CN116196342A - 桑寄生活性物质在制备治疗骨关节炎的药物中的应用 - Google Patents
桑寄生活性物质在制备治疗骨关节炎的药物中的应用 Download PDFInfo
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Abstract
本发明公开了桑寄生活性物质在制备治疗骨关节炎的药物中的应用。本发明发现桑寄生中除了槲皮素含有多种具有抗炎活性的化合物,通过DPPH实验发现桑寄生中除了槲皮素含有多种具有抗氧化活性的化合物。本发明首次发现3,4‑二羟基苯甲酸乙酯、3,4‑二羟基苯甲醛、没食子酸乙酯能够降低软骨细胞中ADAMTS5、MMP13表达水平,表明3,4‑二羟基苯甲酸乙酯、3,4‑二羟基苯甲醛、没食子酸乙酯能够抑制细胞外软骨基质(ECM)的异常降解,3,4‑二羟基苯甲酸乙酯、3,4‑二羟基苯甲醛、没食子酸乙酯能够降低软骨细胞中iNOS和COX2的表达从而抑制炎症,能够用于治疗骨性关节炎。
Description
技术领域
本发明属于天然药物化学领域,涉及桑寄生活性物质在制备治疗骨关节炎的药物中的应用。
背景技术
骨关节炎(OA)是最常见的退行性关节疾病,随着人口的老龄化越来越常见。OA主要表现为关节软骨丧失、骨赘形成、软骨下骨改变、炎症和疼痛。关节软骨是OA研究的一个重要方面。关节软骨由软骨细胞和细胞外基质(ECM)组成。OA的发生伴随着关节软骨分解代谢和合成代谢的失衡。主要迹象是胶原网络的侵蚀和聚集核心蛋白的减少,以及基质金属蛋白酶(MMP)家族和带有血小板凝血酶敏感蛋白样模体的解整链蛋白金属蛋白酶家族(ADAMTS)的增加,炎症相关蛋白一氧化氮合酶(iNOS)和环氧化酶2(COX2)的表达也增加。同时炎症因子和活性氧也被认为是OA的重要参与者。OA通常伴有炎症因子和活性氧的增加。
桑寄生为桑寄生科植物桑寄生Taxillus chinensis(DC.)Danser的干燥带叶茎枝。现收载于2020年版《中国药典》。具有祛风湿,补肝肾,强筋骨,安胎元之功效。用于风湿痹痛,腰膝酸软,筋骨无力,崩漏经多,妊娠漏血,胎动不安,头晕目眩。桑寄生含有多种化学成分,如黄酮、酚酸、挥发油、萜类衍生物和其他化学成分。
目前主要对于桑寄生中槲皮素的研究较多,但对其他化学成分、药理作用方面的研究较少,缺乏足够的证据阐明桑寄生作为传统中药材的作用价值。因此对桑寄生进行提取分离,从中寻找具有抗骨性关节炎的化合物具有重要意义及应用价值。
发明内容
本发明的目的是针对现有技术的上述不足,提供桑寄生活性物质在制备治疗骨关节炎的药物中的应用。
本发明的目的可通过以下技术方案实现:
桑寄生活性物质在制备治疗骨关节炎的药物中的应用。
作为本发明的一种优选,所述的桑寄生活性物质选自3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯中的任意一种。
作为本发明的一种优选,所述的桑寄生活性物质用于制备抗炎和抗氧化的治疗骨关节炎的药物中的应用。
作为本发明的一种优选,所述的桑寄生活性物质用于制备抑制细胞外软骨基质异常降解的药物中的应用。
作为本发明的一种优选,所述的桑寄生活性物质用于制备骨关节炎细胞外软骨基质异常降解的药物中的应用。
有益效果:
本发明通过NO实验发现桑寄生中除了槲皮素含有多种具有抗炎活性的化合物,包括3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯在内的多种物质。从中挑选抗炎和抗氧化活性都很好的化合物3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯进行抗骨性关节炎的研究。发现他们都有抗骨性关节炎的作用,3,4-二羟苯甲醛的效果最好,与槲皮素药效相当。本发明首次发现3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯能够降低软骨细胞中ADAMTS5、MMP13表达水平,表明3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯能够抑制细胞外软骨基质(ECM)的异常降解,3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯能够降低抑制iNOS和COX2的表达从而抑制炎症,能够用于治疗骨性关节炎。
附图说明
图1为本发明从桑寄生中提取和分离到的化合物的结构式。
图2化合物1的1H NMR(600MHz,CD3OD)。
图3化合物1的13C NMR(150MHz,CD3OD)。
图4化合物3的1H NMR(600MHz,CD3OD)。
图5化合物3的13C NMR(150MHz,CD3OD)。
图6化合物91H NMR(500MHz,CD3OD)。
图7化合物913C NMR(125MHz,CD3OD)。
图8化合物141H NMR(500MHz,CD3OD)。
图9化合物1413C NMR(125MHz,CD3OD)。
图10为本发明从桑寄生中提取和分离到的化合物1,3,9和槲皮素对原代大鼠软骨细胞毒性的影响。
图11为本发明从桑寄生中提取和分离到的化合物1,3,9和槲皮素对软骨细胞中ADAMTS5、MMP13、iNOS、COX2蛋白表达的影响。
具体实施方式
本发明实施例中所使用到的仪器和材料如下:
