5.9/1.8 Hz,H-3),4.97(1H,dd,J＝5.9/4.5 Hz,H-4),2.58(1H,m,H-5),5.08(1H,dd,J＝8.1/1.0 Hz,H-6),3.71(1H,brs,H-7),2.48(1H,m,H-9),3.92(1H,br d,J＝13.2 Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.05(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.97(2H,brd,J＝8.9 Hz,H-2″,6″),7.16(2H,d,J＝8.9 Hz,H-3″,5″),5.23(2H,s,-CH2-O-),7.75(1H,d,J＝1.9 Hz,H-2″′),7.67(1H,d,J＝8.3 Hz,H-5″′),7.47(1H,dd,J＝8.3/1.9 Hz,H-6″′).13C NMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.9(C-1″),131.6(C-2″,6″),115.0(C-3″,5″),162.1(C-4″),165.3(C-7″),67.9(-CH2-O-),137.7(C-1″′),129.6(C-2″′),130.6(C-3″′),131.2(C-4″′),130.8(C-5″′),128.0(C-6″′).HRESIMS:calcd for C29H30Cl2NaO12[M+Na]+663.1007,found:663.1010.
III-11：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.6 Hz,H-1),6.42(1H,dd,J＝5.9/1.7 Hz,H-3),4.97(1H,dd,J＝5.9/4.5 Hz,H-4),2.58(1H,m,H-5),5.08(1H,dd,J＝8.1/1.1 Hz,H-6),3.71(1H,br s,H-7),2.48(1H,m,H-9),3.92(1H,dd,J＝13.3/5.1 Hz,H-10a),3.72(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9Hz,H-1′),3.05(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.97(2H,br d,J＝8.9 Hz,H-2″,6″),7.16(2H,br d,J＝8.9 Hz,H-3″,5″),5.33(2H,s,-CH2-O-),7.66(2H,br d,J＝8.3 Hz,H-2″′,6″′),7.87(2H,d,J＝8.3 Hz,H-3″′,5″′).13C NMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.2(C-3),101.8(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.5(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),122.0(C-1″),131.6(C-2″,6″),115.0(C-3″,5″),162.1(C-4″),165.3(C-7″),68.6(-CH2-O-),142.2(C-1″′),128.2(C-2″′,6″′),132.5(C-3″′,5″′),110.7(C-4″′),118.7(CN″′).HRESIMS:calcdfor C30H31NNaO12[M+Na]+620.1738,found:620.1741.
III-12：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.6 Hz,H-1),6.42(1H,dd,J＝5.9/1.7 Hz,H-3),4.96(1H,dd,J＝5.9/4.6 Hz,H-4),2.58(1H,m,H-5),5.08(1H,brd,J＝8.2Hz,H-6),3.71(1H,br s,H-7),2.47(1H,m,H-9),3.92(1H,dd,J＝13.3/5.1 Hz,H-10a),3.72(2H,m,H-10b,6′a),4.62(1H,d,J＝7.8 Hz,H-1′),3.05(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.42(1H,m,H-6′b),7.97(2H,br d,J＝8.9 Hz,H-2″,6″),7.22(2H,br d,J＝8.9 Hz,H-3″,5″),5.48(2H,s,-CH2-O-),7.68(1H,d,J＝8.5 Hz,H-3″′),8.43(1H,d,J＝8.5 Hz,H-4″′),8.00(1H,brd,J＝8.5 Hz,H-6″′),7.63(1H,brt,J＝8.5 Hz,H-7″′),7.80(1H,brt,J＝8.5 Hz,H-8″′),8.03(1H,brd,J＝8.5 Hz,H-9″′).13C NMR(125 MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.8(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.9(C-1″),131.6(C-2″,6″),115.0(C-3″,5″),162.3(C-4″),165.3(C-7″),71.0(-CH2-O-),156.9(C-2″′),119.6(C-3″′),137.2(C-4″′),127.2(C-5″′),128.0(C-6″′),126.7(C-7″′),130.0(C-8″′),128.6(C-9″′),147.0(C-10″′).HRESIMS:calcd for C32H34NO12[M+H]+624.2076,found:624.2066.
III-13：1H NMR(500 MHz,DMSO-d6)：δH 5.10(1H,d,J＝9.6 Hz,H-1),6.42(1H,dd,J＝5.9/1.7 Hz,H-3),4.97(1H,dd,J＝5.9/4.6 Hz,H-4),2.58(1H,m,H-5),5.08(1H,dd,J＝8.2/1.0 Hz,H-6),3.71(1H,br s,H-7),2.47(1H,m,H-9),3.92(1H,dd,J＝13.3/5.2 Hz,H-10a),3.72(2H,m,H-10b,6′a),4.62(1H,d,J＝7.8Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.42(1H,m,H-6′b),7.96(2H,br d,J＝8.9 Hz,H-2″,6″),7.14(2H,br d,J＝8.9 Hz,H-3″,5″),5.18(2H,s,-CH2-O-),7.27(2H,brd,J＝8.3 Hz,H-2″′,6″′),7.76(2H,brd,J＝8.3 Hz,H-3″′,5″′).13C NMR(125 MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.8(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.7(C-1″),131.5(C-2″,6″),115.0(C-3″,5″),162.3(C-4″),165.3(C-7″),68.8(-CH2-O-),136.3(C-1″′),130.0(C-2″′,6″′),137.3(C-3″′,5″′),94.2(C-4″′).HRESIMS:calcd forC29H31INaO12[M+Na]+721.0752,found:721.0771.
III-14：1H NMR(500 MHz,DMSO-d6)：δH 5.13(1H,d,J＝9.9 Hz,H-1),6.45(1H,brd,J＝5.8 Hz,H-3),4.99(1H,brt,J＝5.2 Hz,H-4),2.61(1H,m,H-5),5.11(1H,brd,J＝8.3 Hz,H-6),3.74(1H,br s,H-7),3.94(1H,dd,J＝13.2/5.1 Hz,H-10a),3.74(2H,m,H-10b,6′a),4.63(1H,d,J＝7.8 Hz,H-1′),3.05(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.44(1H,m,H-6′b),8.03(2H,br d,J＝8.7 Hz,H-2″,6″),7.33(2H,br d,J＝8.7 Hz,H-3″,5″),6.17(2H,s,-CH2-O-),8.35(2H,d,J＝8.8 Hz,H-1″′,8″′),7.59(4H,m,H-2″′,3″′,6″′,7″′),8.17(2H,d,J＝8.3 Hz,H-4″′,5″′),8.74(1H,s,H-10″′).13CNMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.2(C-3),101.8(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.8(C-1″),131.5(C-2″,6″),115.0(C-3″,5″),163.0(C-4″),165.4(C-7″),62.7(-CH2-O-),126.8(C-1″′,8″′),125.3(C-2″′,7″′),124.1(C-3″′,6″′),129.0(C-4″′,5″′),126.7(C-9″′),128.9(C-10″′),130.5(C-4a″′,10a″′),131.0(C-8a″′,9a″′).HRESIMS:calcd for C37H36NaO12[M+Na]+695.2099,found:695.2112.
III-15：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.7 Hz,H-1),6.42(1H,dd,J＝5.9/1.7 Hz,H-3),4.97(1H,dd,J＝5.9/4.6 Hz,H-4),2.57(1H,m,H-5),5.07(1H,dd,J＝8.1/0.9 Hz,H-6),3.71(1H,br s,H-7),2.47(1H,m,H-9),3.92(1H,dd,J＝13.3/5.1 Hz,H-10a),3.72(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.95(2H,brd,J＝8.8 Hz,H-2″,6″),7.14(2H,brd,J＝8.8 Hz,H-3″,5″),5.15(2H,s,-CH2-O-),7.21(2H,brd,J＝8.0 Hz,H-2″′,6″′),7.36(2H,brd,J＝8.0Hz,H-3″′,5″′),2.57(2H,t,J＝7.6 Hz,H-7″),1.54(2H,quint,J＝7.6Hz,H-8″),1.29(2H,sext,J＝7.6 Hz,H-9″),0.89(3H,t,J＝7.6 Hz,H-10″).13C NMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.5(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.6(C-1″),131.5(C-2″,6″),114.9(C-3″,5″),162.6(C-4″),165.4(C-7″),69.5(-CH2-O-),133.6(C-1″′),128.0(C-2″′,6″′),128.4(C-3″′,5″′),142.3(C-4″′),34.6(C-7″′),33.1(C-8″′),21.7(C-9″′),13.8(C-10″′).HRESIMS:calcd forC33H39O12[M-H]-627.2447,found:627.2458.
