五种苔类植物的化学成分及其抗肿瘤活性研究
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摘要
苔藓植物在植物进化过程中介于藻类植物与蕨类植物之间,是一类代表着从水生到陆生过渡的高等植物类群,从形态学上可以分为苔纲、藓纲和角苔纲。在民间,苔藓植物被广泛用于治疗外伤、烧伤、炎症、肺结核、肝脏疾病、惊厥和水肿等症。大部分苔藓植物均不被各种昆虫或其他动物所采食,也不会被真菌、细菌或病毒所感染。近年来,国内外对苔类植物研究较多,已从中分离获得了大量结构新颖的萜类和芳香类化合物,其中许多具有良好的生物活性。
本文对中国的五种苔类植物,包括采自广西的圆叶异萼苔、齿边广萼苔、延叶叶苔、透明叶苔和采自贵州的双齿异萼苔的化学成分进行了系统研究,采用MCI柱层析、硅胶柱层析、Sephadex LH-20柱层析、C1s反相硅胶柱层析以及HPLC等分离手段共分离了78个次级代谢产物。通过核磁共振、质谱、圆二色谱和X射线单晶衍射等方法确定了化合物的结构,包括60个二萜、4个三萜、6个甾体以及8个其他类化合物,其中新化合物41个。本文对圆叶异萼苔和延叶叶苔的成分研究尚属首次。
从圆叶异萼苔Heteroscyphus tener)中分离并鉴定了8个化合物,包括5个ent-半日花烷型(1-5)和3个壳梭孢烷型(6-8)二萜,其中1-4为新化合物。测定了化合物1-8对9种细胞株(PC3, DU145, K562, A549, NCI-H292, NCI-H1299, NCI-H446, HBE, RWPE1)的细胞毒性,结果显示化合物3和5有中等偏弱的活性。对化合物5在前列腺癌PC3和DU145细胞株中的细胞毒机制进行了进一步的研究,发现其通过诱导细胞内ROS水平的升高,引起DNA氧化损伤,进而诱导细胞周期阻滞在G0/G1期,从而诱发细胞凋亡。
从双齿异萼苔(H. coalitus)中分离并鉴定了16个化合物,骨架类型比较多,包括1个具有新颖骨架的香豆素类衍生物(9)、1个视黄烷型二萜(10)以及1个单萜查尔酮衍生物(11)等,其中10为首次从苔藓植物中分得的视黄烷型二萜类化合物。测定了化合物9-12对3株肿瘤细胞(PC3,DU145,HepG-2)的细胞毒活性,它们均表现出中等偏弱的活性。从化学分类学角度对异萼苔属植物进行了分析,发现所研究的这两种同属植物在化学上完全不同,而圆叶异萼苔有可能属于毛耳苔亚目。
从齿边广萼苔(Chandonanthus hirtellus)中分离并鉴定了7个西松烷型二萜(25-31)、1个壳梭孢烷型二萜(6)以及3个简单芳香化合物(32-34),其中25-29为新化合物。筛选了化合物25-31对6种肿瘤细胞株(PC3, A549, NCI-H292, NCI-H1299, A172, PC12)的细胞毒性,它们大都表现出较弱的活性。我们得到的西松烷型二萜可以作为该属植物的化学标记物。
从延叶叶苔(Jungermannia fauriana)中分离并鉴定了24个对映-贝壳杉烷型二萜化合物(35-58),其中35-54为新化合物。从透明叶苔(J. hyalina)中得到了23个相同骨架的化合物(56-78),其中59-70为新化合物。化学分类学分析表明这两种植物都富含对映-贝壳杉烷二萜化合物,这类化合物在叶苔属中较为常见,可以作为化学标记物。含有相同的3个化合物说明这两种植物可能有着一定的亲缘关系。另外,以甜菊苷为原料合成了3个相同类型的化合物80-82。系统筛选了所得化合物对24株人类细胞的细胞毒活性。发现该类化合物毒性比较大,对细胞种类的选择性差。系统的构效关系分析表明α,β不饱和酮的结构是活性的必需基团,18或19位的甲基羟基化后会降低活性,羧基化使活性进一步降低,但是羧基成酯或成酰胺会使活性大大增强。通过一种巯基荧光探针染色发现该类化合物进入细胞后显著降低了荧光强度,且没有明显的分布特点,这可能是其作用选择性差和毒性大的主要原因。化合物82具有碱性基团,对其作用的细胞巯基探针的荧光定量发现它进入细胞后只是部分降低了荧光强度。通过对溶酶体的染色发现,82作用于溶酶体,2h后就可以引起溶酶体明显的肿胀。这说明碱性基团修饰可能会使其选择性分布于溶酶体,从而改变了该类化合物在细胞内的分布和作用方式。
对化合物的作用机制研究中,发现化合物81可以引起ROS升高,还原剂NAC可以同时逆转ROS升高和细胞毒,但是VC为还原剂时虽能逆转升高的ROS,但是不能逆转细胞死亡。通过HPLC-MS/MS的方法研究发现,当将化合物81加入到含有NAC的培养基中后几乎检测不到化合物原型的存在,但却同时检测到了加成产物81-NAC。这说明NAC之所以会逆转细胞毒是因为与化合物发生反应,使之失去药效集团。所以很多学者在研究该类化合物时用NAC作为还原剂来证明ROS的作用是不准确的,ROS也可能不是引起细胞死亡的主要因素。
