王建軍,劉宇婧,徐家星,2,王 敖,王業(yè)玲,龍春林,3*
1中央民族大學(xué),北京100081;2云南農(nóng)業(yè)大學(xué);3中國(guó)科學(xué)院昆明植物研究所,昆明650201
菊科地膽草屬(Elephantopus)植物全球約30余種,大部分產(chǎn)于美洲,少數(shù)種分布于熱帶非洲、亞洲及大洋洲;僅地膽草(E.scaberL.)和白花地膽草(E.tomentosusL.)2個(gè)種分布于我國(guó)華南和西南部。該屬植物為多年生堅(jiān)硬草本,被柔毛。葉互生,頭狀花序多數(shù),密集成團(tuán)球狀復(fù)頭狀花序,復(fù)頭狀花序基部被數(shù)個(gè)葉狀苞片所包圍,具堅(jiān)硬的花序梗,在莖和枝端單生或排列成傘房狀,具數(shù)個(gè)花;總苞圓柱形或長(zhǎng)圓柱形,稍壓扁;總苞片2層,覆瓦狀,交叉對(duì)生,長(zhǎng)圓形,頂端急尖或具小刺尖?;ㄍ行?,無(wú)毛;花全部?jī)尚裕?,結(jié)實(shí),花冠管狀。花藥頂端短尖,基部短箭形,具鈍耳;花柱分枝絲狀,被微毛,頂端鉆形;瘦果長(zhǎng)圓形,頂端截形,具10條肋,被短柔;冠毛1層,具5條硬剛毛,基部寬扁;該屬的模式種為地膽草(E.scarberL.)[1]。該屬的幾個(gè)種被多個(gè)國(guó)家作為傳統(tǒng)藥物使用并記載,早在上世紀(jì)六十年代已有人從地膽草中分離得到具有抗腫瘤作用的倍半萜烯雙內(nèi)酯成分 Elephantin 和 Elephantopin[2],隨著研究的深入,從該屬植物中分離得到的倍半萜烯內(nèi)酯類(lèi)成分不斷增多,人們進(jìn)一步開(kāi)展了對(duì)該屬多個(gè)物種不同成分生物活性的檢驗(yàn)與分析。
該屬植物在美、亞、非以及大洋洲均有分布,不同種類(lèi)的各個(gè)部位在10多個(gè)國(guó)家或地區(qū)被用于治療不同的疾病,但不同國(guó)家或地區(qū)的藥用方法有所不同。詳細(xì)信息見(jiàn)表1。
在地膽草屬的30多種植物中,有4種是最常用的傳統(tǒng)藥物,它們分別是E.scaberL.,E.mollisL.,E.spicatusAubl.和E.tomentosusL.。其用法也因地而異,主要有煎服和搗碎外敷兩種方法。雖然各地區(qū)對(duì)該屬的不同物種用法不同,但在用途方面卻有極大的相似性。比如,印度和尼日利亞都將該屬植物用于關(guān)節(jié)炎癥,而臺(tái)灣、老撾、泰國(guó)均將其用作止咳藥。綜合上述信息,該屬植物多具有抗菌消炎的作用,主要用于治療呼吸系統(tǒng)疾病、胃腸道疾病和泌尿系統(tǒng)等疾病。
在發(fā)展中國(guó)家,傳統(tǒng)用藥方式是基礎(chǔ)醫(yī)療體系的重要組成部分[31],基于植物的傳統(tǒng)知識(shí)已經(jīng)成為搜尋新藥與食物的公認(rèn)工具[32],對(duì)于地膽草屬植物藥用的傳統(tǒng)知識(shí),需要進(jìn)行更多的科學(xué)研究,以進(jìn)一步檢驗(yàn)與驗(yàn)證其傳統(tǒng)知識(shí)的正確性和有效性。
表1 地膽草屬植物的傳統(tǒng)利用Table 1 Traditional uses of Elephantopus