III-16：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.2 Hz,H-1),6.43(1H,dd,J＝5.9/1.5 Hz,H-3),4.97(1H,dd,J＝5.9/4.8 Hz,H-4),2.58(1H,m,H-5),5.08(1H,brd,J＝8.1 Hz,H-6),3.71(1H,br s,H-7),2.47(1H,m,H-9),3.92(1H,dd,J＝13.2/5.1 Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.42(1H,m,H-6′b),7.96(2H,brd,J＝8.9 Hz,H-2″,6″),7.14(2H,brd,J＝8.9 Hz,H-3″,5″),5.14(2H,s,-CH2-O-),6.62(2H,d,J＝2.2 Hz,H-2″′,6″′),6.46(1H,t,J＝2.2 Hz,H-4″′),3.74(6H,s,OCH3″′×2).13C NMR(125 MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.8(C-6),58.2(C-7),65.8(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.6(C-1″),131.5(C-2″,6″),114.9(C-3″,5″),162.4(C-4″),165.3(C-7″),69.4(-CH2-O-),138.7(C-1″′),105.5(C-2″′,6″′),160.6(C-3″′,5″′),92.9(C-4″′),55.2(OCH3″′×2).HRESIMS:calcd for C31H35O14[M-H]-631.2032,found:631.2045.
III-17：1H NMR(500 MHz,DMSO-d6+D2O)：δH 5.10(1H,d,J＝9.6 Hz,H-1),6.41(1H,dd,J＝5.9/1.7 Hz,H-3),4.95(1H,dd,J＝5.9/4.6 Hz,H-4),2.56(1H,m,H-5),5.07(1H,dd,J＝8.0/1.0 Hz,H-6),3.69(1H,br s,H-7),2.48(1H,m,H-9),3.92(1H,d,J＝13.3Hz,H-10a),3.71(2H,m,H-10b,6′a),4.61(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),3.42(1H,dd,J＝11.9/6.8 Hz,H-6′b),7.96(2H,brd,J＝8.9 Hz,H-2″,6″),7.17(2H,brd,J＝8.9 Hz,H-3″,5″),5.36(2H,s,-CH2-O-),7.72(2H,d,J＝8.8 Hz,H-2″′,6″′),8.25(1H,brd,J＝8.8 Hz,H-3″′,5″′).13C NMR(125 MHz,DMSO-d6+D2O):δC93.2(C-1),141.4(C-3),102.0(C-4),35.4(C-5),80.1(C-6),58.5(C-7),66.1(C-8),41.9(C-9),58.7(C-l0),98.1(C-l′),73.5(C-2′),77.5(C-3′),70.3(C-4′),76.3(C-5′),61.4(C-6′),122.2(C-1″),131.8(C-2″,6″),115.2(C-3″,5″),162.2(C-4″),165.6(C-7″),68.5(-CH2-O-),141.4(C-1″′),128.6(C-2″′,6″′),123.9(C-3″′,5″′),147.3(C-4″′).HRESIMS:calcd for C29H30NO14[M-H]-616.1672,found:616.1682.
III-18：1H NMR(500 MHz,DMSO-d6+D2O)：δH 5.10(1H,d,J＝9.6 Hz,H-1),6.41(1H,dd,J＝5.9/1.5 Hz,H-3),4.96(1H,dd,J＝5.9/4.8 Hz,H-4),2.57(1H,m,H-5),5.08(1H,brd,J＝8.3 Hz,H-6),3.70(1H,br s,H-7),2.47(1H,m,H-9),3.93(1H,d,J＝13.2 Hz,H-10a),3.71(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.19(2H,m,H-3′,5′),3.42(1H,dd,J＝11.9/6.7 Hz,H-6′b),7.97(2H,brd,J＝8.9 Hz,H-2″,6″),7.23(2H,brd,J＝8.9 Hz,H-3″,5″),5.64(2H,s,-CH2-O-),7.68(1H,brd,J＝7.5 Hz,H-2″′),7.51(1H,brt,J＝7.5Hz,H-3″′),8.06(1H,brd,J＝7.5 Hz,H-4″′),7.94(1H,brd,J＝8.3 Hz,H-5″′),7.58(2H,m,H-6″′,7″′),7.97(1H,brd,J＝8.3 Hz,H-2″′).13C NMR(125MHz,DMSO-d6+D2O):δC 93.2(C-1),141.4(C-3),102.0(C-4),35.4(C-5),80.1(C-6),58.5(C-7),66.1(C-8),41.9(C-9),58.7(C-l0),98.1(C-l′),73.5(C-2′),77.5(C-3′),70.3(C-4′),76.3(C-5′),61.4(C-6′),121.9(C-1″),131.8(C-2″,6″),115.3(C-3″,5″),162.8(C-4″),165.7(C-7″),68.4(-CH2-O-),131.3(C-1″′),127.3(C-2″′),125.7(C-3″′),128.8(C-4″′),133.6(C-4a″′),129.2(C-5″′),126.9(C-6″′),126.4(C-7″′),124.0(C-8″′),132.0(C-8a″′).HRESIMS:calcd for C33H33O12[M-H]-621.1978,found:621.1982.
III-19：1H NMR(500 MHz,DMSO-d6+D2O)：δH 5.10(1H,d,J＝9.5 Hz,H-1),6.41(1H,dd,J＝5.9/1.7 Hz,H-3),4.96(1H,dd,J＝5.9/4.5 Hz,H-4),2.56(1H,m,H-5),5.07(1H,dd,J＝8.1/1.0 Hz,H-6),3.70(1H,brs,H-7),2.48(1H,m,H-9),3.93(1H,d,J＝13.3Hz,H-10a),3.71(2H,m,H-10b,6′a),4.61(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.42(1H,dd,J＝11.9/6.8 Hz,,H-6′b),7.97(2H,brd,J＝8.9 Hz,H-2″,6″),7.18(2H,brd,J＝8.9 Hz,H-3″,5″),5.24(2H,s,-O-CH2-),7.30(2H,d,J＝8.2 Hz,H-2″′,6″′),7.50(2H,d,J＝8.2 Hz,H-3″′,5″′),7.43(1H,dd,J＝7.7/1.1 Hz,H-3″″),7.61(1H,td,J＝7.7/1.1 Hz,H-4″″),7.48(1H,td,J＝7.7/1.1 Hz,H-5″″),7.73(1H,dd,J＝7.7/1.1 Hz,H-6″″).13C NMR(125 MHz,DMSO-d6+D2O):δC 93.3(C-1),141.4(C-3),102.0(C-4),35.4(C-5),80.1(C-6),58.5(C-7),66.1(C-8),42.0(C-9),58.7(C-l0),98.1(C-l′),73.5(C-2′),77.6(C-3′),70.3(C-4′),76.4(C-5′),61.5(C-6′),121.9(C-1″),131.8(C-2″,6″),115.3(C-3″,5″),162.8(C-4″),165.7(C-7″),69.6(-O-CH2-),140.5(C-1″′),128.1(C-2″′,6″′),128.6(C-3″′,5″′),141.1(C-4″′),135.7(C-1″″),131.0(C-2″″),130.8(C-3″″),129.6(C-4″″),131.9(C-5″″),127.9(C-6″″),168.8(C-7″″),52.3(OCH3″″).HRESIMS:calcd forC37H38NaO14[M+Na]+729.2154,found:729.2154.
