CN113321695B - 一种甾体类化合物及其制备方法和应用 - Google Patents
一种甾体类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及天然药物领域，公开一种来源于波罗蜜果肉中的具有新颖化学结构的甾体类化合物及其制备方法和在抗肿瘤药物中的应用，所述化合物artoheterophoid经多种体外抗肿瘤活性评价结果表明：该化合物具有显著的抗肿瘤活性，具有与阳性对照药相当的抑制蛋白酪氨酸激酶的活性，可以进一步开发成以蛋白酪氨酸激酶为靶标的抗肿瘤药物，可在抗肿瘤药物中应用，分离纯化工艺简单，反应条件温和，具有现实意义。
Description
技术领域
本发明属于天然药物领域，具体涉及一种来源于菠罗蜜果肉中的具有新颖化学结构的甾体类化合物的制备方法及其在抗肿瘤药物中的应用。
背景技术
恶性肿瘤目前已经成为人类最大致死病因，全球范围内恶性肿瘤发病率和死亡率呈持续上升趋势。随着肿瘤发生机制的不断被阐明以及抗肿瘤作用靶点的不断被发现，靶向抑制肿瘤信号转导成为新型抗肿瘤药物开发的重要方向。在各种分子靶点中，蛋白酪氨酸激酶(Protein Tyrosine Kinase，PTK)是目前研究最多且效果最明显的抗肿瘤药物靶点之一，已成为抗肿瘤靶向治疗药物的研究重点和热点，具有广阔的应用前景。目前临床上使用的小分子靶向抗肿瘤药物主要为酪氨酸激酶抑制剂类抗肿瘤药物，包括单靶点酪氨酸激酶抑制剂和多靶点酪氨酸激酶抑制剂。酪氨酸激酶通过一个复杂的细胞内网络通路控制细胞增殖，生存，细胞凋亡，血管生成，侵袭和转移，肿瘤组织最初可能对单靶点酪氨酸激酶抑制剂有反应，但可以通过多种机制获得拮抗能力，肿瘤存在这些逃逸机制是多靶点治疗必要性的基础。临床实践同样表明，单靶点酪氨酸激酶抑制剂类抗肿瘤药物，如厄洛替尼和吉非替尼，尽管选择性强、毒副作用小，但在使用过程中易产生耐药性，无法彻底杀灭肿瘤细胞，而联合用药又会带来严重的不良反应，影响各自的药动学特性。相对于单靶点药物和多种单靶点药物联合用药来说，多靶点药物具有更多的优越性。多靶点药物可有效避免产生药物之间的相互作用，减少不良反应，治疗作用更全面等优点。很多多靶点酪氨酸激酶抑制剂类抗肿瘤药物，因其疗效高、毒性小的临床特点，已逐渐成为某些肿瘤治疗的一线用药，如伊马替尼等靶向抗肿瘤药物。
桑科(Moraceae)波罗蜜属(Artocarpus)植物全世界约有50种，分布于热带亚洲，自斯里兰卡、印度、巴基斯坦、孟加拉国、缅甸、泰国、马来西亚、印度尼西亚、巴布亚新几内亚至所罗门群岛等地。我国约有15种和2变种，集中分布于海南、广东、广西、云南、贵州、福建及台湾等省区[中国科学院中国植物志编委会.中国植物志.第23卷.科学出版社.北京:1998,pp 40-55.]。在民间，波罗蜜属植物作药用植物已有很长历史,常用于肝硬化、高血压、风湿病、疟疾、痢疾以及肺结核等疾病的治疗；现代药理学研究表明该属植物中的化学成分具有广泛的生物活性如抗肿瘤、抗炎、抗疟、抗结核、抗真菌、抗病毒、抗血小板凝结以及抗氧化等多种生物活性[Zheng,Z.P.；Xu,Y.；Qin,C.；Zhang,S.；Gu,X.H.；Lin,Y.Y.；Xie,G.B.；Wang,M.F.；Chen,J.Characterization of antiproliferative activityconstituents from Artocarpus heterophyllus.Journal of Agricultural and FoodChemistry 2014,62,5519-5527.；Sun,G.C.；Zheng,Z.P.；Lee,M.H.；Xu,Y.J.；Kang,S.；Dong,Z.G.；Wang,M.F.；Gu,Z.N.；Li,H.T.；Chen,W.Chemoprevention of colorectalcancer by artocarpin,a aietary phytochemical fromArtocarpusheterophyllus.Journal ofAgricultural and Food Chemistry 2017,65,3474-3480.；Fang,S.C.；Hsu,C.L.；Yen,G.C.Anti-inflammatory effects of phenolic compoundsisolated from the fruits ofArtocarpus heterophyllus.Journal of Agriculturaland Food Chemistry 2008,56,4463-4468.；Boonlaksiri,C.；Oonanant,W.；Kongsaeree,P.；Kittakoop,P.；Tanticharoen,M.