趙雪淞,李盛鈺,楊　旭,周義發(fā)

(1.遼寧工程技術(shù)大學(xué)礦業(yè)學(xué)院,遼寧阜新 123000;2.吉林省農(nóng)業(yè)科學(xué)院農(nóng)產(chǎn)品加工研究所/國(guó)家乳品加工技術(shù)研發(fā)分中心,吉林長(zhǎng)春 130033;3.東北師范大學(xué)生命科學(xué)學(xué)院,吉林長(zhǎng)春 130024)

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甾體糖苷抗腫瘤活性構(gòu)效關(guān)系研究

趙雪淞1,李盛鈺2,楊旭3,周義發(fā)3

(1.遼寧工程技術(shù)大學(xué)礦業(yè)學(xué)院,遼寧阜新 123000;2.吉林省農(nóng)業(yè)科學(xué)院農(nóng)產(chǎn)品加工研究所/國(guó)家乳品加工技術(shù)研發(fā)分中心,吉林長(zhǎng)春 130033;3.東北師范大學(xué)生命科學(xué)學(xué)院,吉林長(zhǎng)春 130024)

為研究甾體糖苷的苷元和糖鏈結(jié)構(gòu)對(duì)其抗腫瘤活性的影響,采用噻唑藍(lán)(MTT)比色法測(cè)定了五種結(jié)構(gòu)相關(guān)的甾體糖苷薯蕷皂苷、纖細(xì)皂苷、邊緣茄堿、澳洲茄堿和查茄堿對(duì)人宮頸癌細(xì)胞(Hela細(xì)胞)、人肝癌細(xì)胞(H7402細(xì)胞)和小鼠成纖維細(xì)胞(L929細(xì)胞)增殖的影響,隨后測(cè)定了化學(xué)修飾的6-O-雙硫酸茄堿、6-O-硫酸查茄堿和全乙酰化查茄堿對(duì)人結(jié)腸癌細(xì)胞(HCT-8細(xì)胞)增殖的影響。結(jié)果發(fā)現(xiàn),以查茄三糖為糖鏈的薯蕷皂苷、邊緣茄堿和查茄堿抗增殖活性明顯高于以其它三糖為糖鏈的纖細(xì)皂苷和澳洲茄堿;甾體糖苷對(duì)人源癌細(xì)胞的抑制作用更強(qiáng);6-O-雙硫酸茄堿、6-O-硫酸查茄堿和全乙?；榍褖A無(wú)抗增殖活性。構(gòu)效關(guān)系分析表明,苷元“F”環(huán)結(jié)構(gòu)對(duì)活性有一定影響,糖鏈的單糖組成和結(jié)構(gòu)對(duì)抗腫瘤活性有顯著影響;糖鏈上的羥基在甾體糖苷的抗腫瘤活性中發(fā)揮關(guān)鍵作用。

甾體糖苷,抗腫瘤活性,化學(xué)修飾,構(gòu)效關(guān)系

甾體糖苷是存在于許多植物中的次生代謝產(chǎn)物。研究顯示,甾體糖苷具很好的抗腫瘤活性[1-2],例如邊緣茄堿能有效抑制人胸腺癌細(xì)胞(MCF-7)、人肝癌細(xì)胞(Hep3B)等多種人類(lèi)惡性腫瘤細(xì)胞生長(zhǎng)[3-6],薯蕷皂苷能顯著抑制腫瘤細(xì)胞增殖并誘導(dǎo)細(xì)胞凋亡[7-12]。進(jìn)一步研究顯示,甾體糖苷糖鏈的長(zhǎng)短以及結(jié)構(gòu)等對(duì)糖苷的活性有重要影響,例如查茄堿、茄堿和番茄堿對(duì)人結(jié)腸癌細(xì)胞(HT29)和人肝癌細(xì)胞(HepG2)具有明顯的抑制作用,而它們的水解產(chǎn)物活性明顯降低[13],邊緣茄堿和澳洲茄堿能夠抑制人結(jié)腸癌細(xì)胞(HCT-8)的增殖,它們的水解產(chǎn)物對(duì)HCT-8細(xì)胞的抑制活性顯著下降,而6-O-硫酸邊緣茄堿對(duì)HCT-8細(xì)胞無(wú)抑制活性[14]。