III-20：1H NMR(500 MHz,DMSO-d6+D2O)：δH 5.09(1H,d,J＝9.6 Hz,H-1),6.41(1H,dd,J＝5.9/1.5 Hz,H-3),4.95(1H,dd,J＝5.9/4.6 Hz,H-4),2.55(1H,m,H-5),5.07(1H,d,J＝8.1 Hz,H-6),3.69(1H,brs,H-7),2.47(1H,m,H-9),3.92(1H,d,J＝13.3 Hz,H-10a),3.71(2H,m,H-10b,6′a),4.61(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),3.42(1H,dd,J＝12.0/6.8 Hz,H-6′b),7.96(2H,d,J＝8.9 Hz,H-2″,6″),7.16(2H,d,J＝8.9 Hz,H-3″,5″),5.33(2H,s,-CH2-O-),7.72(2H,d,J＝8.3 Hz,H-2″′,6″′),7.94(2H,d,J＝8.3 Hz,H-3″′,5″′),3.19(3H,s,SO2CH3).13C NMR(125 MHz,DMSO-d6+D2O):δC 93.2(C-1),141.4(C-3),102.0(C-4),35.4(C-5),80.1(C-6),58.5(C-7),66.1(C-8),41.9(C-9),58.7(C-l0),98.1(C-l′),73.5(C-2′),77.5(C-3′),70.3(C-4′),76.3(C-5′),61.4(C-6′),122.1(C-1″),131.9(C-2″,6″),115.3(C-3″,5″),162.4(C-4″),165.6(C-7″),68.8(-CH2-O-),142.7(C-1″′),127.5(C-2″′,6″′),128.5(C-3″′,5″′),140.4(C-4″′),43.8(SO2CH3″′).HRESIMS:calcd for C30H34NaO14S[M+Na]+673.1561,found:673.1556.
III-21：1H NMR(500 MHz,DMSO-d6)：δH 5.13(1H,d,J＝9.7 Hz,H-1),6.44(1H,dd,J＝5.9/1.7 Hz,H-3),4.98(1H,dd,J＝5.9/4.8 Hz,H-4),2.60(1H,m,H-5),5.10(1H,m,H-6),3.73(1H,br s,H-7),3.93(1H,dd,J＝13.3/5.3 Hz,H-10a),3.75(2H,m,H-10b,6′a),4.63(1H,d,J＝7.8 Hz,H-1′),3.05(2H,m,H-2′,4′),3.19(2H,m,H-3′,5′),3.44(1H,m,H-6′b),8.02(2H,br d,J＝8.8 Hz,H-2″,6″),7.32(2H,br d,J＝8.8 Hz,H-3″,5″),6.24(2H,s,-CH2-O-),8.46(2H,d,J＝8.8Hz,H-1″′,8″′),7.70(2H,td,J＝8.8/1.0 Hz,H-2″′,7″′),7.89(2H,td,J＝8.8/1.0 Hz,H-3″′,6″′),8.02(2H,d,J＝8.8 Hz,H-4″′,5″′).13C NMR(125MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),122.1(C-1″),131.5(C-2″,6″),115.1(C-3″,5″),162.5(C-4″),165.3(C-7″),61.8(-CH2-O-),126.8(C-1″′,8″′),124.6(C-2″′,7″′),130.3(C-3″′,6″′),129.8(C-4″′,5″′),148.0(C-9″′),137.8(C-4a″′,10a″′),124.9(C-8a″′,9a″′).HRESIMS:calcd for C36H36NO12[M+H]+674.2232,found:674.2236.
III-22：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.7 Hz,H-1),6.42(1H,dd,J＝5.9/1.7 Hz,H-3),4.97(1H,dd,J＝5.9/4.5 Hz,H-4),2.58(1H,m,H-5),5.08(1H,dd,J＝8.1/1.0 Hz,H-6),3.71(1H,br s,H-7),2.48(1H,m,H-9),3.92(1H,dd,J＝13.3/5.1 Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.05(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.43(1H,m,H-6′b),7.97(2H,br d,J＝8.8 Hz,H-2″,6″),7.18(2H,brd,J＝8.8 Hz,H-3″,5″),5.25(2H,s,-CH2-O-),7.87(2H,br d,J＝8.6 Hz,H-2″′,6″′),7.59(2H,br d,J＝8.6 Hz,H-3″′,5″′),7.75(1H,d,J＝1.7 Hz,H-3″″),6.55(1H,dd,J＝1.7/1.5 Hz,H-4″″),8.50(1H,d,J＝1.5 Hz,H-5″″).13C NMR(125MHz,DMSO-d6):δC 93.0(C-1),141.1(C-3),101.7(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.5(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.7(C-1″),131.5(C-2″,6″),115.0(C-3″,5″),162.6(C-4″),165.4(C-7″),69.0(-CH2-O-),139.4(C-1″′),129.1(C-2″′,6″′),118.4(C-3″′,5″′),134.2(C-4″′),141.1(C-3″″),107.9(C-4″″),127.8(C-5″″).HRESIMS:calcd for C32H35N2O12[M+H]+639.2185,found:639.2177.
III-23：1H NMR(400 MHz,DMSO-d6)：δH 5.09(1H,d,J＝9.8 Hz,H-1),6.40(1H,brd,J＝5.8 Hz,H-3),4.97(1H,br t,J＝5.3 Hz,H-4),2.55(1H,m,H-5),5.06(1H,m,H-6),3.67(1H,br s,H-7),2.46(1H,m,H-9),3.91(1H,dd,J＝13.3/5.1Hz,H-10a),3.72(2H,m,H-10b,6′a),4.60(1H,d,J＝7.7 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),7.89(2H,br d,J＝8.8 Hz,H-2″,6″),7.16(2H,brd,J＝8.8 Hz,H-3″,5″),6.68(1H,s,-CH-O-),7.50(4H,d,J＝7.5 Hz,H-C-2″′,6″′,C-2″″,6″″),7.35(4H,t,J＝7.5 Hz,H-C-3″′,5″′,C-3″″,5″″),7.27(2H,s,t,J＝7.5Hz,H-4″″,4″″).13C NMR(100MHz,DMSO-d6):δC 93.1(C-1),141.2(C-3),101.8(C-4),35.2(C-5),79.9(C-6),58.3(C-7),65.9(C-8),41.8(C-9),58.6(C-l0),98.0(C-l′),73.5(C-2′),77.5(C-3′),70.3(C-4′),76.5(C-5′),61.5(C-6′),121.8(C-1″),131.5(C-2″,6″),116.2(C-3″,5″),161.5(C-4″),165.4(C-7″),80.1(-CH-O-),141.0(C-1″′,1″″),126.6(C-2″′,6″′,2″″,6″″),128.8(C-3″′,5″′,C-3″″,5″″),127.9(C-4″″,4″″).HRESIMS:calcd for C35H36NaO12[M+Na]+671.2099,found:671.2106.
实施例4胡黄连苷II经结构修饰获得梓醇衍生物的制备
在反应瓶中加入胡黄连25mg(0.05mmol)和3mL N,N-二甲基甲酰胺(DMF)，室温搅拌下加入R1X(0.10mmol)(表1)和无水K2CO3(21mg,0.15mmol)，于30℃反应至终点(TLC跟踪)。加入适量100-200目硅胶拌样，减压回收溶剂至呈流沙状，经硅胶和MCI柱层析分离得到相应的式IV类化合物，收率在50％-98％之间。
IV-1：1H NMR(500MHz,DMSO-d6)：δH 5.10(1H,d,J＝9.6Hz,H-1),6.41(1H,dd,J＝5.9/1.7Hz,H-3),4.96(1H,dd,J＝5.8/4.5Hz,H-4),2.58(1H,m,H-5),5.07(1H,dd,J＝8.1/1.0Hz,H-6),3.71(1H,brs,H-7),2.47(1H,dd,J＝9.6/7.9Hz,H-9),3.90(1H,dd,J＝13.3/4.9Hz,H-10a),3.73(2H,m,H-10b,6′a),4.61(1H,d,J＝7.9Hz,H-1′),3.02(2H,m,H-2′,4′),3.16(2H,m,H-3′,5′),3.41(1H,m,H-6′b),7.50(1H,d,J＝2.0Hz,H-2″),7.02(1H,d,J＝8.6Hz,H-5″),7.54(1H,dd,J＝8.6/2.0Hz,H-6″),3.85(3H,s,OCH3),8.01(2H,dd,J＝8.0/1.2Hz,H-2″′,6″′),7.58(2H,t,J＝8.0Hz,H-3″′,5″′),7.54(1H,dt,J＝8.0/1.2Hz,H-4″′),5.72(2H,s,H-8″′),4.32(1H,dd,,J＝7.3/5.4Hz,10-OH),4.55(1H,dd,,J＝7.5/4.8Hz,10-OH),.13C NMR(125MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.8(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.8(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.8(C-1″),112.3(C-2″),151.9(C-3″),148.5(C-4″),112.6(C-5″),123.2(C-6″),165.4(C-7″),55.7(OCH3),134.2(C-1″′),128.9(C-2″′,6″′),127.9(C-3″′,5″′),133.9(C-4″′),193.9(C-7″′),70.5(C-8″′).HRESIMS:calcd for C31H33O14[M-H]-629.1876,found:629.1875.