；Thebtaranonth,Y.An antimalarial stilbene fromArtocarpus integer.Phytochemistry 2000,54,415-417.；Puntumchai,A.；Kittakoop,P.；Rajviroongit,S.；Vimuttipong,S.；Likhitwitayawuid,K.；Thebtaranonth,Y.Lakoochins A and B,New antimycobacterial stilbene derivatives fromArtocarpus lakoocha.Journal of Natural Products 2004,67,485-486.；Jayasinghe,L.；Balasooriya,B.S.；Padmini,W.C.；Hara,N.；Fujimoto,Y.Geranyl chalconederivatives with antifungal and radical scavenging properties from the leavesof Artocarpus nobilis.Phytochemistry2004,65,1287-1290.；Likhitwitayawuid,K.；Sritularak,B.；Benchanak,K.；Lipipun,V.；Mathew,J.；Schinazi,R.F.Phenolics withantiviral activity from Millettia erythrocalyx andArtocarpus lakoocha.NaturalProduct Research 2005,19,177-182.；Weng,J.R.；Chan,S.C.；Lu,Y.H.；Lin,H.C.；Ko,H.H.；Lin,C.N.Antiplatelet prenylflavonoids from Artocarpuscommunis.Phytochemistry 2006,67,824-829.；Lin,K.W.；Liu,C.H.；Tu,H.Y.；Ko,H.H.；Wei,B.L.Antioxidantprenylflavonoids from Artocarpus communis and Artocarpuselasticus.Food Chemistry 2009,115,558-562.]。正因为如此，该属植物一直备受植物化学和药理学界科研工作者的青睐。自1971年起，对该属植物中的化学成分及其药理活性的研究一直是天然产物化学的热点之一。目前国内外学者从该属植物中共分离得到220余个化合物，包括黄酮类、芪类、甾体类和三萜类等等多种结构类型化合物[Altman,L.J.；Zito,S.W.Sterols and triterpenes from the fruit ofArtocarpusaltilis.Phytochemistry1976,15,829-830.；Pant,R.；Chaturvedi,K.4-Hydroxyundecyldocosanoate and cycloartenone in Artocarpus integra latex.Phytochemistry1989,28,2197-2199.；Hano,Y.；Aida,M.；Nomura,T.Two new natural diels-alder-typeadducts from the root bark of Artocarpus heterophyllus.Journal of NaturalProducts 1990,53,391-395.；Barik,B.R.；Bhaumik,T.；Dey,A.K.；Kundu,A.B.Triterpenoids from Artocarpus heterophyllus.Phytochemistry 1994,35,1001-1004.；Wang,Y.H.；Hou,A.J.；Chen,L.；Chen,D.F.；Sun,H.D.；Zhao,Q.S.；Bastow,K.F.；Nakanish,Y.；Wang,X.H.；Lee,K.H.New Isoprenylated flavones,artochamins A-E,andcytotoxic principles from Artocarpus chama.Journal of Natural Products2004,67,757-761.；Wei,B.L.；Weng,J.R.；Chiu,P.H.；Hung,C.F.；Wang,J.P.；Lin,C.N.Antiinflammatory flavonoids from Artocarpus heterophyllus and Artocarpuscommunis.Journal of Agricultural and Food Chemistry 2005,53,3867-3871.