經(jīng)過(guò)多年研究,已經(jīng)證實(shí)甾體糖苷有很高的藥用價(jià)值和開(kāi)發(fā)潛力,但是其結(jié)構(gòu)與活性的關(guān)系研究還停留在初步階段,其抗腫瘤活性的構(gòu)效關(guān)系并不十分清楚,阻礙了甾體糖苷開(kāi)發(fā)利用。為深入探討甾體糖苷結(jié)構(gòu)與其抗腫瘤活性的關(guān)系,本文首次比較了五種結(jié)構(gòu)相關(guān)的甾體糖苷薯蕷皂苷、纖細(xì)皂苷、邊緣茄堿、澳洲茄堿和查茄堿(圖1)的抗腫瘤活性特點(diǎn),分析了構(gòu)效關(guān)系。此外,馬鈴薯糖苷生物堿查茄堿和茄堿及其-OH硫酸化和乙?；揎棶a(chǎn)物6-O-硫酸查茄堿、6-O-雙硫酸茄堿和全乙?；榍褖A(圖2)也被首次比較了抗腫瘤活性。本研究將為甾體糖苷類(lèi)抗腫瘤藥物的開(kāi)發(fā)奠定理論基礎(chǔ),并具有指導(dǎo)意義。

1　材料與方法

1.1材料與儀器

人宮頸癌上皮細(xì)胞Hela、人肝癌細(xì)胞H7402、小鼠成纖維細(xì)胞L929和人結(jié)腸癌細(xì)胞HCT-8吉林省腫瘤醫(yī)院贈(zèng)送;RPMI-1640培養(yǎng)基、小牛血清 GIBCO公司;胰蛋白酶、EDTASIGMA公司;MTT、二甲基亞砜(DMSO,生物級(jí))和HEPESAMRESCO公司;其余試劑均為國(guó)產(chǎn)分析純。

邊緣茄堿、澳洲茄堿提取自龍葵未成熟果實(shí);茄堿、查茄堿提取自馬鈴薯皮;制備方法均為0. 5 硫酸室溫浸提、硅膠柱層析分離純化、NMR鑒定,具體參見(jiàn)文獻(xiàn)[15-16];薯蕷皂苷、纖細(xì)皂苷 提取自穿龍薯蕷的干燥根莖,制備方法為70%乙醇室溫浸提、硅膠柱層析分離純化、NMR鑒定,具體參見(jiàn)文獻(xiàn)[17];6-O-硫酸查茄堿、6-O-雙硫酸茄堿 制備方法為4,4′-雙甲氧基三苯甲基氯對(duì)C-6位羥基進(jìn)行選擇性保護(hù),然后將剩余羥基進(jìn)行全乙?；Ｗo(hù),使用三氟乙酸的二氯甲烷液將C-6位伯醇羥基的保護(hù)基脫去,然后對(duì)C-6位羥基進(jìn)行定位硫酸化修飾,最后脫去乙?；Ｗo(hù)獲得產(chǎn)物,具體方法參見(jiàn)文獻(xiàn)[17-18];全乙?；榍褖A采用乙酸酐-吡啶法合成,具體方法參見(jiàn)文獻(xiàn)[17]。上述樣品以 DMSO(生物使用級(jí))為溶劑,配制儲(chǔ)備液(15 μmol/mL),保存于-4 ℃下。

MCO-15AC型二氧化碳恒溫培養(yǎng)箱SANYO公司;BCN-B60B型生物超凈工作臺(tái)北京東聯(lián)哈爾濱儀器制造有限公司;LD4-2/4000r型低速離心機(jī)北京醫(yī)用離心機(jī);MDF-U32V型超低溫冰箱SANYO公司;YOS-30B型液氮罐成都液氮容器廠;XDS-1B型倒置生物顯微鏡重慶光電儀器有限公司;YXQ-LS-30S型立式壓力蒸汽滅菌器上海博訊實(shí)業(yè)有限公司;酶標(biāo)儀BIO-RAD公司。