仪器:Agilent 1100Series LC/MSD Trap质谱仪(Agilent,America);BrukerAvance-500 NMR(1H:500MHz,13C:125MHz)与Bruker AV III-600NMR(1H:600MHz,13C:150MHz)核磁共振波谱仪(Bruker,Karlsruhe,Germany),在室温条件下测定1D NMR和2DNMR谱图(内标:TMS);分析型高效液相色谱为Agilent 1260系列,检测器为DAD型,色谱工作站为Agilent ChemStation,Shim-pack VP-ODS色谱柱(Ф4.6×250mm,i.d.,5μm);制备型高效液相色谱为岛津LC-20AR,检测器为SPD-20A型,Shim-pack ODS色谱柱(Ф20×250mm,i.d.,10μm)。
材料及试剂:薄层硅胶(GF254)及柱层析用硅胶(200-300目)为青岛海洋化工有限公司产品;D101大孔吸附树脂为青岛海洋化工有限公司产品;Sephadex LH-20为Pharmacia公司产品;ODS RP-C18反相硅胶填料(40-63μm):日本富士硅化学株式会社;甲醇(色谱级)、乙腈(色谱级)为上海星可高纯溶剂有限公司产品;甲醇、乙醇、石油醚、二氯甲烷、乙酸乙酯和丙酮等试剂(分析纯)为南京化学试剂有限公司和江苏汉邦科技有限公司产品。
桑寄生于2021年9月28日从安徽桐花堂中药饮片科技有限公司购买。凭证样本(编号CM202109)存放在中国药科大学天然药物化学系教研室内。
实施例1
1、提取分离
用75%EtOH提取5.0kg桑寄生的带叶茎枝3次。然后在真空中浓缩后获得粗残余物(450.3g)。用CH2Cl2/MeOH(10:1-1:1,v/v)通过硅胶柱色谱分离得到五种组分(A-E)。通过MCI分离Fr.B以获得5个子组分(Fr.B.1-Fr.B.5)。化合物3(12.3mg)和7(3.0mg)使用MeOH/H2O(20:80)的制备HPLC从Fr.B.1获得。使用MeOH/H2O洗脱的ODS将Fr.B.2分为5个子组分(Fr.B.2.1-Fr.B.2.5)。化合物3(28.6mg)、6(10.4mg)、8(31.6mg)和11(14.2mg)用MeOH/H2O(30:70)通过制备HPLC分离从Fr.B.2.2中得到。Fr.B.2.3通过制备HPLC MeOH/H2O(45:65)分离,得到化合物1(42.9mg)。使用MeOH/H2O洗脱的ODS将Fr.B.3分成9个子组分(Fr.B.3.1-Fr.B.3.9),然后用PE/EtOAc(10:1-0:1)通过硅胶CC纯化,得到化合物1(22.6mg)、2(3.6mg)、5(8.2mg)、19(5.1mg)。通过MCI分离Fr.C以获得5个子组分(Fr.C.1-Fr.C.5)。Fr.C.2在Sephadex LH-20中用MeOH洗脱,然后用MeOH/H2O(30:70)通过制备HPLC分离,得到化合物4(606.1mg)和18(32.3mg)。Fr.C.3在Sephadex LH-20中用MeOH洗脱,然后通过制备HPLC MeOH/H2O(30:70)分离,得到化合物9(8.2mg)和16(18.8mg)。通过MCI分离Fr.D以获得6个子组分(Fr.D1-Fr.D.6)。用MeOH/H2O洗脱的ODS纯化Fr.D.1,然后用MeOH-H2O(20:80)通过制备HPLC分离,得到化合物20(21.5mg)和21(6.0mg)。Fr.D.2用MeOH/H2O洗脱的ODS纯化,然后用Sephadex LH-20分离,得到4(72.6mg)、17(90.5mg)、20(46.1mg)、22(6.6mg)。Fr.D.4用ODS和Sephadex LH-20纯化,用MeOH/H2O洗脱,然后用MeOH-H2O(40:60)通过制备HPLC分离,得到化合物10(20.4mg)、12(138.7mg)、13(17.1mg)、14(4.2mg)、15(1.9mg)。
2、结构鉴定
(1)化合物1
外观:白色无定形粉末。
ESI-MS:m/z 182.97[M+H]+。
1H NMR(600MHz,CD3OD)显示:在低场区有3个芳氢质子信号:6.70(1H,d,J=7.8Hz),7.32(1H,dd,J=7.8,1.8),7.31(1H,d,J=1.8);在高场区有一组乙基信号化学位移偏向低场:4.18(2H,q,J=7.1),1.24(3H,t,J=7.1),推测含有一连有氧的乙基。
13C-NMR(150MHz,CD3OD)显示:低场区有7个碳,一个为羰基碳168.4,和苯环的6个碳;高场区有两个碳,结合氢谱,为乙基。
综上分析,确定该化合物为具有三取代的苯环,一个酯羰基,一个连有酯羰基的乙基,与文献(Huang,S.-C;Yen,G.-C;Chang,L.-L.et al.Identification of anAntioxidant,Ethyl Protocatechuate,in Peanut Seed Testa.J.Agric.FoodChem.2003,51,2380-2383.)比较,确定结构为3,4-二羟基苯甲酸乙酯。
(2)化合物2
外观:黄色无定形粉末。
ESI-MS:m/z 178.98[M+H]+。
1H NMR(600MHz,CD3OD)显示:在低场区有一个醛基氢:9.47(1H,d,J=7.9);5个烯氢,根据偶合常数推测含有一个反式双键的烯烃:7.48(1H,d,J=15.6,),6.55(1H,dd,J=15.6,7.9);在高场区含有一个甲氧基信号峰:3.81(3H,s)。
13C-NMR(150MHz,CD3OD)显示:低场区有9个碳,除了苯环的6个碳,剩余3个碳推测为一个醛基194.8和一个乙烯基,高场区有1个碳为甲氧基55.1。
综上分析,确定该化合物为具有三取代的苯环,连有一个共轭烯烃,一个醛基,一个甲氧基,与文献(Sy,L.K.;Brown,G.D.Coniferaldehyde derivatives from tissueculture of Artemisia annua and Tanacetum parthenium.Phytochemistry.1999,50,781-785.)比较,确定结构为松柏醛。