倍半萜烯內(nèi)酯是一類(lèi)無(wú)色、具苦味且相對(duì)穩(wěn)定的親脂性成分,起始于反-反-焦磷酸法尼酯(trans,trans-farnesyl pyrophosphate),經(jīng)最初的環(huán)化反應(yīng)和氧化修飾而成[33]。其基本類(lèi)型依據(jù)碳環(huán)骨架的不同可分為 A.Germacranolides,B.Eudesmanolides,C.Eremophilanolides,D.Guaianolides,E.Pseudoguaiano-lides和 F.Xanthanolides 六種類(lèi)型[34],其結(jié)構(gòu)見(jiàn)圖1。菊科作為一個(gè)包括17個(gè)族、82個(gè)亞族的大科,倍半萜烯內(nèi)酯類(lèi)成分在其大約1500個(gè)屬中廣泛存在,而現(xiàn)在已知的倍半萜烯內(nèi)酯類(lèi)化合物大約有4000個(gè)[35]。繼上世紀(jì)60年代分離得到elephantin和elephantopin之后,70年代中期 molephantin,molephantinin和phantomolin也作為細(xì)胞毒性物質(zhì)從E.mollis中分離得到[36]。迄今為止,從地膽草屬中共分離得到的倍半萜烯內(nèi)酯類(lèi)化合物已有29個(gè),具體信息見(jiàn)表2和圖2。
圖1 倍半萜烯內(nèi)酯類(lèi)成分的主要結(jié)構(gòu)類(lèi)型Fig.1 Themain structure types of sesquiterpene lactone
表2 地膽草屬中倍半萜烯內(nèi)酯類(lèi)化合物Table 2 Sesquiterpene lactone compounds from Elephantopus
25 2,5-epoxy-2β-hydroxy-8α-(2-methylbut-2-enoyloxy)-4(15),10(14),11(13)-gemacratrien-12,6α-olide A E.mollis 50 26 Phantomolin A E.mollis 36,51 27 2β-Methoxy-2-deethoxy-phantomolin A E.mollis 52 28 2β-Methoxy-2-deethoxy-8-O-deacylphantomolin-8-O-tiglinate A E.mollis 52 29 Elescaberin A E.scaber 53 30 8-[4-Hydroxytigloyloxy]-preeupatundin D E.mollis 68 31 8-[4-Hydroxytigloyloxy]-5-desoxy-8-desacyleuparotin D E.mollis 68 32 2,5-epoxy-2β-hydroxy-8α-(2-methylpropenoyloxy)-4(15),10(14),11(13)-germacratrien-1-2,6α-olide D E.mollis 54 33 (4βH)-8α-(2-methylpropenoyloxy)-2-oxo-1(5),10(14),11(13)-guaiatrien-12,6α-olide D E.mollis 54 34 (4βH)-5α-hydroxy-8α-(2-methylpropenoyloxy)-1(10),11(13)-guaiadiene-12,6α-olide D E.mollis 54
圖2 倍半萜烯內(nèi)酯類(lèi)化合物的結(jié)構(gòu)Fig.2 The structure of sesquiterpene lactone compounds
迄今為止,從地膽草屬植物中發(fā)現(xiàn)的化合物結(jié)構(gòu)類(lèi)型除倍半萜烯內(nèi)酯類(lèi)之外還分離得到了27個(gè)其他結(jié)構(gòu)類(lèi)型的化合物;其中三萜類(lèi)化合物10個(gè),黃酮類(lèi)4個(gè),二咖啡酸類(lèi)3個(gè),甾醇類(lèi)2個(gè)以及其他類(lèi)型的8個(gè)化合物。其中二咖啡酸類(lèi)化合物,如3,5-di-O-caffeoyl quinic acid,4,5-di-O-caffeoyl quinic acid 及 1α,2β-O-dicaffeoylcyclopentan-3β-ol等,因其存在多酚羥基結(jié)構(gòu),故該類(lèi)化合物具有良好的抗氧化功能。各化合物的具體信息見(jiàn)表3和圖3;