1.2實(shí)驗(yàn)方法

人宮頸癌上皮細(xì)胞Hela、人肝癌細(xì)胞H7402、小鼠成纖維細(xì)胞L929和人結(jié)腸癌細(xì)胞HCT-8的生長(zhǎng)抑制檢測(cè)采用MTT比色法[14,25]。取對(duì)數(shù)生長(zhǎng)期細(xì)胞以每孔100 μL細(xì)胞懸液(1×104個(gè)/孔)接種于 96 孔培養(yǎng)板,5% CO2、37 ℃孵箱培養(yǎng)24 h后,每孔加入不同濃度的藥物,每個(gè)濃度設(shè)3個(gè)平行孔,另設(shè)溶劑對(duì)照組;繼續(xù)培養(yǎng)48 h,然后甩棄孔內(nèi)液體,重新向每孔加入100 μL培養(yǎng)基與 MTT 的混合液(9∶1,MTT濃度為5 mg/mL),再培養(yǎng)4 h后棄去孔內(nèi)培養(yǎng)液,每孔加入150 μL DMSO,振蕩10 min,使結(jié)晶物充分溶解,用酶標(biāo)儀在570 nm波長(zhǎng)處測(cè)定各孔光吸收度值(A),按下式計(jì)算細(xì)胞增殖抑制率。

抑制率(%)=(1-實(shí)驗(yàn)組吸光度值/對(duì)照組吸光度值)×100

半數(shù)抑制濃度 IC50為抑制率達(dá)到50%時(shí)的藥物濃度。

1.3統(tǒng)計(jì)方法

組間比較和不同濃度條件下抑制率的比較均采用t檢驗(yàn),用軟件SPSS 16.0進(jìn)行統(tǒng)計(jì)學(xué)處理。

2　結(jié)果與討論

2.1糖苷結(jié)構(gòu)對(duì)甾體糖苷抗腫瘤活性的影響

為了解糖苷結(jié)構(gòu)對(duì)其抗腫瘤活性的影響,五種結(jié)構(gòu)相關(guān)的糖苷α-邊緣茄堿、α-澳洲茄堿、α-查茄堿、薯蕷皂苷和纖細(xì)皂苷對(duì)人宮頸癌上皮細(xì)胞(Hela細(xì)胞)、人肝癌細(xì)胞(H7402細(xì)胞)和小鼠成纖維細(xì)胞(L929細(xì)胞)增殖的影響被檢測(cè)了(表1,圖1)。結(jié)果表明,薯蕷皂苷、查茄堿和邊緣茄堿對(duì)三種腫瘤細(xì)胞均有顯著的抑制作用,其中對(duì)人源癌細(xì)胞的抑制作用更強(qiáng);薯蕷皂苷的抑制活性與查茄堿相近,略高于邊緣茄堿;澳洲茄堿和纖細(xì)皂苷對(duì)三種腫瘤細(xì)胞的抑制作用較弱。

表1　邊緣茄堿、澳洲茄堿、查茄堿、薯蕷皂苷和纖細(xì)皂苷對(duì)H7402、

圖1　邊緣茄堿、澳洲茄堿、查茄堿、薯蕷皂苷和纖細(xì)皂苷對(duì)H7402、Hela和L929細(xì)胞的抑制作用Fig.1　Inhibitory effect of solamargine,solasonine,chaconine,dioscin and gracillin on the growth of L929,H7402 and Hela cells

圖2　邊緣茄堿、澳洲茄堿、查茄堿、薯蕷皂苷和纖細(xì)皂苷的化學(xué)結(jié)構(gòu)Fig.2　Chemical structure of solamargine,solasonine,chaconine,dioscin and gracillin

邊緣茄堿和澳洲茄堿、薯蕷皂苷和纖細(xì)皂苷分別為苷元部分結(jié)構(gòu)相同,糖鏈結(jié)構(gòu)不同;邊緣茄堿、查茄堿和薯蕷皂苷的糖鏈結(jié)構(gòu)相同(均為由一個(gè)葡萄糖和二個(gè)鼠李糖組成的查茄三糖),苷元結(jié)構(gòu)不同(圖2)。以查茄三糖為糖鏈的三種甾體糖苷抗腫瘤活性明顯高于其它糖鏈的二種甾體糖苷,說(shuō)明糖鏈的單糖組成和結(jié)構(gòu)顯著影響甾體糖苷的生物活性。該結(jié)果符合甾體糖苷的膜破壞作用機(jī)制。一些甾體糖苷對(duì)腫瘤細(xì)胞的抑制作用是由于其能與生物膜上的甾醇類(lèi)物質(zhì)專(zhuān)一性結(jié)合,形成復(fù)合物,從而改變細(xì)胞膜的組織結(jié)構(gòu),最后造成膜的破裂。膜破壞作用是甾體糖苷最重要的活性作用機(jī)制[19-21]。甾體糖苷分子糖基之間的相互作用可能介導(dǎo)了糖苷-甾醇復(fù)合體在膜上的聚集[20]。一些研究證實(shí)以查茄三糖為糖鏈的糖苷對(duì)生物膜的溶解、破壞作用明顯強(qiáng)于以茄三糖為糖鏈的糖苷,并且發(fā)現(xiàn)查茄三糖糖鏈比茄三糖糖鏈能更有效的與細(xì)胞上的受體位點(diǎn)結(jié)合[20],細(xì)胞膜上可能存在與甾體糖苷的糖鏈部分特異性結(jié)合的不同受體[22]。