(3)化合物3
外观:褐色针晶。
ESI-MS:m/z 138.96[M+H]+。
1H NMR(600MHz,CD3OD)显示:在低场区有一个醛基氢:9.58(1H,s);3个烯氢:6.80(1H,d,J=7.8),7.21(1H,d,J=7.8),7.20(1H,s)。
13C-NMR(150MHz,CD3OD)显示:低场区有7个碳,除了苯环的6个碳,剩余1个碳推测为一个醛基193.0。
综上分析,确定该化合物为具有三取代的苯环,连有一个醛基,与文献(Supaluk,P.;Prasit,B.;Apilak,W.et al.Antimicrobial and Antioxidative Activities ofBioactive Constituents from Hydnophytum formicarum Jack.Molecules.2008,13,904-921.)比较,确定结构为3,4-二羟基苯甲醛。
(4)化合物4
外观:褐色结晶性粉末。
ESI-MS:m/z 154.93[M+H]+。
1H NMR(500MHz,CD3OD)显示:在低场区有3个芳香氢:7.46(1H,s),6.82(1H,d,J=8.0),7.44(1H,d,J=8.0)。
13C-NMR(125MHz,CD3OD)显示:低场区有7个碳,除了苯环的6个碳,剩余1个碳推测为一个羧基170.2。
综上分析,确定该化合物为具有三取代的苯环,连有一个羧基,与文献(Lee,S.Y.;Kim,K.H.;Lee,I.K.et al.A New Flavonol Glycoside from Hylomecon vernalis.ArchPharm Res.2012,35(3),415-421.)比较,确定结构为原儿茶酸。
(5)化合物5
外观:淡黄色粉末。
TC-5(lariciresinol):淡黄色粉末;
ESI-MS:m/z 383.07[M+Na]+。
1H NMR(500MHz,CD3OD):δH 2.39(1H,dd,J=13.6,11.2,H-7α),2.83(1H,dd,J=13.6,4.8,H-7β),2.63(1H,m,H-8),3.53(1H,dd,J=10.9,6.4,H-9α),3.88(1H,dd,J=8.4,6.4,H-9β),4.65(1H,d,J=6.6,H-7'),2.27(1H,p,J=7.1,H-8'),3.75~3.71(1H,m,H-9'α),3.62(1H,dd,J=8.5,5.9,H-9'β),6.81~6.53(6H,m,H-Arom),3.73(3H,s,3-OMe),3.74(3H,s,3'-OMe)。
13C-NMR(125MHz,CD3OD):δC 132.1(C-1),112.0(C-2),147.6(C-3),144.4(C-4),114.8(C-5),120.8(C-6),32.3(C-7),42.5(C-8),72.1(C-9),134.4(C-1'),109.2(C-2'),147.6(C-3'),145.7(C-4'),114.6(C-5'),118.4(C-6'),82.6(C-7'),52.7(C-8'),59.0(C-9'),55.0(OMe)。
综上分析,与文献(Bae,K.E.;Chong,H.S.;Kim,D.S.et al.Compounds fromViburnum sargentii Koehne and evaluation of their cytotoxic effects on humancancer cell lines.Molecules.2010,15(7),4599-4609.)比较,确定结构为落叶松脂素。
(6)化合物6
外观:白色无定形粉末。
ESI-MS:m/z 138.97[M+K]+。
1H NMR(500MHz,CD3OD)显示:在低场区有4个芳香氢:7.89(2H,d,J=8.0),6.83(2H,d,J=8.0)。
13C-NMR(125MHz,CD3OD)显示:163.2(C-1,2),116.0(C-3,6),133.0(C-4,5)。
综上分析,与文献(Sheng,L.;Yang,Y.;Zhang,Y.et al.Chemical constituentsof Patrinia heterophylla Bunge and selective cytotoxicity against six humantumor cells.Journal of Ethnopharmacology.2019,236,129–135.)比较,确定结构为儿茶酚。
(7)化合物7
外观:白色无定形粉末。
ESI-MS:m/z 343.03[M+Na]+。
1H NMR(500MHz,CD3OD)显示:3.79(1H,dd,J=10.5,6.5,H-1a),3.65(1H,m,H-1b),2.86(1H,m,H-3),4.87(1H,d,J=5.5,H-3),6.58(1H,d,J=2.0,H-2'),6.65(1H,d,J=8.0,H-5'),6.57(1H,dd,J=8.0,2.0,H-6'),6.61(1H,d,J=2.0,H-2"),6.66(1H,d,J=8.0,H-5"),6.62(1H,dd,J=8.0,2.0,H-6"),3.71(3H,s,OCH3-3'),3.65(3H,s,OCH3-3")。
13C-NMR(125MHz,CD3OD)显示:63.0(C-1),54.8(C-2),74.1(C-3),130.8(C-1'),113.1(C-2'),147.0(C-3'),144.8(C-4'),114.0(C-5'),121.7(C-6'),135.1(C-1"),110.1(C-2"),147.1(C-3"),145.2(C-4"),114.2(C-5"),118.9(C-6"),54.9(OCH3-3'),55.4(OCH3-3")。
