转筋草生物碱成分及抗肿瘤转移活性研究
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摘要
转筋草(Pachysandra terminalis Sieb. Zucc)为黄杨科(Buxaceae)板凳果属(Pachysandra)植物粉蕊黄杨的带根全草,是湖北省鄂西地区土家族常用民间药物,味苦,辛,性温,具有祛风湿、舒筋活血、通经止带的功效。民间常用来治风湿发热、筋骨痛、精神病狂躁不安、闭经等症。现代药理学研究表明转筋草具有细胞毒性、抑制胃酸分泌、抗溃疡和抑制胆碱酯酶等活性。转筋草中富含生物碱、甾醇、三萜等化学成分,其主要成分富贵草型甾体生物碱的研究报道较多,全草含有30种以上的孕甾烷类生物碱,除此还含有大量的三萜类和甾醇类。日本学者菊池彻于上世纪六七十年代报道了28个甾体生物碱类化合物以及9个五环三萜类化合物。
肿瘤转移是导致大多数恶性肿瘤患者死亡的原因,切断转移途径对肿瘤,尤其是晚期肿瘤的治疗至关重要。趋化运动是细胞最基本的功能之一,直接参与免疫细胞归巢、神经发育等生命活动。研究表明,趋化运动在肿瘤转移中起着关键的作用,因此,癌细胞运动调节相关蛋白可能成为治疗癌症转移的靶点。
肿瘤发生浸润和转移的过程中,均存在细胞粘附分子(cellular adhesion molecule,CAM)及其介导的粘附行为改变。目前已知的粘附分子中,整合素(integrin)是一族细胞表面分子,介导细胞-细胞间、细胞-细胞外基质间相互粘附。研究表明整合素与其相应的配体共同参与肿瘤的侵袭与转移。
蛋白激酶C(Protein Kinase C,PKC)是细胞内重要的信号传导分子。研究发现,EGF诱导的乳腺癌细胞趋化运动通过PI3K/PDK1/Akt/PKCξ信号通路,AKt2及其下游底物PKCξ在乳腺癌细胞的侵袭和转移中起着重要作用。
本文在发现转筋草乙醇提取物具有很强的抗乳腺癌细胞趋化迁移作用的基础上,系统开展了转筋草生物有效化学成分研究。以转筋草全草为研究对象,通过乙醇提取、不同溶剂萃取、酸碱法分离,得到不同极性部位及转筋草总生物碱,利用常压柱色谱、中压柱色谱、大孔吸附树脂和凝胶柱色谱色谱分离、制备高效液相色谱纯化,从转筋草的乙醇提取物中共分得30个化合物,进一步利用IR、UV、MS、1H-NMR、13C-NMR、1H-1H COSY、HMBC、HSQC、ROESY等有机波谱技术和化学方法,鉴定了各化合物的结构,其中5个为未见文献报道的新化合物,分别为3β-(dimethylamino)-pregn-20a-ol-16-one (1),3β-(dimethylamino)-pregn-16-one-5,17-diene (2),3β-(dimethylamino)-pregn-20α-ol-16-one-5-ene (3),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-11a-ol-16-ene (4),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-16-ene (5)。
本文进一步对分离鉴定的各化合物进行了抗肿瘤转移活性筛选,发现具有抗肿瘤转移活性的主要为生物碱类化合物,对乳腺癌细胞MDA-MB-231趋化运动具有明显的抑制作用,其中化合物2、6-8、11-17、19显示出很强的抑制作用；化合物5对肺腺癌细胞A549趋化运动起到明显的抑制作用。Western Blot实验结果表明,转筋草中孕甾烷生物碱化合物的抗肿瘤转移作用机制可能与抑制肿瘤细胞integrin β1、PKCξ蛋白磷酸化有关。
Pachysandra terminalis Sieb. Zucc, the whole plant of Pachysandra terminalis (Buxaceae), is widely distributed in the southwest and northwest of the People's Republic of China, as a Tujia traditional medicine against pain and stomach problems. Pachysandra terminalis also has the properties of reducing tussis, expelling wind and removing cold, promoting blood circulation to arrest pain. Mordern pharmacology research suggests Pachysandra terminalis has the activities of cytotoxic, anti-ulcer and exhibiting anticholinesterase activity.
Phytochemical investigations of this species revealed the presence of several steroidal alkaloids as well as triterpenes and sterols. In recent years, a large number of steroidal alkaloids have been isolated from Pachysandra axillaries, Pachysandra procumbens, and species of the genus Sarcococca.