；Toume,K.；Habu,T.；Arai,M.A.；Koyano,T.；Kowithayakorn,T.；Ishibashi,M.Prenylatedflavonoids and resveratrol derivatives isolated from Artocarpus communis withthe ability to overcome TRAIL resistance.Journal of Natural Products 2015,78,103-110.；Yuan,W.J.；Yuan,J.B.；Peng,J.B.；Ding,Y.Q.；Zhu,J.X.；Ren,G.Flavonoidsfrom the roots of Artocarpus heterophyllus.Fitoterapia 2017,117,133-137.；Nguyen,M.T.；Le,T.H.；Nguyen,H.X.；Koyano,Y.Q.；Koyano,T.；Arai,M.A.；Dang,P.H.；Do,T.V.；Abe,M.；Takagi,R.；Nguyen,N.T.Artocarmins G-M,prenylated 4-chromenonesfrom the stems of Artocarpus rigida and their tyrosinase inhibitoryactivities.Journal of Natural Products 2017,80,3172-3178.]。
桑科波罗蜜属植物菠萝蜜(A.heterophyllus)是一种集水果、木本粮食及珍贵用材于一体的热带树种。它的成熟果实为世界著名的热带水果，果实硕大，果肉味道甘甜，香气浓，素有“热带水果皇后”之美称。菠萝蜜果树全身是宝，果肉可鲜食或加工成罐头、果脯以及果汁，它既是美味食品，又是良药，性味甘、微酸、无毒，有生津、止渴解烦、醒酒、益气、助消化之功效；种子富含淀粉，可煮食；树的枝叶和根可药用，具有消肿、解毒的功效。为了更好地利用这种极具海南特色的热带水果资源，促进海南菠罗蜜相关产业的快速发展，有必要对菠罗蜜中所含有的功能性成分及其产业化关键技术进行系统研究。前期研究发现菠萝蜜果肉的乙醇提取物的生物活性进行了系统评价，研究中发现菠萝蜜乙醇提取物具有显著的抗肿瘤活性，尤其是对人早幼粒细胞性白血病细胞株(HL-60))和人肺癌细胞株(A-549)，其IC50分别为0.28和0.96μg/mL，同时表现出了和阳性对照药舒尼替尼相当的多靶点酪氨酸激酶抑制活性。
发明内容
本发明的目的是提供一种从波罗蜜果肉中分离得到的具有新颖化学结构的甾体类化合物artoheterophoid，该化合物具有显著的抗肿瘤活性和与阳性对照药相当的蛋白酪氨酸激酶的抑制活性，可以进一步开发成以蛋白酪氨酸激酶为靶标的抗肿瘤药物。
为了实现上述目的，本发明的技术方案为：提供一种甾体类化合物，化学名为artoheterophoid，其化学结构如下：
本发明的另一目的是提供一种甾体类化合物artoheterophoid的制备方法，包括以下步骤：
A.将波罗蜜果肉用甲醇或85％乙醇溶液冷浸提取5次，过滤，收集滤液，再减压浓缩至无醇味，得醇提取物；
B.将醇提取物加蒸馏水制成混悬液，依次用石油醚和乙酸乙酯进行萃取，石油醚萃取液减压浓缩，得石油醚萃取浸膏；
C.将石油醚萃取浸膏进行柱色谱分离纯化，得到单体化合物artoheterophoid。
进一步地，上述步骤C具体包括：
(1)将石油醚萃取浸膏用硅胶柱层析划段，分别按体积比95:5、85:15、75:25和55:45进行石油醚-乙酸乙酯梯度洗脱，收集体积比为55:45的石油醚-乙酸乙酯洗脱物；
(2)取体积比为55:45的石油醚-乙酸乙酯洗脱物用MCI树脂柱层析去除色素，分别按体积比为35:65、65:35和85:15用甲醇-水梯度洗脱，收集体积比为65:35的甲醇-水洗脱物；
(3)取体积比为65:35的甲醇-水洗脱物进行反相硅胶柱层析，分别按体积比为65:35、75:25和85:15的甲醇-水梯度洗脱，收集体积比为75:25的甲醇-水洗脱物进行浓缩；
(4)取浓缩后的甲醇-水洗脱物用制备型高效液相色谱分离，流动相为甲醇-水，体积比78:22，得到单体化合物artoheterophoid。
本发明的再一目的在于提供甾体类化合物artoheterophoid在制备抗肿瘤药物中的应用，尤其是提供甾体类化合物artoheterophoid在制备以蛋白酪氨酸激酶为靶标的靶向抗肿瘤药物方面的应用。
进一步地，所述肿瘤细胞株包括HL-60(人原髓细胞白血病细胞)、A549(人肺癌细胞)、SMMC-7721(人肝癌细胞)、MCF-7(人乳腺癌细胞))和SW480(人结肠癌细胞)等五种肿瘤细胞株。