综上分析,与文献(Duan,Y.-H.;Li,C.;Dai,Y.et al.A New Phenylpropanediolfrom Sarcandra glabra(Chloranthaceae).Plant Diversity.2012,34(2):208-210.)比较,确定结构为(2S)-3,3-di-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol。
(8)化合物8
外观:白色结晶性粉末。
ESI-MS:m/z 168.92[M+H]+。
1H NMR(500MHz,CD3OD)显示:在低场区有3个芳香氢:7.41(1H,s),6.69(1H,d,J=8.5),7.42(1H,d,J=8.5);在高场区有1个甲氧基:3.74(3H,s)。
13C-NMR(125MHz,CD3OD)显示:低场区有7个碳,除了苯环的6个碳,剩余1个碳推测为一个羧基170.1。
综上分析,确定该化合物为具有三取代的苯环,连有1个羧基和1个甲氧基,与文献(Supaluk,P.;Saowapa,S.;Apilak,W,et al.Bioactive metabolites from Spilanthesacmella Murr.Molecules.2009,14(2),850-67.)比较,确定结构为香草酸。
(9)化合物9
外观:白色无定形粉末。
ESI-MS:m/z 198.95[M+H]+。
1H NMR(500MHz,CD3OD)显示:在低场区有2个芳香氢:7.06(2H,s);在高场区有1个乙基:4.29(2H,q,J=7.0),1.36(3H,t,J=7.0)。
13C-NMR(125MHz,CD3OD)显示:低场区有7个碳,除了苯环的6个碳,剩余1个碳推测为一个酯基168.6。
综上分析,确定该化合物为具有一个苯环,一个酯基,一个乙基,与文献(Qin,Y.;Wen,Q.;Cao,J.et al.Flavonol glycosides and other phenolic compounds fromViola tianshanica and their anti-complement activities.Pharm Biol.2016,54(7),1140-1147.)比较,确定结构为没食子酸乙酯。
(10)化合物10
外观:黄色粉末。
ESI-MS:m/z 486.98[M+Na]+。
1H NMR(600MHz,CD3OD)显示:6.10(1H,s,H-6),6.28(1H,s,H-8),7.61(1H,s,H-2'),6.76(1H,d,J=8.4,H-5'),7.48(1H,d,J=8.4,H-6'),为黄酮类化合物;5.14(1H,d,J=7.2,Glc-1"),3.13-3.62为糖上的氢,推测黄酮苷元上连有一个葡萄糖。
13C-NMR(150MHz,CD3OD)显示:157.1(C-2),134.2(C-3),178.1(C-4),161.6(C-5),98.5(C-6),164.6(C-7),93.3(C-8),157.6(C-9),104.3(C-10),121.7(C-1'),114.6(C-2'),148.5(C-3'),144.5(C-4'),116.2(C-5'),121.8(C-6');糖上碳:102.9,74.3,76.7,69.8,77.0,61.6。
综上分析,确定该化合物为黄酮苷,与文献(Lee,J.H.;Ku,C.H.;Baek,N.etal.Phytochemical Constituents from Diodia teres.Arch Pharm Res.2004,27(1),40-43.)比较,确定结构为异槲皮素。
(11)化合物11
外观:白色结晶性粉末。
ESI-MS:m/z 220.94[M+Na]+。
1H NMR(500MHz,CD3OD)显示:在低场区2个芳香氢7.35(2H,s),在高场区有一个甲氧基3.90(6H,s)。
13C-NMR(125MHz,CD3OD)显示:121.4(C-1),106.8(C-2/6),147.4(C-3/5),106.8(C-6),55.3(OCH3-3/5)。
综上分析,确定该化合物为黄酮苷,与文献(Panyo,J.;Matsunami,K.;Panichayupakaranant,P.Bioassay-guided isolation and evaluation ofantimicrobial compounds from Ixora megalophylla against some oralpathogens.Pharm Biol.2016,54(9),1522-7.)比较,确定结构为丁香酸。
(12)化合物12
外观:黄色粉末。
ESI-MS:m/z 470.98[M+Na]+。
1H NMR(500MHz,CD3OD)显示:6.19(1H,s,H-6),6.35(1H,s,H-8),7.35(1H,d,J=2.0,H-2'),6.92(1H,d,J=8.5,H-5'),7.31(1H,dd,J=8.5,2.0,H-6'),推测为黄酮类化合物;5.37(1H,d,J=1.5),0.97-4.26为糖上的氢,推测黄酮苷元上连有一个甲基六碳糖。
13C-NMR(125MHz,CD3OD)显示:157.1(C-2),134.9(C-3),178.2(C-4),161.7(C-5),98.5(C-6),164.4(C-7),93.4(C-8),157.9(C-9),104.5(C-10),121.6(C-1'),115.0(C-2'),144.9(C-3'),148.4(C-4'),115.6(C-5'),121.6(C-6');糖上碳:102.1,70.7,70.8,71.9,70.5,16.3。