Metastasis accounts for the majority of patients'deaths due to cancer, and thus cut off the metastatic process is of critical importance for cancer treatment, especially in late stage. Chemotaxis is one of the basic functions of cells, and directly participates in vital activities of immunological cell homing, neural development and so on. The latest researches show that chemotaxis plays critical role in cancer matastasis, and the main contribution to cancer metastasis arises from the failure of restriction in cancer cell migration. So, cell migration mediation-associated proteins are to be target of cancer metastasis treatment.
Integrins are a family of heterodimers comprised of a and β subunits. Integrin (31combines with the a subunits to form12different integrin receptors, which bind extracellular matrix (ECM) molecules such as collagen and fibronectin. A large number of reports have shown that integrin β1is closely involved with cancer cell adhesion and metastasis.
the protein kinase C (PKC) family, consisting of12serine/threonine kinases, can be divided into three subfamilies based on their activation mechanism. PKC plays pleiotropic roles in cell polarity, migration, and adhesion, and PKC ξ has been indicated to play an important role in determining cell polarity. Studies using isozyme-specific inhibitors suggest that PKC ξ is also involved in chemokine-triggered cell adhesion and actin assembly in polymorphonuclear cells, presumably mediated by G protein.
The occurrence of steroidal alkaloids in Pachysandra is well documented, but little phytochemical work has been carried out on Pachysandra terminalis. In order to search the bioactive constituents from natural source, we began to study the chemical consitituents from Pachysandra terminalis. By repeated column chromatography, including Silica gel, Toyopearl HW-40and preparative HPLC,30compounds were isolated from extracts of Pachysandra terminalis. By using IR, MS,1H-NMR,13C-NMR,1H COSY, HMBC, HSQC, ROESY spectra and chemical methods, five new alkaloids,3β-(dimethylamino)-pregn-20a-ol-16-one (1),30-(dimethylamino)-pregn-16-one-5,17-diene (2),3β-(dimethylamino)-pregn-20a-ol-16-one-5-ene (3),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-11α-ol-16-ene (4),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-16-ene (5); along with25known compounds were identified.
In the anti-tumor metastasis screening experiment of these compounds, alkaloids played a role in anti-tumor metastasis with both MDA-MB-231and A549cell lines. alkaloid compounds2,5,6-8,11-17, and19revealed significant anti-tumor metastasis activity, while they didn't reveal cytotoxic acticity at that concentration. Western Blot analysis suggest that integrin β1and PKCξ may be key molecules in the signal transduction pathway targeted by these alkaloid compounds.
肿瘤转移是导致大多数恶性肿瘤患者死亡的原因,切断转移途径对肿瘤,尤其是晚期肿瘤的治疗至关重要。趋化运动是细胞最基本的功能之一,直接参与免疫细胞归巢、神经发育等生命活动。研究表明,趋化运动在肿瘤转移中起着关键的作用,因此,癌细胞运动调节相关蛋白可能成为治疗癌症转移的靶点。
肿瘤发生浸润和转移的过程中,均存在细胞粘附分子(cellular adhesion molecule,CAM)及其介导的粘附行为改变。目前已知的粘附分子中,整合素(integrin)是一族细胞表面分子,介导细胞-细胞间、细胞-细胞外基质间相互粘附。研究表明整合素与其相应的配体共同参与肿瘤的侵袭与转移。
蛋白激酶C(Protein Kinase C,PKC)是细胞内重要的信号传导分子。研究发现,EGF诱导的乳腺癌细胞趋化运动通过PI3K/PDK1/Akt/PKCξ信号通路,AKt2及其下游底物PKCξ在乳腺癌细胞的侵袭和转移中起着重要作用。
本文在发现转筋草乙醇提取物具有很强的抗乳腺癌细胞趋化迁移作用的基础上,系统开展了转筋草生物有效化学成分研究。以转筋草全草为研究对象,通过乙醇提取、不同溶剂萃取、酸碱法分离,得到不同极性部位及转筋草总生物碱,利用常压柱色谱、中压柱色谱、大孔吸附树脂和凝胶柱色谱色谱分离、制备高效液相色谱纯化,从转筋草的乙醇提取物中共分得30个化合物,进一步利用IR、UV、MS、1H-NMR、13C-NMR、1H-1H COSY、HMBC、HSQC、ROESY等有机波谱技术和化学方法,鉴定了各化合物的结构,其中5个为未见文献报道的新化合物,分别为3β-(dimethylamino)-pregn-20a-ol-16-one (1),3β-(dimethylamino)-pregn-16-one-5,17-diene (2),3β-(dimethylamino)-pregn-20α-ol-16-one-5-ene (3),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-11a-ol-16-ene (4),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-16-ene (5)。