本发明首次从波罗蜜果肉的醇提取物的石油醚萃取浸膏中分离鉴定了一个化学结构新颖的甾体类化合物artoheterophoid。多种体外活性评价结果表明：该化合物具有显著的体外抗肿瘤活性，同时具有与阳性对照药伊马替尼相当的蛋白酪氨酸激酶的抑制活性，可以进一步开发成以蛋白酪氨酸激酶为靶标的靶向抗肿瘤药物，具有开发成以蛋白酪氨酸激酶为靶标的靶向抗肿瘤药物的前景。
具体实施方式
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规实验条件。
实施例一：化合物artoheterophoid的制备方法
A.将阴干的波罗蜜果干粉末(22.9kg，海南)用85％乙醇溶液冷浸提取5次，每次提取三天，过滤，收集滤液，减压浓缩至无醇，得醇提取物；
B.将该醇提取物加蒸馏水制成混悬液，依次用石油醚和乙酸乙酯萃取，石油醚萃取液经减压浓缩，得石油醚萃取物827.8g和乙酸乙酯萃取物983.3g；；
C.将石油醚萃取物进行柱色谱分离纯化：
(1)将石油醚萃取浸膏经硅胶柱层析划断，以石油醚-乙酸乙酯(体积比为95:5、85:15、75:25、55:45)为洗脱剂进行梯度洗脱，收集石油醚-乙酸乙酯(体积比55:45)洗脱物；
(2)取石油醚-乙酸乙酯(体积比55:45)洗脱物用MCI树脂柱层析去除色素，以甲醇-水(体积比35:65、65:35、85:15)为洗脱剂进行梯度洗脱，收集甲醇-水(体积比65:35)洗脱物；
(3)取甲醇-水(体积比65:35)洗脱物进行反相硅胶柱层析，以甲醇-水(体积比65:35、75:25、85:15)为洗脱剂进行梯度洗脱，收集甲醇-水(体积比75:25)洗脱物进行浓缩；
(4)取浓缩后的甲醇-水洗脱物用制备型高效液相色谱分离，流动相为甲醇-水(体积比78:22)，得到纯的化合物artoheterophoid(216.7mg)。
结构确证：通过旋光光谱、紫外(UV)光谱、红外(IR)光谱、核磁共振(NMR)谱和质谱(MS)等多种现代波谱技术的综合解析，确定了化合物artoheterophoid的化学结构。
Artoheterophoid:白色无定形粉末，IR(KBr)vmax3032,2938,2853,1742,1664,1635,1613,1453,1440,1407,1382,1211,1178,1126和890cm–1；UV(CH3OH)λmax(logε)219(4.36),252(3.97)和286(3.68)nm；ESI-MS m/z 337[M+Na]+；HR-ESI-MS m/z 337.1775[M+Na]+(Calcd for C20H26NaO3,337.1774)；1H-NMR(400MHz,CDCl3)δ:6.14(1H,s,H-4),5.96(1H,s,H-1),3.69(3H,s,2-OCH3),2.50(1H,ddd,J＝13.2,4.8,1.2Hz,H-6α),2.42(1H,ddd,J＝13.2,4.8,2.6Hz,H-6β),2.23(1H,dd,J＝18.0,7.8Hz,H-15α),2.17(1H,d,J＝16.8Hz,H-17α),2.00(1H,dd,J＝18.0,13.6Hz,H-15β),1.98(1H,d,J＝16.8Hz,H-17β),1.94(1H,overlapped,H-12α),1.93(1H,overlapped,H-7α),1.87(1H,m,H-11α),1.82(1H,m,H-11β),1.78(1H,overlapped,H-8),1.53(1H,m,H-14),1.44(1H,dd,J＝12.6,4.8Hz,H-12β),1.30(3H,s,H3-19),1.22(1H,m,H-9),1.14(1H,m,H-7β),0.98(3H,s,H3-18)；13C-NMR(100MHz,CDCl3)δ:217.2(C-16),181.2(C-3),168.4(C-5),150.5(C-2),123.7(C-4),122.2(C-1),55.5(C-17),54.8(2-OCH3),53.4(C-9),50.7(C-14),43.7(C-10),39.3(C-13),39.2(C-15),37.8(C-12),34.9(C-8),33.9(C-7),32.1(C-6),22.9(C-11),20.1(C-19),18.1(C-18)。
实施例二：化合物artoheterophoid的制备方法
A.将阴干的波罗蜜果肉的干燥粉末(108.5kg，海南)用甲醇冷浸提取5次，每次5天，过滤，收集滤液，减压浓缩至无醇味，得甲醇提取物；
B.将甲醇提取物加蒸馏水制成混悬液，依次用石油醚和乙酸乙酯萃取，石油醚萃取液减压浓缩，得石油醚萃取物4258.7g和乙酸乙酯萃取物5023.5g；