IV-2：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.6 Hz,H-1),6.42(1H,brd,J＝5.8 Hz,H-3),4.97(1H,brt,J＝5.1 Hz,H-4),2.59(1H,m,H-5),5.09(1H,brd,J＝8.1Hz,H-6),3.71(1H,brs,H-7),2.47(1H,m,H-9),3.90(1H,dd,J＝13.3/4.9Hz,H-10a),3.74(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.42(1H,m,H-6′b),7.50(1H,d,J＝1.4 Hz,H-2″),7.00(1H,d,J＝8.5 Hz,H-5″),7.60(1H,dd,J＝8.5/1.4 Hz,H-6″),3.85(3H,s,OCH3),4.55(2H,s,H-2″′),7.41(1H,s,N-H),7.39(1H,s,N-H′),4.36(1H,dd,,J＝7.3/5.4 Hz,10-OH),4.58(1H,dd,,J＝7.4/4.7 Hz,10-OH),13CNMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.2(C-3),101.8(C-4),35.2(C-5),80.0(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.5(C-l0),97.9(C-l′),73.5(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.5(C-6′),122.2(C-1″),112.3(C-2″),151.8(C-3″),148.8(C-4″),112.9(C-5″),123.3(C-6″),165.5(C-7″),55.8(OCH3),169.4(C-l″′),67.3(C-2″′)。HRESIMS:calcd for C25H30NO14[M-H]-568.1672,found:568.1667.
IV-3：1H NMR(500 MHz,DMSO-d6)：δH 5.12(1H,d,J＝9.6 Hz,H-1),6.42(1H,dd,J＝5.9/1.8 Hz,H-3),4.97(1H,dd,J＝5.9/4.5 Hz,H-4),2.59(1H,m,H-5),5.09(1H,dd,J＝8.1/1.0 Hz,H-6),3.71(1H,brs,H-7),2.48(1H,m,H-9),3.92(1H,dd,J＝13.2/4.7 Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.05(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),7.52(1H,m,H-2″),7.05(1H,d,J＝8.6 Hz,H-5″),7.57(1H,dd,J＝8.6/2.0 Hz,H-6″),3.87(3H,s,OCH3),5.75(2H,s,Ar-O-CH2-),8.11(2H,d,J＝8.5 Hz,H-2″′,6″′),7.88(2H,d,J＝8.5 Hz,H-3″′,5″′),7.77(2H,brd,J＝7.3 Hz,H-2″′,6″′),7.52(2H,brt,J＝7.3 Hz,H-3″′,5″′),7.45(1H,td,J＝7.3/1.1 Hz,H-4″′).13C NMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.2(C-3),101.9(C-4),35.2(C-5),80.0(C-6),58.3(C-7),66.0(C-8),41.9(C-9),58.5(C-l0),97.9(C-l′),73.5(C-2′),77.5(C-3′),70.3(C-4′),76.5(C-5′),61.5(C-6′),121.9(C-1″),112.4(C-2″),152.0(C-3″),148.6(C-4″),112.7(C-5″),123.3(C-6″),165.5(C-7″),55.8(OCH3),70.6(Ar-O-CH2-),133.1(C-1″′),129.2(C-2″′,6″′),127.1(C-3″′,5″′),145.3(C-6″′),193.5(C-7″′),138.9(C-1″″),127.1(C-2″″,6″″),128.7(C-3″″,5″″),128.6(C-6″″).HRESIMS:calcd for C37H37O14[M-H]-705.2189,found:705.2206.
IV-4：1H NMR(500 MHz,CD3OD):δH 5.21(1H,d,J＝9.2 Hz,H-1),6.39(1H,dd,J＝5.9/1.6 Hz,H-3),5.02(1H,dd,J＝5.9/4.2 Hz,H-4),2.66(1H,m,H-5),5.16(1H,dd,J＝7.9/1.1 Hz,H-6),3.77(1H,d,J＝1.1 Hz,H-7),2.70(1H,m,H-9),4.19(1H,d,J＝13.2 Hz,H-10a),3.87(1H,d,J＝13.2 Hz,H-10b),4.81(1H,d,J＝7.9Hz,H-1′),3.28(2H,m,H-2′,4′),3.34(1H,m,H-5′),3.43(1H,t,J＝9.0 Hz,H-3′),3.66(1H,dd,J＝12.0/6.7 Hz,H-6′a),3.94(1H,dd,J＝12.0/2.1 Hz,H-6′b),7.63(1H,d,J＝2.0 Hz,H-2″),7.07(1H,d,J＝8.5 Hz,H-5″),7.61(1H,dd,J＝8.5/2.0 Hz,H-6″),3.88(3H,s,OCH3″),5.53(2H,s,Ar-O-CH2-),7.91(1H,d,J＝8.4 Hz,H-3″′),7.70(1H,dd,J＝8.4/2.0 Hz,H-4″′),7.96(1H,d,J＝2.0 Hz,H-6″′),3.94(3H,s,OCH3″′).13C NMR(125 MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),82.1(C-6),60.4(C-7),67.1(C-8),43.4(C-9),61.4(C-l0),99.9(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.9(C-5′),63.1(C-6′),124.1(C-1″),113.9(C-2″),153.9(C-3″),150.9(C-4″),114.0(C-5″),125.1(C-6″),168.1(C-7″),56.8(OCH3),69.6(Ar-CH2-O-),142.5(C-1″′),128.7(C-2″′),132.1(C-3″′),130.0(C-4″′),128.4(C-5″′),131.9(C-6″′),167.8(C-7″′),53.0(OCH3″′).HRESIMS:calcd forC32H35BrClO15[M+Cl]-773.0853,found:773.0871.
IV-5：1H NMR(500 MHz,CD3OD):δH 5.20(1H,d,J＝9.1 Hz,H-1),6.38(1H,dd,J＝6.0/1.6 Hz,H-3),5.01(1H,dd,J＝6.0/4.1 Hz,H-4),2.65(1H,m,H-5),5.14(1H,dd,J＝7.8/1.1 Hz,H-6),3.77(1H,d,J＝1.1 Hz,H-7),2.68(1H,m,H-9),4.19(1H,d,J＝13.2 Hz,H-10a),3.86(1H,d,J＝13.2 Hz,H-10b),4.81(1H,d,J＝8.0Hz,H-1′),3.28(2H,m,H-2′,4′),3.34(1H,m,H-5′),3.42(1H,t,J＝9.0 Hz,H-3′),3.65(1H,dd,J＝12.0/6.7 Hz,H-6′a),3.94(1H,dd,J＝12.0/2.1 Hz,H-6′b),7.57(1H,d,J＝2.0 Hz,H-2″),7.00(1H,d,J＝8.6 Hz,H-5″),7.68(1H,dd,J＝8.6/2.0 Hz,H-6″),3.86(3H,s,OCH3″),4.90(1H,m,H-1″′),1.97(2H,m,H-2″′,5″′),1.84(4H,m,H-2″′,3″′,4″′,5″′),1.66(2H,m,H-3″′,4″′).13C NMR(125 MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),81.9(C-6),60.4(C-7),67.0(C-8),43.4(C-9),61.4(C-l0),99.9(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),122.9(C-1″),114.1(C-2″),153.9(C-3″),151.0(C-4″),114.5(C-5″),125.1(C-6″),167.9(C-7″),56.7(OCH3),81.8(C-l″′),33.9(C-2″′,5″′),25.1(C-3″′,4″′).HRESIMS:calcd for C28H35O13[M-H]-579.2083,found:579.2080.