除了上述細(xì)胞毒作用,甾體糖苷對(duì)腫瘤細(xì)胞的生長(zhǎng)抑制作用還與其對(duì)細(xì)胞信號(hào)的調(diào)節(jié)有關(guān)。一些研究證實(shí),甾體糖苷能夠降低基質(zhì)金屬蛋白酶和端粒酶水平,通過(guò)對(duì)凋亡蛋白的調(diào)節(jié)誘導(dǎo)細(xì)胞凋亡,抑制腫瘤血管生長(zhǎng)因子的信號(hào)傳導(dǎo)途徑等[6,23-25]。研究表明,邊緣茄堿的2-位鼠李糖在其誘導(dǎo)細(xì)胞凋亡中起至關(guān)重要的作用[26],這進(jìn)一步解釋了含有查茄三糖的甾體糖苷的良好的抗腫瘤活性的作用機(jī)制。

薯蕷皂苷和邊緣茄堿的結(jié)構(gòu)極為相似,二者糖鏈部分結(jié)構(gòu)相同,苷元部分僅“F”環(huán)有差別,薯蕷皂苷為含“O”環(huán),而邊緣茄堿為含“N”環(huán),薯蕷皂苷的活性略高于邊緣茄堿,說(shuō)明苷元的“F”環(huán)結(jié)構(gòu)對(duì)活性有一定影響。

2.2糖鏈結(jié)構(gòu)對(duì)甾體糖苷抗腫瘤活性的影響

圖3　查茄堿、茄堿、6-O-硫酸查茄堿、6-O-雙硫酸茄堿和全乙酰化查茄堿的化學(xué)結(jié)構(gòu)Fig.3　Chemical structure of chaconine,solanine,6-O-sulfated chaconine,6,6′-di-O-sulfated solanine and per-O-acetyled chaconine

上述研究發(fā)現(xiàn),甾體糖苷的糖鏈組成和結(jié)構(gòu)顯著影響甾體糖苷的抗腫瘤活性。為了進(jìn)一步評(píng)估甾體糖苷的糖鏈部分對(duì)其抗腫瘤活性的影響,我們對(duì)茄堿和查茄堿糖鏈上的羥基進(jìn)行了化學(xué)修飾,制備了6-O-雙硫酸茄堿、6-O-硫酸查茄堿和全乙?；榍褖A(圖3),采用MTT比色法檢測(cè)了它們對(duì)人結(jié)腸癌細(xì)胞(HCT-8)的抗腫瘤活性(圖4)。結(jié)果表明,查茄堿和茄堿對(duì)人結(jié)腸癌細(xì)胞增殖有明顯的抑制作用,呈劑量依賴(lài)關(guān)系;以查茄三糖(由一個(gè)葡萄糖和二個(gè)鼠李糖組成)為糖鏈的查茄堿的抗腫瘤活性高于以茄三糖(由一個(gè)半乳糖、一個(gè)葡萄糖和一個(gè)鼠李糖組成)為糖鏈的茄堿,這個(gè)結(jié)果與上面的研究結(jié)果一致;二種6-O-硫酸化修飾的糖苷6-O-雙硫酸茄堿和6-O-硫酸查茄堿對(duì)人結(jié)腸癌細(xì)胞均無(wú)抑制活性,說(shuō)明糖鏈的6-OH 在甾體糖苷抗腫瘤活性中起至關(guān)重要的作用,此結(jié)果與我們以前的研究一致[14];全乙?；榍褖A對(duì)HCT-8細(xì)胞也無(wú)抑制活性。甾體糖苷糖鏈上羥基的硫酸化和乙酰化修飾可能導(dǎo)致了糖苷脂溶性下降,從而失去了與膜甾醇結(jié)合的能力和細(xì)胞信號(hào)傳導(dǎo)能力,導(dǎo)致甾體糖苷生物活性消失。