综上分析,确定该化合物为黄酮苷,与文献(Badria,F.A.;Ameen,M.;Akl,M.R.etal.Evaluation of Cytotoxic Compounds from Calligonum comosum L.Growing inEgypt.Calligonum Compounds.2007,62(3),656-660.)比较,确定结构为槲皮苷。
(13)化合物13
外观:黄色粉末。
ESI-MS:m/z 456.98[M+Na]+。
1H NMR(500MHz,CD3OD)显示:6.23(1H,s,H-6),6.41(1H,s,H-8),7.52(1H,s,H-2'),6.92(1H,d,J=8.5,H-5'),7.51(1H,d,J=8.5,H-6'),推测为黄酮类化合物;5.49(1H,s),3.37-4.36为糖上的氢,推测黄酮苷元上连有一个五碳糖。
13C-NMR(125MHz,CD3OD)显示:157.2(C-2),133.5(C-3),178.6(C-4),161.7(C-5),98.5(C-6),164.6(C-7),93.4(C-8),158.0(C-9),104.2(C-10),121.6(C-1'),115.0(C-2'),145.0(C-3'),148.4(C-4'),115.4(C-5'),121.7(C-6');糖上碳:108.1,81.9,77.3,86.6,61.2。
综上分析,确定该化合物为黄酮苷,与文献(Chin,Y.-W.;Lim,S.-W.;Kim,Y.-C.Hepatoprotective flavonol glycosides from the aerial parts of Rodgersiapodophylla.Planta Med.2004,70(6),576-577.)比较,确定结构为扁蓄苷。
(14)化合物14
外观:黄色粉末。
ESI-MS:m/z 302.97[M+H]+。
1H NMR(500MHz,CD3OD)显示:6.20(1H,d,J=2.0,H-6),6.40(1H,d,J=2.0,H-8),7.75(1H,d,J=2.0,H-2'),6.90(1H,d,J=8.5,H-5'),7.65(1H,d,J=8.5,H-6'),推测为黄酮类化合物。
13C-NMR(125MHz,CD3OD)显示:146.6(C-2),135.8(C-3),175.9(C-4),161.1(C-5),97.8(C-6),164.2(C-7),93.0(C-8),156.8(C-9),103.1(C-10),122.8(C-1'),114.6(C-2'),144.8(C-3'),147.4(C-4'),114.8(C-5'),120.3(C-6')。
综上分析,与文献(Jung,M.;Park,M.Acetylcholinesterase Inhibition byFlavonoids from Agrimonia pilosa.Molecules.2007,12,2130-2139.)比较,确定结构为槲皮素。
(15)化合物15
外观:棕色无定形粉末。
ESI-MS:m/z 447.78[M+Na]+。
1H NMR(600MHz,CD3OD)显示:5.00(1H,d,J=6.0),4.11(1H,m,H-3),2.73(1H,dd,J=16.8,5.4,H-4a),2.64(1H,dd,J=16.8,6.0,H-4b),6.31(1H,s,H-6),6.79(1H,s,H-2'),6.71(1H,d,J=8.4,H-5'),6.67(1H,d,J=8.4,H-6'),8.31(1H,s,H-3"),7.53(1H,s,H-6")。
13C-NMR(150MHz,CD3OD)显示:81.4(C-2),66.1(C-3),25.9(C-4),156.1(C-5),95.0(C-6),150.9(C-7),100.2(C-8),152.6(C-9),104.8(C-10),130.4(C-1'),114.0(C-2'),115.0(C-5'),117.8(C-6'),130.1(C-1"),112.3(C-2"),113.1(C-3"),144.8(C-4"),152.7(C-5"),114.0(C-6"),162.5(C-7")。
综上分析,与文献(Zhang,Y.-F.;Xiao,G.-D,;Sun,L.et al.A new flavan-3-ollactone and other constituents from Euonymus alatus with inhibitoryactivities on alpha-glucosidase and differentiation of 3T3-L1cells.Nat ProdRes.2013,27(17),1513-20.)比较,确定结构为儿茶素内酯A。
(16)化合物16
外观:无色针晶。
ESI-MS:m/z 409.10[M+Na]+。
1H NMR(600MHz,CD3OD)显示:1.65(1H,dd,J=12.6,1.8,H-2a),1.31(1H,dd,J=12.6,9.6,H-2b),2.30(1H,dd,J=14.6,4.1,H-4a),1.71(1H,dd,J=14.6,8.4,H-4b),7.07(1H,d,J=15.8,H-7),6.08(1H,d,J=15.8,H-8),2.19(3H,s,H-10),0.86(3H,s,H-11),1.09(3H,s,H-12),1.12(3H,s,H-13);4.24(1H,d,J=7.8),3.03-3.75为糖上的氢。