本文进一步对分离鉴定的各化合物进行了抗肿瘤转移活性筛选,发现具有抗肿瘤转移活性的主要为生物碱类化合物,对乳腺癌细胞MDA-MB-231趋化运动具有明显的抑制作用,其中化合物2、6-8、11-17、19显示出很强的抑制作用；化合物5对肺腺癌细胞A549趋化运动起到明显的抑制作用。Western Blot实验结果表明,转筋草中孕甾烷生物碱化合物的抗肿瘤转移作用机制可能与抑制肿瘤细胞integrin β1、PKCξ蛋白磷酸化有关。
Pachysandra terminalis Sieb. Zucc, the whole plant of Pachysandra terminalis (Buxaceae), is widely distributed in the southwest and northwest of the People's Republic of China, as a Tujia traditional medicine against pain and stomach problems. Pachysandra terminalis also has the properties of reducing tussis, expelling wind and removing cold, promoting blood circulation to arrest pain. Mordern pharmacology research suggests Pachysandra terminalis has the activities of cytotoxic, anti-ulcer and exhibiting anticholinesterase activity.
Phytochemical investigations of this species revealed the presence of several steroidal alkaloids as well as triterpenes and sterols. In recent years, a large number of steroidal alkaloids have been isolated from Pachysandra axillaries, Pachysandra procumbens, and species of the genus Sarcococca.
Metastasis accounts for the majority of patients'deaths due to cancer, and thus cut off the metastatic process is of critical importance for cancer treatment, especially in late stage. Chemotaxis is one of the basic functions of cells, and directly participates in vital activities of immunological cell homing, neural development and so on. The latest researches show that chemotaxis plays critical role in cancer matastasis, and the main contribution to cancer metastasis arises from the failure of restriction in cancer cell migration. So, cell migration mediation-associated proteins are to be target of cancer metastasis treatment.
Integrins are a family of heterodimers comprised of a and β subunits. Integrin (31combines with the a subunits to form12different integrin receptors, which bind extracellular matrix (ECM) molecules such as collagen and fibronectin. A large number of reports have shown that integrin β1is closely involved with cancer cell adhesion and metastasis.
the protein kinase C (PKC) family, consisting of12serine/threonine kinases, can be divided into three subfamilies based on their activation mechanism. PKC plays pleiotropic roles in cell polarity, migration, and adhesion, and PKC ξ has been indicated to play an important role in determining cell polarity. Studies using isozyme-specific inhibitors suggest that PKC ξ is also involved in chemokine-triggered cell adhesion and actin assembly in polymorphonuclear cells, presumably mediated by G protein.
The occurrence of steroidal alkaloids in Pachysandra is well documented, but little phytochemical work has been carried out on Pachysandra terminalis. In order to search the bioactive constituents from natural source, we began to study the chemical consitituents from Pachysandra terminalis. By repeated column chromatography, including Silica gel, Toyopearl HW-40and preparative HPLC,30compounds were isolated from extracts of Pachysandra terminalis. By using IR, MS,1H-NMR,13C-NMR,1H COSY, HMBC, HSQC, ROESY spectra and chemical methods, five new alkaloids,3β-(dimethylamino)-pregn-20a-ol-16-one (1),30-(dimethylamino)-pregn-16-one-5,17-diene (2),3β-(dimethylamino)-pregn-20a-ol-16-one-5-ene (3),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-11α-ol-16-ene (4),20β-(dimethylamino)-3β-(senecioylamino)-5a-pregn-16-ene (5); along with25known compounds were identified.
In the anti-tumor metastasis screening experiment of these compounds, alkaloids played a role in anti-tumor metastasis with both MDA-MB-231and A549cell lines. alkaloid compounds2,5,6-8,11-17, and19revealed significant anti-tumor metastasis activity, while they didn't reveal cytotoxic acticity at that concentration. Western Blot analysis suggest that integrin β1and PKCξ may be key molecules in the signal transduction pathway targeted by these alkaloid compounds.
引文
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