本论文对中国的五种苔类植物的系统化学成分研究得到了41个新结构化合物。抗肿瘤活性筛选发现了具有中等活性的半日花烷型二萜,并且报道了其中的化合物5通过ROS途径引起细胞周期G0/G1阻滞和凋亡,以及一批具有较好活性的对映-贝壳杉烷型二萜,并总结了其构效关系。首次采用一种小分子荧光探针来检测化合物在细胞内的分布,并针对分布特点特异性改造了化合物结构。首次采用液质联用方法证明了还原剂NAC与对映-贝壳杉烷型二萜类化合物发生反应而使其毒性消失。根据系统的化学成分研究总结了所研究植物的化学分类学规律。
The bryophytes are taxonomically placed between the algae and the pteridophytes. Morphologically, they are divided into three classes, liverworts, mosses, and hornworts. The bryophytes have been used as medicinal plants to cure cuts, burns, scalds, pneumonia, pulmonary tuberculosis, neurasthenia, convulsions, edema, and so on. Generally, almost all species of bryophytes are not attacked by insects, snails, and mammals, nor infected by bacteria, fungi, and viruses. In recent years, studies on bryophytes have revealed various diterpenoids and aromatic compounds with interesting chemical structures, many of which show significant biological activity.
In this research, five Chinese liverworts, Heteroscyphus tener, Chandonanthus hirtellus, Jungermannia fauriana, and J. hyalina collected from Guangxi Zhuang Autonomous Region, and H. coalitus collected from Guizhou Province were phytochemically investigated. A total of78secondary metabolites,41of which were new compounds, including60diterpenoids, four triterpenoids, and six sterides, were obtained following separation and purification by column chromatography (CC) on silica gel, MCI, reversed-phase C18silica gel, and Sephadex LH-20, as well as by HPLC. Their structures were elucidated on the basis of NMR, MS, CD, and X-ray. This work represents the first phytochemical study on H. tener and J. fauriana.
Five ent-labdane diterpenoids (1-5), four of which were new ones (1-4), and three known fusicoccane-type diterpenoids (6-8) were isolated from the Chinese liverwort Heteroscyphus tener. The absolute configuration of compound1was defined by single-crystal X-ray diffraction using Cu Ka radiation. Cytotoxicity tests of compounds1-8revealed that compounds3and5exhibited weak activity against nine cell lines (PC3, DU145, K562, A549, NCI-H292, NCI-H1299, NCI-H446, HBE, and RWPE1). Further research found that the apoptotic effect of compound5was induced through ROS-mediated DNA damage and cell cycle arrest at the G0/G1phase in both DU145and PC3cells.