13C-NMR(150MHz,CD3OD)显示:34.6(C-1),43.8(C-2),71.3(C-3),36.8(C-4),67.0(C-5),69.7(C-6),143.9(C-7),132.4(C-8),198.8(C-9),24.1(C-10),26.1(C-11),28.1(C-12),18.8(C-13);101.5,73.7,76.7,70.2,76.4,61.3为糖上的碳,推测含有一个葡萄糖。
综上分析,与文献(Wan,C.-P;Chen,C.-Y.;Li,M.-X.et al.ChemicalConstituents and Antifungal Activity of Ficus hirta Vahl.Fruits.Plants(Basel).2017,6(4),1-9.)比较,确定结构为淫羊藿苷B2(Icariside B2)。
(17)化合物17
外观:白色无定形粉末。
ESI-MS:m/z 312.98[M+Na]+。
1H NMR(500MHz,CD3OD)显示:4.59(1H,d,J=7.5,H-2),3.99(1H,m,H-3),2.86(1H,dd,J=16.1,5.4,H-4a),2.52(1H,dd,J=16.1,8.1,H-4b),5.88(1H,d,J=2.1,H-6),5.95(1H,s,H-8),6.85(1H,s,H-2'),6.78(1H,d,J=8.1,H-5'),6.73(1H,d,J=8.1,H-6')。
13C-NMR(125MHz,CD3OD)显示:82.8(C-2),68.8(C-3),28.4(C-4),146.2(C-5),95.6(C-6),157.8(C-7),96.4(C-8),157.5(C-9),146.2(C-10),132.2(C-1'),116.2(C-2'),146.2(C-3'),156.9(C-4'),120.1(C-5'),115.3(C-6')。
综上分析,与文献(Hou,A.-J.;Liu,Y.-Z.;Yang,H.et al.Hydrolyzable tanninsand related polyphenols from Eucalyptus globulus.JAsianNatProd Res.2000,2(3),205-212.)比较,确定结构为(+)-儿茶素。
(18)化合物18
外观:黄色晶体。
ESI-MS:m/z 267.06[M+Na]+。
1H NMR(500MHz,CD3OD)显示:1.78(1H,m,H-4a),1.67(1H,m,H-4b),1.46(1H,m,H-6a),1.35(1H,m,H-6b),6.08(1H,d,J=15.8,H-7),5.80(1H,dd,J=15.8,6.2,H-8),4.36(1H,m,H-9),1.29(3H,d,J=6.5,H-10),1.22(3H,s,H-11),1.16(3H,s,H-12),0.86(3H,s,H-13)。
13C-NMR(125MHz,CD3OD)显示:39.3(C-1),77.5(C-2),76.4(C-3),44.3(C-4),63.9(C-5),45.1(C-6),129.8(C-7),134.7(C-8),68.2(C-9),22.8(C-10),26.1(C-11),24.8(C-12),25.7(C-13)。
综上分析,与文献(Nascimento,M.;Arruda,A.C.;Arruda M.S.P.etal.Aripuanin,a megastigmane skeleton from Ficusaripuanensis.Fitoterapia.1999,70,628-629.)比较,确定结构为Aripuanin。
(19)化合物19
外观:棕色粉末。
ESI-MS:m/z 186.96[M+K]+。
1H NMR(600MHz,CD3OD)显示:7.41(3H,m,H-1,2,6),7.60(2H,m,H-3,5),7.66(1H,d,J=15.6,H-7),6.51(1H,d,J=15.6,H-8)。
13C-NMR(150MHz,CD3OD)显示:131.3(C-1),130.0(C-2,6),129.1(C-3,5),136.1(C-4),145.8(C-7),120.2(C-9),171.1(C-9)。
综上分析,与文献(靳永亮,陈冠宜,刘文琴,等.桂枝化学成分研究[J].广西植物,2022,42(5):860-865.)比较,确定结构为肉桂酸。
(20)化合物20
外观:无色油状物。
ESI-MS:m/z 467.08[M+Na]+。
1H NMR(500MHz,CD3OD)显示:5.76(1H,s,H-2),7.97(1H,d,J=16.0,H-4),6.51(1H,d,J=16.0,H-5),2.08(3H,d,J=1.3,H-6),1.80(2H,m,H-2'),2.19(1H,dd,J=13.8,6.9,H-4'a),1.98(1H,dd,J=13.8,7.1,H-4'b),3.80(1H,dd,J=7.4,2.1,H-7'a),3.75(1H,d,J=7.4,H-7'b),1.17(3H,s,H-9'),0.94(3H,s,H-10');4.36(1H,d,J=7.8,Glc-1"),3.12-3.80为糖上氢。
13C-NMR(125MHz,CD3OD)显示:168.4(C-1),118.0(C-2),149.9(C-3),130.5(C-4),133.6(C-5),19.8(C-6),48.0(C-1'),41.4(C-2'),72.5(C-3'),41.5(C-4'),86.2(C-5'),75.8(C-7'),81.8(C-8'),18.3(C-9'),14.9(C-10'),101.7(Glc-1"),73.7(Glc-2"),76.7(Glc-3"),70.3(Glc-4"),76.6(Glc-5"),61.4(Glc-6")。