表3 地膽草屬中其他類(lèi)型化合物Table 3 Other compounds(excluding sesquiterpene lactone)from Elephantopus
圖3 地膽草屬其他類(lèi)型化合物結(jié)構(gòu)Fig.3 The structures of other compounds(excluding sesquiterpene lactone)from Elephantopus
經(jīng)系統(tǒng)研究證明,地膽草屬植物具有抑菌、抗病毒及原蟲(chóng)和抗腫瘤等多種生物學(xué)活性。
地膽草(E.scarber)的水提物對(duì)變異鏈球菌S.mutansMT5091(serotype c)和S.mutansOMZ 176(serotype d)均有較強(qiáng)的抑制作用,最低抑菌濃度(MIC)分別為 7.8、15.6 mg/mL[61];對(duì)抗酸性草分枝桿菌M.phlei,石膏樣小孢子菌M.gypseum以及須癬毛癬菌T.mentagrophytes真菌也具有較強(qiáng)的抑制作用[62]。而其葉子和莖的80%乙醇提取物對(duì)枯草芽孢桿菌B.subtilis、金黃色葡萄球菌S.a(chǎn)ureus、大腸桿菌E.coli和銅綠假單胞菌P.a(chǎn)eruginosa的生長(zhǎng)也同樣具有抑制作用[63]。
地膽草中分離得到的 1α,2β-O-dicaffeoylcyclopentan-3β-ol等二咖啡酸類(lèi)物質(zhì),經(jīng)細(xì)胞病變(CPE)抑制試驗(yàn)證明該化合物對(duì)呼吸道合胞體病毒(RSV)具有良好的抑制活性(IC50=0.63μg/mL),較利巴韋林(IC50=1.50μg/mL)對(duì) RSV的抑制作用更強(qiáng)[60];其全草的甲醇提取物在200μg/mL在紫外線存在的條件下對(duì)小兒麻痹癥病毒(polio virus)具有抑制作用,在濃度為100μg/mL時(shí)對(duì)辛德畢斯病毒(Sindbis)也同樣具有抑制作用;E.mollis葉子的二氯甲烷提取物對(duì)杜氏利什曼原蟲(chóng)L.donovani有很強(qiáng)的抑制活性(IC50=0.6μg/mL),它對(duì)惡性瘧原蟲(chóng)P.falciparum及羅得西亞布氏錐蟲(chóng)T.bruceirhodesiense 具有高選擇抗性[64,65]。
E.mollis的乙酸乙酯提取物通過(guò)caspase-3依賴(lài)途徑能夠顯著誘導(dǎo)肝癌HepG2細(xì)胞凋亡,其最低EC50為9.38 ±0.43 μg/mL;同時(shí)該提取物對(duì)肺癌NCI-H23細(xì)胞,乳腺癌T-47D細(xì)胞,卵巢癌Caov-3細(xì)胞也有抑制作用[66]。地膽草的氯仿提取物濃度為100 mg/kg時(shí),可以有效地推遲由7,12-dimethylbenz anthracene(DMBA)誘導(dǎo)的小鼠皮膚乳突淋瘤的形成,并能夠減少該類(lèi)腫瘤細(xì)胞的平均數(shù)量與重量。該成分對(duì)由20-methylcholanthrene(20-MCA)誘導(dǎo)小鼠的軟組織肉瘤有很好的抑制作用,可延長(zhǎng)患病小鼠的壽命[67]。而被視為地膽草屬特征性物質(zhì)的 deoxyelephantopin(DET)[68],能強(qiáng)烈抑制 TS/A 細(xì)胞的轉(zhuǎn)移、增殖、入侵以及群落的形成;與紫杉醇相比,DET能更有效地抑制小鼠原位腫瘤細(xì)胞(68%vs 99%)及惡性乳腺腫瘤細(xì)胞的生長(zhǎng)[69,70];同時(shí)DET亦可以誘導(dǎo)并激發(fā)鼻咽癌細(xì)胞中的細(xì)胞周期阻滯與細(xì)胞凋亡,其對(duì)治療鼻咽癌有巨大的潛在價(jià)值[71]。而由地膽草中分離得到的 scabertopin和isodeoxyelephantopin兩種物質(zhì)在體外對(duì)人肝癌細(xì)胞(SMMC-7721)、人宮頸癌細(xì)胞(Hela)、人結(jié)腸癌細(xì)胞(Caco-2)具有抑制作用[72]。最新研究表明,DET和Isodeoxyelephantopin可引起L-929腫瘤細(xì)胞活力降低,其 IC50分別為 2.7和 3.3 μg/mL,且 DET 對(duì)DLA腫瘤細(xì)胞具有很大的抑制活性[73]。