IV-6：1H NMR(500 MHz,DMSO-d6)：δH 5.12(1H,d,J＝9.3 Hz,H-1),6.43(1H,brd,J＝5.6 Hz,H-3),4.98(1H,brt,J＝5.1 Hz,H-4),2.59(1H,m,H-5),5.09(1H,brd,J＝8.1Hz,H-6),3.71(1H,brs,H-7),2.48(1H,m,H-9),3.92(1H,dd,J＝13.2/5.0Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.8 Hz,H-1′),3.04(2H,m,H-2′,4′),3.19(2H,m,H-3′,5′),7.49(1H,d,J＝1.2 Hz,H-2″),7.18(1H,d,J＝8.6 Hz,H-5″),7.61(1H,dd,J＝8.6/1.2Hz,H-6″),3.83(3H,s,OCH3),5.15(2H,s,Ar-CH2-O-),7.28(2H,d,J＝8.2 Hz,H-2″′,6″′),7.40(2H,d,J＝8.2 Hz,H-3″′,5″′),2.47(3H,s,SCH3).13C NMR(125 MHz,DMSO-d6):δC92.9(C-1),141.1(C-3),101.8(C-4),35.2(C-5),79.9(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.8(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.6(C-1″),112.1(C-2″),152.2(C-3″),148.8(C-4″),112.7(C-5″),123.3(C-6″),165.5(C-7″),55.6(OCH3),69.5(Ar-CH2-O-),132.9(C-1″′),125.9(C-2″′,6″′),128.7(C-3″′,5″′),138.1(C-4″′),14.6(SCH3).HRESIMS:calcd for C31H35O13S[M-H]-647.1804,found:647.1796.
IV-7：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.6 Hz,H-1),6.42(1H,dd,J＝5.6/1.6 Hz,H-3),4.97(1H,dd,J＝5.9/4.7 Hz,H-4),2.59(1H,m,H-5),5.08(1H,dd,J＝8.1/0.7 Hz,H-6),3.71(1H,brs,H-7),2.48(1H,m,H-9),3.92(1H,dd,J＝13.2/5.0 Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),7.51(1H,d,J＝1.9 Hz,H-2″),7.17(1H,d,J＝8.6 Hz,H-5″),7.62(1H,dd,J＝8.6/1.9 Hz,H-6″),3.84(3H,s,OCH3),5.21(2H,s,-CH2-O-),7.73(1H,d,J＝1.8 Hz,H-2″),7.67(1H,br d,J＝8.3 Hz,H-5″),7.45(1H,dd,J＝8.3/1.8 Hz,H-6″).13C NMR(125MHz,DMSO-d6):δC 93.0(C-1),141.2(C-3),101.8(C-4),35.2(C-5),80.0(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.5(C-l0),97.9(C-l′),73.5(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),122.0(C-1″),112.2(C-2″),151.8(C-3″),148.8(C-4″),112.8(C-5″),123.3(C-6″),165.5(C-7″),55.7(OCH3),68.4(-CH2-O-),137.7(C-1″′),129.7(C-2″′),130.7(C-3″′),131.2(C-4″′),130.8(C-5″′),128.1(C-6″′).HRESIMS:calcd forC30H31Cl2O13[M-H]-669.1147,found:669.1155.
IV-8：1H NMR(500 MHz,CD3OD):δH 5.20(1H,d,J＝9.0 Hz,H-1),6.38(1H,brd,J＝5.9 Hz,H-3),4.99(1H,m,H-4),2.65(1H,m,H-5),5.14(1H,brd,J＝6.7 Hz,H-6),3.76(1H,brs,H-7),2.66(1H,m,H-9),4.18(1H,d,J＝13.2 Hz,H-10a),3.86(1H,d,J＝13.2 Hz,H-10b),4.81(1H,d,J＝8.0 Hz,H-1′),3.28(2H,m,H-2′,4′),3.35(1H,m,H-5′),3.43(1H,m,H-3′),3.66(1H,dd,J＝11.9/6.6 Hz,H-6′a),3.94(1H,dd,J＝11.9/1.9 Hz,H-6′b),7.60(1H,m,H-2″),7.06(1H,m,H-5″),7.64(1H,m,H-6″),3.90(3H,s,OCH3″),5.25(2H,s,-CH2-O-),7.64(2H,m,H-2″′,6″′),7.73(2H,m,H-3″′,5″′).13C NMR(125 MHz,CD3OD):δC95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),82.1(C-6),60.4(C-7),67.0(C-8),43.4(C-9),61.4(C-l0),99.9(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),122.8(C-1″),113.9(C-2″),153.8(C-3″),150.9(C-4″),114.1(C-5″),125.0(C-6″),167.7(C-7″),56.7(OCH3),70.8(-CH2-O-),144.0(C-1″′),129.2(C-2″′,6″′),133.6(C-3″′,5″′),112.8(C-4″′),119.8(CN″′).HRESIMS:calcd for C31H33NNaO13[M+Na]+650.1844,found:650.1839.
IV-9：1H NMR(500 MHz,DMSO-d6)：δH 5.12(1H,d,J＝9.6 Hz,H-1),6.42(1H,dd,J＝5.9/1.6 Hz,H-3),4.97(1H,dd,J＝5.9/4.8 Hz,H-4),2.59(1H,m,H-5),5.08(1H,brd,J＝8.1 Hz,H-6),3.71(1H,brs,H-7),2.47(1H,m,H-9),3.92(1H,dd,J＝13.3/4.7 Hz,H-10a),3.74(2H,m,H-10b,6′a),4.63(1H,d,J＝7.8 Hz,H-1′),3.05(2H,m,H-2′,4′),3.19(2H,m,H-3′,5′),7.53(1H,d,J＝2.0 Hz,H-2″),7.22(1H,d,J＝8.6 Hz,H-5″),7.60(1H,dd,J＝8.6/2.0 Hz,H-6″),3.88(3H,s,OCH3),5.46(2H,s,-CH2-O-),7.67(1H,d,J＝8.5 Hz,H-3″′),8.43(1H,d,J＝8.5 Hz,H-4″′),8.00(1H,brd,J＝8.5 Hz,H-6″′),7.63(1H,brt,J＝8.5 Hz,H-7″′),7.79(1H,brt,J＝8.5 Hz,H-8″′),8.02(1H,brd,J＝8.5Hz,H-9″′).13CNMR(125 MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.8(C-4),35.2(C-5),80.0(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),122.0(C-1″),112.2(C-2″),152.0(C-3″),148.8(C-4″),112.8(C-5″),123.4(C-6″),165.4(C-7″),55.8(OCH3),71.4(-CH2-O-),156.9(C-2″′),119.6(C-3″′),137.2(C-4″′),127.3(C-5″′),128.0(C-6″′),126.8(C-7″′),130.0(C-8″′),128.6(C-9″′),147.0(C-10″′).HRESIMS:calcd for C33H36NO13[M+H]+654.2181,found:654.2185.