综上分析,与文献(Yang,L.-P.;Gu,X.-L.;Chen,J.-X.et al.Chemicalconstituents from Canarium album Raeusch and their anti-influenza A virusactivities.Journal of Natural Medicines.2018,72(3),808-815.)比较,确定结构为二氢相酸-3'-O-β-D-吡喃葡萄糖苷(Dihydrophaseicacid-3'-O-β-D-glucopyranoside)。
(21)化合物21
外观:白色无定形粉末。
ESI-MS:m/z 357.15[M+Na]+。
1H NMR(500MHz,CD3OD)显示:有一个芳香氢:6.13(2H,s,H-3,5);4.66(1H,d,J=7.3),3.20-3.79为糖上氢。
13C-NMR(125MHz,CD3OD)显示:在低场有6个芳香碳:129.7,154.8,154.8,94.6,156.0,154.8;106.3,75.8,78.3,71.4,77.9,62.7为糖上的碳。
综上分析,与文献(Hideaki,O.;Mami,T.;Shogo,I.et al.Phenolic compoundsfrom Coix Lachryma-jobi Var.Ma-yuen.Phytochemistry.1989,28(3),883-886.)比较,确定结构为3,5-二甲氧基-4-(β-D-吡喃葡萄糖基)苯酚(leonuriside A)。
(22)化合物22
外观:白色无定形粉末。
ESI-MS:m/z 383.00[M+Na]+。
1H NMR(500MHz,CD3OD)显示:有2个芳香氢:7.22(2H,s);5.10(1H,d,J=7.5),3.07-3.58为糖上氢。
13C-NMR(125MHz,CD3OD)显示:在低场有6个芳香碳:126.6,107.8,107.8,152.7,152.7,138.6;1个羰基碳167.5;102.4,74.6,77.1,70.4,77.8,61.3为糖上的碳。
综上分析,与文献(Bao,G.;Wang,L.;Cheng,K.et al.Diterpenoid and PhenolicGlycosides from the roots of Rhododendron mole.PlantaMed.2003,69,434-439.)比较,确定结构为丁香酸葡萄糖苷。
(23)化合物23
外观:白色无定形粉末。
ESI-MS:m/z 186.94[M+Na]+。
1H NMR(500MHz,CD3OD)显示:7.46(2H,d,J=8.5,H-2,6),6.82(2H,d,J=8.5,H-3,5),7.61(1H,d,J=15.5,H-7),6.30(1H,d,J=15.5,H-8)。
13C-NMR(125MHz,CD3OD)显示:125.9(C-1),129.6(C-2),115.4(C-3),159.6(C-4),115.4(C-5),129.6(C-6),145.0(C-7),114.4(C-8),169.9(C-9)。
综上分析,与文献(Ashour,A.;Amer,M.;Marzouk,A.et al.Corncobs as apotential source of functional chemicals.Molecules 2013,18(11),13823-13830.)比较,确定结构为对香豆素酸。
综上,本实施例以桑寄生为原材料,从其75%乙醇提取物中分离得到23个化合物(化学结构见图2),分别为:3,4-二羟基苯甲酸乙酯(1)、松柏醛(2)、3,4-二羟苯甲醛(3)、原儿茶酸(4)、落叶松脂素(5)、儿茶酚(6)、(2S)-3,3-二-(4-羟基-3-甲氧基苯基)-丙烷-1,2-二醇(7)、香草酸(8)、没食子酸乙酯(9)、异槲皮素(10)、丁香酸(11)、槲皮苷(12)、扁蓄苷(13)、槲皮素(14)、儿茶素内酯A(15)、淫羊藿苷B2(16)、(+)-儿茶素(17)、Aripuanin(18)、肉桂酸(19)、二氢相酸-3'-O-β-D-吡喃葡萄糖苷(20),3,5-二甲氧基-4-(β-D-吡喃葡萄糖基)苯酚(21),丁香酸葡萄糖苷(22),对香豆素酸(23)。其中,化合物5,7,15,16,18,20为首次从该植物中分离得到。
实施例2
(1)3,4-二羟基苯甲酸乙酯(化合物1)的提取分离流程
用75%EtOH提取5.0kg桑寄生的带叶茎枝3次。然后在真空中浓缩后获得粗残余物(450.3g)。用CH2Cl2/MeOH(10:1-1:1,v/v)通过硅胶柱色谱分离得到五种组分(A-E)。通过MCI分离Fr.B以获得5个子组分(Fr.B.1-Fr.B.5)。使用MeOH/H2O洗脱的ODS将Fr.B.2分为5个子组分(Fr.B.2.1-Fr.B.2.5)。Fr.B.2.3通过制备HPLC MeOH/H2O(45:65,Rt=22.0)分离,得到化合物1(42.9mg)。使用MeOH/H2O洗脱的ODS将Fr.B.3分成9个子组分(Fr.B.3.1-Fr.B.3.9),然后用PE/EtOAc(10:1-0:1)通过硅胶CC纯化Fr.B.3.4,得到化合物1(22.6mg)。化合物1的氢谱和碳谱见图2和图3。
(2)3,4-二羟基苯甲醛(化合物3)的提取分离流程