圖4　查茄堿、茄堿、6-O-雙硫酸茄堿、6-O-硫酸查茄堿和全乙?；榍褖A對(duì)HCT-8細(xì)胞的抑制作用Fig.4　Inhibitory effects of chaconine,solanine,6-O-sulfated chaconine,6,6′-di-O-sulfated solanine and per-O-acetyled chaconine on the growth of HCT-8 cells

3　結(jié)論

甾體糖苷具有良好的抗腫瘤活性,有很高的藥用價(jià)值和開(kāi)發(fā)潛力。本文通過(guò)比較結(jié)構(gòu)相關(guān)的甾體糖苷及其化學(xué)修飾物的抗腫瘤活性,發(fā)現(xiàn)以查茄三糖為糖鏈的三種甾體糖苷抗腫瘤活性明顯高于其它糖鏈的二種甾體糖苷;同樣是以查茄三糖為糖鏈的薯蕷皂苷和邊緣茄堿,苷元“F”環(huán)為含“O”環(huán)的薯蕷皂苷抗腫瘤活性略高于苷元“F”環(huán)為含“N”環(huán)的邊緣茄堿;糖鏈上羥基的硫酸化和乙?；揎検骨褖A和查茄堿失去了抗腫瘤活性。構(gòu)效分析表明,甾體糖苷苷元的結(jié)構(gòu)、糖鏈的單糖組成和結(jié)構(gòu)等對(duì)甾體糖苷的活性有重要的影響。

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Structure-antineoplastic activity relationships of steroid glycosides

ZHAO Xue-song1,LI Sheng-yu2,YANG Xu3,ZHOU Yi-fa3

(1.College of Mining Industry,Liaoning Technical University,Fuxin 123000,China;2.Institute of Agro-food Technology,Jilin Academy of Agricultural Sciences/National R&D Branch Centre for Milk Processing,Changchun 130033;3.School of Life Sciences,Northeast Normal University,Changchun 130024,China)

In order to assess the roles of the carbohydrate side chain and aglycon part of steroid glycosides in influencing antineoplastic activities of these compounds,the antiproliferative activities against human cervical carcinoma(Hela),liver cancer(H7402)and mouse fibroblast(L929)cells of a series of structurally related individual compounds including dioscin,gracillin,solamargine,solasonine and chaconine,were examined using a microculture tetrazolium(MTT)assay. And then,the antiproliferative activities against human colonic cancer(HCT-8)cells of a series of chemically modified steroid glycosides including 6-O-sulfated chaconine,6,6′-di-O-sulfated solanine and per-O-acetyled chaconine were examined using a MTT assay. The results showed that the antiproliferative activity of the chacotriose-containing steroid glycosides dioscin,chaconine and solamargine was higher significantly than other trisaccharide-containing steroid glycosides solasonine and gracillin. The effectiveness against the human carcinoma cells was greater than against the mouse fibroblast cells. 6-O-sulfated chaconine,6,6′-di-O-sulfated solanine and per-O-acetyled chaconine shown no antiproliferative activity against human HCT-8 cells. Structure-activity relationship studies indicated that the F ring structure of the aglycon unit influence biological activity;the composition,nature and the order of attachment of the sugars in the oligosaccharide associated with the steroid glycosides,were important in the antineoplastic properties;the-OH group of the sugar molecules seem to be an vital factor related to antineoplastic activity.

steroid glycosides,antineoplastic activities,chemical modification,structure-activity relationship

2015-10-12

趙雪淞(1971-)，女，博士，教授，研究方向：植物化學(xué)，E-mail：zhaoxs210@163.com。

高等學(xué)校博士學(xué)科點(diǎn)專(zhuān)項(xiàng)科研基金(20070200004)。

TS201.6

A

1002-0306(2016)11-0345-05

10.13386/j.issn1002-0306.2016.11.063