IV-10：1H NMR(500 MHz,DMSO-d6)：δH 5.11(1H,d,J＝9.9 Hz,H-1),6.43(1H,brd,J＝5.9 Hz,H-3),4.97(1H,brt,J＝5.2 Hz,H-4),2.59(1H,m,H-5),5.08(1H,brd,J＝8.1Hz,H-6),3.71(1H,brs,H-7),2.47(1H,m,H-9),3.92(1H,dd,J＝13.2/5.0Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.8 Hz,H-1′),3.04(2H,m,H-2′,4′),3.19(2H,m,H-3′,5′),7.49(1H,brs,H-2″),7.16(1H,d,J＝8.6 Hz,H-5″),7.61(1H,brd,J＝8.6 Hz,H-6″),3.83(3H,s,OCH3),5.16(2H,s,Ar-CH2-O-),-),7.26(2H,brd,J＝8.1 Hz,H-2″′,6″′),7.75(2H,brd,J＝8.1 Hz,H-3″′,5″′).13C NMR(125 MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.8(C-4),35.2(C-5),80.0(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.4(C-l0),97.8(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.8(C-1″),112.1(C-2″),152.0(C-3″),148.8(C-4″),112.7(C-5″),123.3(C-6″),165.4(C-7″),55.7(OCH3),69.2(-CH2-O-),136.3(C-1″′),130.1(C-2″′,6″′),137.3(C-3″′,5″′),94.2(C-4″′).HRESIMS:calcd for C30H33INaO13[M+Na]+751.0858,found:751.0858.
IV-11：1H NMR(500 MHz,DMSO-d6)：δH 5.12(1H,d,J＝9.7 Hz,H-1),6.43(1H,dd,J＝5.9/1.7 Hz,H-3),4.97(1H,dd,J＝5.7/4.6 Hz,H-4),2.58(1H,m,H-5),5.08(1H,dd,J＝8.1/0.9 Hz,H-6),3.71(1H,brs,H-7),2.48(1H,m,H-9),3.92(1H,dd,J＝13.3/5.1 Hz,H-10a),3.73(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.05(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),7.49(1H,d,J＝1.9 Hz,H-2″),7.20(1H,d,J＝8.5 Hz,H-5″),7.62(1H,dd,J＝8.5/1.9 Hz,H-6″),3.83(3H,s,OCH3),5.13(2H,s,-CH2-O-),-),7.21(2H,brd,J＝7.9 Hz,H-2″′,6″′),7.36(2H,brd,J＝7.9 Hz,H-3″′,5″′),2.58(2H,t,J＝7.7 Hz,H-7″),1.54(2H,quint,J＝7.7 Hz,H-8″),1.31(2H,sext,J＝7.7 Hz,H-9″),0.89(3H,t,J＝7.7Hz,H-10″).13C NMR(125 MHz,DMSO-d6):δC 93.0(C-1),141.1(C-3),101.8(C-4),35.2(C-5),80.0(C-6),58.2(C-7),65.9(C-8),41.8(C-9),58.3(C-l0),97.9(C-l′),73.4(C-2′),77.5(C-3′),70.2(C-4′),76.4(C-5′),61.3(C-6′),121.9(C-1″),112.0(C-2″),152.7(C-3″),148.8(C-4″),113.1(C-5″),123.5(C-6″),165.5(C-7″),55.5(OCH3),63.0(-CH2-O-),133.6(C-1″′),128.1(C-2″′,6″′),128.4(C-3″′,5″′),142.3(C-4″′),34.6(C-7″′),33.1(C-8″′),21.7(C-9″′),13.8(C-10″′).HRESIMS:calcdfor C34H42NaO13[M+Na]+681.2518,found:681.2522.
IV-12：1H NMR(500 MHz,DMSO-d6+D2O)：δH 5.12(1H,d,J＝9.7 Hz,H-1),6.42(1H,dd,J＝5.9/1.6 Hz,H-3),4.98(1H,dd,J＝5.9/4.6 Hz,H-4),2.60(1H,m,H-5),5.10(1H,dd,J＝8.1/1.0 Hz,H-6),3.72(1H,brs,H-7),2.52(1H,m,H-9),3.94(1H,d,J＝13.3 Hz,H-10a),3.71(2H,m,H-10b,6′a),4.62(1H,d,J＝7.8 Hz,H-1′),3.05(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),7.48(1H,d,J＝2.0 Hz,H-2″),7.74(1H,dd,J＝8.4/2.0 Hz,H-6″),3.67(3H,s,OCH3),6.10(2H,s,-CH2-O-),8.29(2H,d,J＝8.9 Hz,H-1″′,8″′),7.58(5H,m,H-5″,2″′,3″′,6″′,7″′),8.16(2H,d,J＝8.0 Hz,H-4″′,5″′),8.73(1H,s,H-10″′).13C NMR(125MHz,DMSO-d6+D2O):δC 93.4(C-1),141.5(C-3),102.1(C-4),35.2(C-5),80.3(C-6),58.7(C-7),66.2(C-8),42.0(C-9),58.8(C-l0),98.2(C-l′),73.6(C-2′),77.6(C-3′),70.4(C-4′),76.4(C-5′),61.5(C-6′),122.2(C-1″),112.3(C-2″),153.1(C-3″),149.1(C-4″),113.4(C-5″),123.9(C-6″),166.0(C-7″),55.8(OCH3),63.3(-CH2-O-),127.3(C-1″′,8″′),125.8(C-2″′,7″′),124.3(C-3″′,6″′),129.3(C-4″′,5″′),126.9(C-9″′),129.3(C-10″′),131.0(C-4a″′,10a″′),131.3(C-7a″′,8a″′).HRESIMS:calcd for C38H37O13[M-H]-701.2240,found:701.2247.
IV-13：1H NMR(500 MHz,CD3OD):δH 5.19(1H,d,J＝9.2 Hz,H-1),6.37(1H,dd,J＝5.9/1.4 Hz,H-3),5.02(1H,dd,J＝5.9/4.1 Hz,H-4),2.68(1H,m,H-5),5.14(1H,dd,J＝7.8/1.0 Hz,H-6),3.76(1H,s,H-7),2.65(1H,m,H-9),4.18(1H,d,J＝13.2 Hz,H-10a),3.86(1H,d,J＝13.2 Hz,H-10b),4.81(1H,d,J＝7.9 Hz,H-1′),3.28(2H,m,H-2′,4′),3.34(1H,m,H-5′),3.42(1H,t,J＝9.0 Hz,H-3′),3.66(1H,dd,J＝12.0/6.6 Hz,H-6′a),3.94(1H,dd,J＝12.0/2.0 Hz,H-6′b),7.58(1H,d,J＝2.0 Hz,H-2″),7.03(1H,d,J＝8.5 Hz,H-5″),7.64(1H,dd,J＝8.5/2.0Hz,H-6″),3.89(3H,s,OCH3″),5.10(2H,s,-O-CH2-),6.60(2H,d,J＝2.2Hz,H-2″′,6″′),6.41(1H,t,J＝2.2 Hz,H-4″′),3.76(6H,s,OCH3″′×2).13C NMR(125 MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),82.0(C-6),60.4(C-7),67.0(C-8),43.4(C-9),61.4(C-l0),99.9(C-l′),75.0(C-2′),78.8(C-3′),71.9(C-4′),77.8(C-5′),63.1(C-6′),123.7(C-1″),113.9(C-2″),154.2(C-3″),150.8(C-4″),114.1(C-5″),125.0(C-6″),167.8(C-7″),56.7(OCH3),71.8(-CH2-O-),140.5(C-1″′),106.4(C-2″′,6″′),162.7(C-3″′,5″′),100.9(C-4″′),55.9(2×OCH3″′).HRESIMS:calcdfor C32H37O15[M-H]-661.2138,found:661.2149.