用75%EtOH提取5.0kg桑寄生的带叶茎枝3次。然后在真空中浓缩后获得粗残余物(450.3g)。用CH2Cl2/MeOH(10:1-1:1,v/v)通过硅胶柱色谱分离得到五种组分(A-E)。通过MCI分离Fr.B以获得5个子组分(Fr.B.1-Fr.B.5)。化合物3(12.3mg)使用MeOH/H2O(20:80,Rt=25.1)的制备HPLC从Fr.B.1获得。使用MeOH/H2O洗脱的ODS将Fr.B.2分为5个子组分(Fr.B.2.1-Fr.B.2.5)。化合物3(28.6mg)用MeOH/H2O(30:70,Rt=14.3)通过制备HPLC分离从Fr.B.2.2中得到。化合物3的氢谱和碳谱见图4和图5。
(3)没食子酸乙酯(化合物9)的提取分离流程
用75%EtOH提取5.0kg桑寄生的带叶茎枝3次。然后在真空中浓缩后获得粗残余物(450.3g)。用CH2Cl2/MeOH(10:1-1:1,v/v)通过硅胶柱色谱分离得到五种组分(A-E)。通过MCI分离Fr.C以获得5个子组分(Fr.C.1-Fr.C.5)。Fr.C.3在Sephadex LH-20中用MeOH洗脱,然后通过制备HPLC MeOH/H2O(35:65,Rt=19.7)分离,得到化合物9(8.2mg)。化合物9的氢谱和碳谱见图6和图7。
(4)槲皮素(化合物14)的提取分离流程
用75%EtOH提取5.0kg桑寄生的带叶茎枝3次。然后在真空中浓缩后获得粗残余物(450.3g)。用CH2Cl2/MeOH(10:1-1:1,v/v)通过硅胶柱色谱分离得到五种组分(A-E)。通过MCI分离Fr.D以获得6个子组分(Fr.D1-Fr.D.6)。Fr.D.4用ODS和Sephadex LH-20纯化,用MeOH/H2O洗脱,然后用MeOH-H2O(45:55,Rt=38.0)通过制备HPLC分离,得到化合物14(4.2mg)。化合物14的氢谱和碳谱见图8和图9。
实施例3抗炎实验
化合物对LPS诱导RAW264.7细胞产生NO的影响。采用MTT法测定了所有分到的化合物对RAW264.7细胞活力的影响。用50μM的化合物处理细胞,化合物1,2,3,14,22显示出细胞毒性,但细胞活力都大于60%。然后用LPS(100ng/ml)和化合物(50μM)共同培养细胞24h检测化合物NO抑制率。化合物1,2,3,9,14具有很好的抗炎能力,并且它们的一氧化氮抑制率都大于40%。化合物14是槲皮素,这些化合物的抗炎能力与槲皮素相当。化合物1,2,3,14抑制NO的生成可能是因为抑制细胞的活力,化合物9在细胞无毒的情况下也可以抑制NO的生成。结果见表1。
表1桑寄生中化合物的抗NO活性
“a”代表均值±SD(n=3),与空白组相比***P<0.001,**P<0.01,*P<0.05.
3、抗氧化实验
对1,1-二苯基-2-苦辛酰肼(DPPH)自由基的清除活性。质子自由基清除作用被认为是抗氧化的重要机制。DPPH溶液的紫色在517nm处具有特征吸收。当溶液中存在抗氧化剂时,它可以通过提供质子或电子来去除DPPH自由基,溶液的颜色通常会消失。化合物1、3、9、15和17的EC50都小于40μM,并且具有很强的抗氧化能力。化合物14是槲皮素,这些化合物的抗氧化能力大于槲皮素。化合物1,3,9同时具有很好的抗氧化能力和抗炎能力,因此我们选取化合物1,3,9和槲皮素继续进行抗骨性关节炎的研究,结果见表2。
表2桑寄生中化合物的抗氧化活性
“-“表示EC50(μM)值>100.
4、抗骨性关节炎实验
提取原代大鼠软骨细胞,通过MTT法检测化合物1,3,9,槲皮素对原代大鼠软骨细胞的毒性。结果如图3所示,在高剂量(50μM)下化合物3,9,槲皮素与空白组相比对大鼠软骨细胞有一定的细胞毒性,在低剂量下(10μM)没有细胞毒性,因此为更准确高效地检测化合物1,3,9的抗骨性关节炎作用选用低剂量(10μM)处理软骨细胞(与空白组相比,*p<0.05,**p<0.01,***p<0.001)。
用IL-1β(10ng/mL)预处理软骨细胞2h,然后分别加入10μM的化合物1,3,9,槲皮素继续培养48h,然后提取细胞蛋白,通过Western blot实验检测与骨性关节炎相关蛋白的表达(与空白组相比,#p<0.05,##p<0.01,###p<0.001,与IL-1β刺激组相比,*p<0.05,**p<0.01,***p<0.001)。结果如图4所示,当用IL-1β(10ng/mL)刺激大鼠软骨细胞时,ADAMTS5、MMP13、iNOS、COX2的蛋白表达量升高,当加入化合物1,3,9,槲皮素处理后,这些蛋白的表达量较IL-1β(10ng/mL)刺激组相比增加,都有不同程度的降低,特别是化合物3作用效果与槲皮素相当。细胞外软骨基质(ECM)的异常降解可引发严重的骨性关节炎,ADAMTS5和MMP13促进ECM的降解,化合物1,3,9能抑制ADAMTS5和MMP13的表达从而抑制ECM的降解。iNOS和COX2是骨性关节炎中重要的炎症标志,骨性关节炎患者中iNOS和COX2表达升高,化合物1,3,9能抑制iNOS和COX2的表达从而抑制炎症。因此本发明从桑寄生中筛选的化合物3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯是潜在的抗骨关节炎的活性成分,具有广阔的应用前景。
Claims (5)
1.桑寄生活性物质在制备治疗骨关节炎的药物中的应用。
2.根据权利要求1所述的应用,其特征在于所述的桑寄生活性物质选自3,4-二羟基苯甲酸乙酯、3,4-二羟基苯甲醛、没食子酸乙酯中的任意一种。
3.根据权利要求2所述的应用,其特征在于所述的桑寄生活性物质用于制备抗炎和抗氧化的治疗骨关节炎的药物中的应用。
4.根据权利要求2所述的应用,其特征在于所述的桑寄生活性物质用于制备抑制细胞外软骨基质异常降解的药物中的应用。
5.根据权利要求2所述的应用,其特征在于所述的桑寄生活性物质用于制备骨关节炎细胞外软骨基质异常降解的药物中的应用。
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