地膽草和E.mollis的水提物在300 mg/kg時(shí)對(duì)由角叉菜膠(Carrangeenan)誘導(dǎo)的小鼠爪部的急性炎癥具有顯著的抑制活性,對(duì)由complete Freund’s adjuvant(CFA)誘導(dǎo)的慢性炎癥也有良好的抑制作用[74]。E.mollis的 1,3-丁二醇提取物在 0.05% ~0.3%時(shí),能夠顯著減少B16黑色素瘤細(xì)胞中黑色素的含量[75]。E.tomentosus的乙醇提取物在1 mg/mL時(shí)具有的抗氧化活性相當(dāng)于2.1 mM(TECA)的抗氧化能力;其還具有過(guò)氧化氫清除及抑制Fe3+誘導(dǎo)的脂質(zhì)過(guò)氧化作用,在500 mg/kg時(shí)具有減小CCl4誘導(dǎo)的肝毒性的作用[76]。由地膽草中分離得到的單體物質(zhì)3,4-二咖啡奎尼酸(3,4-di-O-caffeoyl quinic acid)在濃度625-1250μg/mL時(shí),對(duì)α-葡萄糖苷酶的抑制率大于80%,且其 EC50在241.80±14.29μg/mL時(shí)較濃度為7.30±0.05 μg/mL阿卡波糖的高30倍,說(shuō)明該物質(zhì)具有良好的抗2型糖尿病活性[77]。
通過(guò)化學(xué)合成來(lái)獲取新藥是西藥研發(fā)的重要手段,但其代價(jià)昂貴且有不良反應(yīng)多;同時(shí)以中藥及民族藥為代表的傳統(tǒng)藥物成為了新藥研發(fā)的重要補(bǔ)充手段。從天然藥物中獲取的藥效單體具有價(jià)格低、不良反應(yīng)少等特點(diǎn),特別是其傳統(tǒng)藥用知識(shí)為其對(duì)癥開(kāi)發(fā)與研制指明了方向,從而節(jié)省大量的人力、物力、財(cái)力。國(guó)內(nèi)外學(xué)者對(duì)地膽草屬植物的傳統(tǒng)醫(yī)藥用途及其生物活性進(jìn)行了較多的研究,發(fā)現(xiàn)其粗提物或是單體具有多樣良好的生物學(xué)活性,特別是由該屬植物E.scarber分離得到的單體物質(zhì)deoxyelephantopin 和 1α,2β-O-dicaffeoylcyclopentan-3β-ol分別在抗鼻咽癌及2型糖尿病方面有很好的治療活性,有待進(jìn)一步研究開(kāi)發(fā)。另外據(jù)WHO統(tǒng)計(jì),每年因利什曼原蟲(chóng)引發(fā)的新增病例就達(dá)200萬(wàn)[78],而E.mollis的粗提物對(duì)利什曼病原蟲(chóng)具有很好的抑制作用,應(yīng)該加深該方面的研究。我們應(yīng)該重視對(duì)地膽草屬植物在抗糖尿病、抗原蟲(chóng)及抗腫瘤活性方面的研究與開(kāi)發(fā),這對(duì)改善與保障人類(lèi)健康具有巨大的潛在價(jià)值。而鑒于該屬植物在傳統(tǒng)藥用中的復(fù)雜性與多樣性,今后人們應(yīng)該從化學(xué)、生物學(xué)、藥學(xué)等多方面來(lái)加大對(duì)該屬植物的研究力度,從而來(lái)促進(jìn)該類(lèi)植物的可持續(xù)利用。
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