IV-14：1H NMR(500 MHz,DMSO-d6+D2O)：δH 5.10(1H,d,J＝9.7 Hz,H-1),6.42(1H,dd,J＝5.9/1.7 Hz,H-3),4.96(1H,dd,J＝5.8/4.6 Hz,H-4),2.58(1H,m,H-5),5.08(1H,dd,J＝8.0/1.0 Hz,H-6),3.70(1H,brs,H-7),2.47(1H,m,H-9),3.92(1H,d,J＝13.3 Hz,H-10a),3.71(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.03(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.42(1H,dd,J＝12.0/6.9 Hz,H-6′b),7.51(1H,d,J＝1.9 Hz,H-2″),7.17(1H,d,J＝8.5 Hz,H-5″),7.61(1H,dd,J＝8.5/1.9 Hz,H-6″),3.85(3H,s,OCH3),5.36(2H,s,-CH2-O-),-),7.72(2H,d,J＝8.8 Hz,H-2″′,6″′),8.26(1H,brd,J＝8.8 Hz,H-3″′,5″′).13C NMR(125 MHz,DMSO-d6+D2O):δC 93.1(C-1),141.3(C-3),101.9(C-4),35.3(C-5),80.2(C-6),58.4(C-7),66.0(C-8),41.9(C-9),58.5(C-l0),98.0(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.3(C-5′),61.4(C-6′),122.2(C-1″),112.3(C-2″),151.9(C-3″),149.0(C-4″),113.0(C-5″),123.5(C-6″),165.6(C-7″),55.9(OCH3),68.9(-CH2-O-),144.5(C-1″′),128.6(C-2″′,6″′),123.8(C-3″′,5″′),147.3(C-4″′).HRESIMS:calcd forC30H32NO15[M-H]-646.1777,found:646.1787.
IV-15：1H NMR(500 MHz,CD3OD):δH 5.21(1H,d,J＝9.2 Hz,H-1),6.39(1H,dd,J＝5.9/1.4 Hz,H-3),5.02(1H,dd,J＝5.9/4.1 Hz,H-4),2.70(1H,m,H-5),5.15(1H,dd,J＝7.9/1.0 Hz,H-6),3.77(1H,brs,H-7),2.65(1H,m,H-9),4.19(1H,d,J＝13.2 Hz,H-10a),3.86(1H,d,J＝13.2 Hz,H-10b),4.80(1H,d,J＝7.9 Hz,H-1′),3.27(2H,m,H-2′,4′),3.41(1H,t,J＝9.0 Hz,H-3′),3.65(1H,dd,J＝11.9/6.6Hz,H-6′a),3.94(1H,dd,J＝11.9/2.0Hz,H-6′b),7.62(1H,d,J＝2.0 Hz,H-2″),7.25(1H,d,J＝8.5 Hz,H-5″),7.72(1H,dd,J＝8.5/2.0 Hz,H-6″),3.85(3H,s,OCH3″),5.63(2H,s,-O-CH2-),7.64(1H,brd,J＝7.2 Hz,H-2″′),7.47(1H,brt,J＝7.2 Hz,H-3″′),8.12(1H,brd,J＝7.2Hz,H-4″′),7.88(1H,brd,J＝8.2 Hz,H-5″′),7.54(2H,m,H-6″′,7″′),7.91(1H,brd,J＝8.2Hz,H-2″′).13C NMR(125MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),82.1(C-6),60.4(C-7),67.1(C-8),43.4(C-9),61.4(C-l0),99.9(C-l′),75.0(C-2′),78.8(C-3′),72.0(C-4′),77.9(C-5′),63.1(C-6′),123.9(C-1″),114.1(C-2″),154.4(C-3″),151.1(C-4″),114.4(C-5″),125.0(C-6″),167.8(C-7″),56.7(OCH3),70.7(-CH2-O-),133.1(C-1″′),128.0(C-2″′),126.4(C-3″′),129.8(C-4″′),135.4(C-4a″′),130.3(C-5″′),127.6(C-6″′),127.1(C-7″′),125.1(C-8″′),133.5(C-8a″′).HRESIMS:calcd for C34H35O13[M-H]-651.2083,found:651.2087.
IV-16：1H NMR(500 MHz,CD3OD):δH 5.20(1H,d,J＝9.1 Hz,H-1),6.38(1H,brd,J＝5.8 Hz,H-3),5.00(1H,dd,J＝5.8/4.2 Hz,H-4),2.69(1H,m,H-5),5.15(1H,brd,J＝7.5Hz,H-6),3.76(1H,brs,H-7),2.64(1H,m,H-9),4.19(1H,d,J＝13.2Hz,H-10a),3.85(1H,d,J＝13.2 Hz,H-10b),4.80(1H,d,J＝7.9 Hz,H-1′),3.26(2H,m,H-2′,4′),3.41(1H,t,J＝9.0 Hz,H-3′),3.65(1H,dd,J＝11.9/6.6 Hz,H-6′a),3.92(1H,m,H-6′b),7.61(1H,d,J＝1.6 Hz,H-2″),7.12(1H,d,J＝8.5 Hz,H-5″),7.68(1H,dd,J＝8.5/1.6 Hz,H-6″),3.91(3H,s,OCH3″),5.25(2H,s,-O-CH2-),7.30(2H,d,J＝8.0 Hz,H-2″′,6″′),7.50(2H,d,J＝8.0 Hz,H-3″′,5″′),7.40(1H,brd,J＝7.5 Hz,H-3″″),7.57(1H,brt,J＝7.5 Hz,H-4″″),7.44(1H,brt,J＝7.5 Hz,H-5″″),7.76(1H,brd,J＝7.5 Hz,H-6″″).13C NMR(125 MHz,CD3OD):δC 95.2(C-1),142.6(C-3),103.1(C-4),36.9(C-5),82.0(C-6),60.4(C-7),67.1(C-8),43.4(C-9),61.4(C-l0),99.9(C-l′),75.0(C-2′),78.8(C-3′),72.0(C-4′),77.9(C-5′),63.1(C-6′),123.8(C-1″),114.0(C-2″),154.3(C-3″),150.9(C-4″),114.2(C-5″),125.0(C-6″),167.8(C-7″),56.7(OCH3),71.7(-O-CH2-),142.6(C-1″′),128.7(C-2″′,6″′),129.8(C-3″′,5″′),143.3(C-4″′),137.3(C-1″″),132.6(C-2″″),131.9(C-3″″),130.8(C-4″″),132.7(C-5″″),128.6(C-6″″),171.1(C-7″″),52.6(OCH3″″).HRESIMS:calcd for C38H40NaO15[M-H]-759.2259,found:759.2252.
IV-17：1H NMR(500 MHz,DMSO-d6+D2O)：δH 5.10(1H,d,J＝9.5 Hz,H-1),6.41(1H,dd,J＝5.9/1.6 Hz,H-3),4.96(1H,dd,J＝5.9/4.6 Hz,H-4),2.57(1H,m,H-5),5.07(1H,dd,J＝8.0/1.0 Hz,H-6),3.69(1H,brs,H-7),2.47(1H,m,H-9),3.92(1H,d,J＝13.3 Hz,H-10a),3.71(2H,m,H-10b,6′a),4.61(1H,d,J＝7.9 Hz,H-1′),3.04(2H,m,H-2′,4′),3.18(2H,m,H-3′,5′),3.42(1H,dd,J＝12.0/6.9 Hz,H-6′b),7.50(1H,d,J＝2.0 Hz,H-2″),7.17(1H,d,J＝8.5 Hz,H-5″),7.61(1H,dd,J＝8.5/2.0 Hz,H-6″),3.83(3H,s,OCH3),5.31(2H,s,-CH2-O-),7.70(2H,d,J＝8.3 Hz,H-2″′,6″′),7.94(2H,d,J＝8.3 Hz,H-3″′,5″′),3.19(3H,s,SO2CH3).13C NMR(125 MHz,DMSO-d6+D2O):δC 93.3(C-1),141.4(C-3),102.0(C-4),35.4(C-5),80.3(C-6),58.6(C-7),66.2(C-8),42.0(C-9),58.7(C-l0),98.1(C-l′),73.5(C-2′),77.6(C-3′),70.4(C-4′),76.4(C-5′),61.5(C-6′),122.3(C-1″),112.4(C-2″),152.1(C-3″),149.1(C-4″),113.1(C-5″),123.7(C-6″),165.8(C-7″),56.0(OCH3),69.2(-CH2-O-),142.7(C-1″′),127.5(C-2″′,6″′),128.6(C-3″′,5″′),140.5(C-4″′),43.8(SO2CH3″′).HRESIMS:calcd for C31H35O15S[M-H]-679.1702,found:679.1718.