C.将石油醚萃取物进行柱色谱分离纯化：
(1)将石油醚部位浸膏用硅胶柱层析进行分离，石油醚-乙酸乙酯(体积比95:5、85:15、75:25和55:45)为洗脱剂进行梯度洗脱，收集石油醚-乙酸乙酯(体积比55:45)洗脱物；
(2)取石油醚-乙酸乙酯(体积比55:45)洗脱物用MCI树脂柱层析去除色素，以甲醇-水(体积比55:45、65:35和85:15)为洗脱剂进行梯度洗脱，收集甲醇-水(体积比65:35)洗脱物；
(3)取甲醇-水(体积比65:35)洗脱物进行反相硅胶柱层析，以甲醇-水(体积比65:35、75:25和85:15)为洗脱剂进行梯度洗脱，收集甲醇-水(体积比75:25)洗脱物进行浓缩；
(4)取浓缩后的甲醇-水洗脱物用制备型高效液相色谱分离，流动相为甲醇-水(体积比78:22)，得到单体化合物II(1128.6mg)。
化合物II的结构确证：白色无定形粉末；HR-ESI-MS显示化合物II的[M+Na]+为m/z337.1775；化合物II与实施例一中制备方法得到的化合物artoheterophoid共TLC，在三种展开体系下[石油醚-乙酸乙酯(7:3)、石油醚-丙酮(5:5)和氯仿-甲醇(19:1)]均为均一斑点，说明该化合物与化合物artoheterophoid为同一化合物。
一、化合物artoheterophoid的抗肿瘤活性研究
1、实验方法：将五种常见肿瘤细胞株HL-60、A549、SMMC-7721、MCF-7和SW480分别用含10％小牛血清的RPMI-1640培养基，在37℃、5％CO2培养箱中培养。采用MTT法进行细胞增殖抑制试验，主要操作为：取对数生长期的肿瘤细胞株，用0.25％的胰蛋白酶消化，10％新生小牛血清的RPMI-1640培养液调制成5×104个/mL的细胞悬液，接种于96孔板中，每孔接种180μL。在37℃，5％CO2饱和湿度条件下培养8-10h，待其贴壁，每个孔加入用PBS配制的样品液，使得样品终浓度分别为0.1、1和10μg/mL。每个浓度平行3孔，继续培养44h后，每孔加入50μLMTT(1mg/mL-1，PBS配制)，在37℃，5％CO2条件下继续温育4h，吸弃孔内培养上清液，每孔加入150μL DMSO，在微型振荡器上摇匀15min，结晶溶解后，在酶联免疫检测仪上选择570nm，测定各孔的吸光值，同时设置空白组(仅加入含细胞的培养液)和对照组(以培养液替代药物)，计算细胞增殖抑制率。抑制率(％)＝(1-实验组3孔OD值平均值/对照组3孔OD值平均值)×100％。以抑制率作纵坐标，作回归曲线，计算出样品IC50值。采用SPSS13.0统计软件包进行数据处理及统计分析。
2、抗肿瘤活性实验结果(见表1)
由本发明实施例一得到的化合物artoheterophoid对所选肿瘤细胞株HL-60、A549、SMMC-7721、MCF-7和SW480均显示不同程度的增殖抑制活性。
表1化合物artoheterophoid的抗肿瘤活性评价结果
二、化合物artoheterophoid的抑制蛋白酪氨酸激酶活性
大鼠脑组织中PTKs的提取：将大鼠大脑取出，剔除脑膜，称重，加入4倍量的冷匀浆液。冰浴中用玻璃匀浆器高速匀浆，离心，收集上清液，再离心10min。收集上清液，上清液中含有胞浆型酪氨酸激酶，而沉淀可作为受体型酪氨酸激酶使用。留取少量上清液用于提取物中蛋白质的含量测定，其余分装，置于-70℃保存备用。
酶标板包被：将底物稀释液加入96孔酶标板中(每孔125μL)，37℃孵育过夜。移除板中过量底物液，加入磷酸盐缓冲液(PBS-Tween20)洗涤，于37℃干燥2h。4℃保存备用。
PTK抑制剂评价：先将样品加入酶标板中，37℃孵育，加入用激酶缓冲液稀释的ATP，37℃孵育，移除板中的反应液，洗涤；加入抗体复合物，37℃孵育；移除板中抗体复合物，洗涤，加入四甲基联苯胺(TMB)显色液，室温避光反应，加入终止液，于450nm波长处测定吸光度(A)值。阳性对照药为伊马替尼。按下述公式计算化合物artoheterophoid的抑制率：抑制率％＝(A正常-A样品)/(A正常-A空白)*100％
结果表明，化合物artoheterophoid对蛋白酪氨酸激酶具有显著的抑制作用(抑制率82.63％)，抑制活性和阳性对照药伊马替尼的抑制活性相当(抑制率76.28％)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (1)
1.一种甾体类化合物在制备以蛋白酪氨酸激酶为靶标的靶向抗肿瘤药物方面的应用，所述化合物化学名为artoheterophoid，其化学结构如下：
。
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