IV-18：1H NMR(500 MHz,DMSO-d6)：δH 5.09(1H,d,J＝9.6 Hz,H-1),6.40(1H,dd,J＝5.9/1.6 Hz,H-3),4.96(1H,dd,J＝5.9/4.5 Hz,H-4),2.57(1H,m,H-5),5.07(1H,dd,J＝8.0/1.0 Hz,H-6),3.69(1H,brs,H-7),2.47(1H,m,H-9),3.94(1H,d,J＝13.2 Hz,H-10a),3.71(2H,m,H-10b,6′a),4.62(1H,d,J＝7.9 Hz,H-1′),3.06(2H,m,H-2′,4′),3.20(2H,m,H-3′,5′),3.43(1H,dd,J＝11.8/6.8 Hz,H-6′b),7.49(1H,d,J＝2.0 Hz,H-2″),7.20(1H,d,J＝8.5 Hz,H-5″),7.61(1H,dd,J＝8.5/2.0 Hz,H-6″),3.82(3H,s,OCH3),5.20(2H,s,-CH2-O-),7.82(2H,brd,J＝8.6 Hz,H-2″′,6″′),7.56(2H,br d,J＝8.6 Hz,H-3″′,5″′),7.73(1H,d,J＝1.7 Hz,H-3″″),6.53(1H,dd,J＝1.7/1.5 Hz,H-4″″),8.43(1H,d,J＝1.5Hz,H-5″″).13C NMR(125 MHz,DMSO-d6):δC 93.4(C-1),141.5(C-3),102.1(C-4),35.5(C-5),80.3(C-6),58.7(C-7),66.2(C-8),42.0(C-9),58.7(C-l0),98.2(C-l′),73.7(C-2′),77.6(C-3′),70.5(C-4′),76.6(C-5′),61.6(C-6′),122.0(C-1″),112.4(C-2″),152.5(C-3″),149.1(C-4″),113.1(C-5″),123.8(C-6″),165.9(C-7″),56.0(OCH3),69.8(-CH2-O-),139.7(C-1″′),129.6(C-2″′,6″′),118.8(C-3″′,5″′),134.6(C-4″′),141.5(C-3″″),108.4(C-4″″),128.1(C-5″″).HRESIMS:calcd for C33H37N2O13[M+H]+669.2290,found:669.2301.
IV-19：1H NMR(400MHz,DMSO-d6)：δH 5.10(1H,d,J＝9.6Hz,H-1),6.41(1H,dd,J＝5.9/1.6Hz,H-3),4.95(1H,dd,J＝5.9/4.6Hz,H-4),2.56(1H,m,H-5),5.04(1H,m,H-6),3.68(1H,brs,H-7),2.45(1H,m,H-9),3.90(1H,m,H-10a),3.72(2H,m,H-10b,6′a),4.61(1H,d,J＝7.8Hz,H-1′),3.03(2H,m,H-2′,4′),3.17(2H,m,H-3′,5′),3.43(1H,dd,J＝12.0/6.9Hz,H-6′b),7.49(1H,d,J＝2.0Hz,H-2″,6″,2″′,6″′,2″″,6″″),7.09(1H,d,J＝8.5Hz,H-5″),3.90(3H,s,OCH3),6.68(1H,s,-CH-O-),7.36(4H,t,J＝7.5Hz,H-C-3″′,5″′,C-3″″,5″″),7.27(2H,s,t,J＝7.5Hz,H-4″″,4″″).13C NMR(100MHz,DMSO-d6):δC 92.9(C-1),141.1(C-3),101.8(C-4),35.1(C-5),79.9(C-6),58.1(C-7),65.8(C-8),41.8(C-9),58.4(C-l0),97.8(C-l′),73.4(C-2′),77.5(C-3′),70.3(C-4′),76.4(C-5′),61.4(C-6′),121.9(C-1″),112.4(C-2″),151.0(C-3″),149.3(C-4″),114.6(C-5″),123.0(C-6″),165.3(C-7″),55.9(OCH3),80.4(-CH-O-),140.9(C-1″′,1″″),126.5(C-2″′,6″′,2″″,6″″),128.6(C-3″′,5″′,C-3″″,5″″),127.8(C-4″″,4″″).HRESIMS:calcd for C36H38NaO13[M+Na]+701.2205,found:701.2205.
实施例5：式I、II、III和IV类化合物对OGG1的抑制作用
待测化合物与含有重组人OGG1蛋白(abcam)(详细检查方法可参考已发表文献：ACS Chem Biol.2015,10(10):2334-43.)。在384孔板中加入五个不同浓度待测样品(包括阳性对照组：OGG1 Inhibitor O8)的10μL缓冲液(20mM Tris-HCl,100mM KCl,0.1％BSA,0.01％Tween-20,pH 7.5)，并设置空白对照。随后加入20nL浓度为12.5μM的OGG1，室温共孵育5min。随后加入20nL的12.5μM 8-oxo-Gua溶液后37℃孵育40min，使用全波长扫描式多功能读数仪(Filters＝Ex 528/20,Em 600/40.Mirror＝Top 570nm with polarizer)进行检测，每个样品平行检测三次。
具体数值见表2，通过表2可知：
本发明所述的式I和式II化合物对OGG1活性具有一定的抑制作用，同时发现梓醇6位连有较大的芳香性基团时(I-3)，抑制OGG1的作用显著提高。进而通过梓苷和胡黄连苷II间接在梓醇6位引入其他基团来探讨其对OGG1的抑制活性，发现式III和式IV化合物抑制OGG1的活性都比梓苷或胡黄连苷II显著提高。因此，本发明所述的梓醇衍生物或/和其可药用衍生物作为活性成分用于制备预防、缓解和/或治疗由OGG1活化所引起的疾病的药物和保健食品。
表2梓醇类衍生物对OGG1的抑制作用
*阳性对照
最后有必要在此说明的是：以上实施例只用于对本发明的技术方案作进一步详细地说明，不能理解为对本发明保护范围的限制，本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。
Claims (3)
1.一种修饰的天然梓醇衍生物在制备用于治疗OGG1活化所引起的疾病的药物中的应用，其特征在于，所述修饰的天然梓醇衍生物的结构如式III或式IV所示：
其中：式III和式IV中的R为：
具有6-14个碳原子的芳基，其未被取代或被以下基团取代一次或多次：卤素、CF3、OCF3、羟基、硝基、亚甲二氧基、亚乙二氧基、氰基或它们的组合；
或者芳基烷基，其中芳基部分具有6-14个碳原子，而烷基部分为支链或非支链的，并具有1-5个碳原子，所述芳基烷基未被取代或在芳基部分被以下基团取代一次或多次：卤素、CF3、OCF3、羟基、硝基、亚甲二氧基、亚乙二氧基、氰基或它们的组合，且其中在烷基部分中，一个或多个-CH2-基团各自任选被-O-或-NH-取代，和/或烷基部分任选被卤素、氧、羟基、氰基，或它们的组合取代；
或者杂环基，其为不饱和的，具有5-10个环原子，其中至少一个环原子为N、O或S原子，其未被取代或被以下基团取代一次或多次：卤素、羟基、氰基、三氟甲基、硝基或它们的组合；
或者杂环烷基，其中杂环部分为不饱和的，并具有5-10个环原子，其中至少一个环原子为N、O或S原子，且烷基部分为支链或非支链的，并具有1-5个碳原子，所述杂环烷基未被取代或在杂环部分被以下基团取代一次或多次：卤素、OCF3、羟基、氰基、CF3、硝基或它们的组合，其中在烷基部分中一个或多个-CH2-基团各自任选被-O-或-NH-取代，和/或烷基部分任选被卤素、氧、羟基、氰基，或它们的组合取代。
2.一种修饰的天然梓醇衍生物在制备用于治疗OGG1活化所引起的疾病的药物中的应用，其特征在于，所述修饰的天然梓醇衍生物具有任意一个如下结构式：
3.根据权利要求1或2所述的应用，其特征在于：所述OGG1活化所引起的疾病选自炎症疾病、自身免疫性疾病、病毒感染性疾病、肿瘤和/或它们的并发症。
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