From the ether extract of the liverwort H. coalitu, sixteen compounds, including a new dihydroisocoumarin derivative, R-(-)-heteroscyphide (9) and a known retinane-type diterpenoid (10), which was the first one isolated from bryophytes. Cytotoxic test found that they exhibited moderate inhibitory activity to three human tumor cell lines (PC3, DU145, and HepG-2). Chemotaxonomy analysis of Heteroscyphus species found that H. tener and H. coalitus were different chemically, and the liverwort H. tener more like belongs to the suborder Jubulineae.
Seven cembrane-type diterpenoids (25-31), five of which were new ones (25-29), a known fusicoccane-type diterpenoid (6), and three aromatic compounds (32-34) were obtained from the liverwort Chandonanthus hirtellus. All isolated compounds were tested for their cytotoxic activities against six tumor cell lines (PC3, A549, NCI-H292, NCI-H1299, A172, and PC12). Unfortunately, they all exhibited week activity. Cembrane-type diterpenoid could be the chemical marker of the genus Chandonanthus.
Twenty-four ent-kaurane diterpenoids (35-58), twenty of which were new (35-54), were isolated from the liverwort Jungermannia fauriana, while twenty-three ent-kaurane diterpenoids (56-78), of which compounds59-70were new, were obtained from J. hyalina. Chemotaxonomy analysis found that these two plants were rich in ent-kaurane diterpenoids, which could be used as the chemical marker of the genus Jungermannia. Containing three same compounds demonstrated they may have a certain kinship. Three ent-kaurane derivatives (80-82) were prepared from stevioside. All of the compounds were tested for their cytotoxic activities against twenty-four human cell lines, suggesting that these compounds have relatively potent toxicity and poor selectivity of cell types. We performed a systematic structure-activity relationship analysis and found that the a,(3-unsaturated carbonyl function is a structural requirement for cytotoxicity in these compounds. The mercapto group was detected by a fluorescent probe. The fluorescence intensity of PC3cells treated with these compounds was significantly reduced, which indicated that these compounds were widely distributed in the cells. However, compound82with a basic group, only partially reduced the intensity of the fluorescence. The lysosomal staining found that82could act on lysosomes, which were observed to be swelled after2h. The basic group modified compound may selectively locate in lysosomes. This modification changed the cell distribution and mode of action of this kind compound.
To investigate whether ROS are involved in apoptosis, we measured cellular changes in the ROS levels using a ROS-sensitive fluorometric probe, DCFH-DA. Our results found that compound81could elevate the ROS levels of treated cells. NAC, a ROS scavenger, blocked the cell death induced by81. However, another antioxidant VC could not reverse the cytotoxicity, although could reverse the rise of ROS. By HPLC-MS/MS method, we found that when compound81was added to the medium containing NAC, the prototype compound was hardly detected, but the detection of the addition product81-NAC. These results showed that the reason for the reversal of cytotoxic of NAC was not scavenging ROS, but reacting with compounds, so that loss of efficacy group. Therefore, it is not accurate that many scholars use NAC as a reducing agent to prove the role of ROS. ROS are probably not the major factor causing cell death.
In this manuscript, phytochemical investigation of five Chinese liverworts led to41new compounds. Cytotoxic test found a group of ent-labdane diterpenoids, of which compound5induced cell cycle arrest at G0/G1and apoptosis through ROS pathway, and ent-kaurane ones, the structure-activity relationships of which were summarized. It is the first report to use a small molecule fluorescent probe to detect the intracellular distribution of these compounds. By HPLC-MS/MS method we proved that the reason for the reversal of cytotoxic of NAC was not scavenging ROS, but reacting with ent-kaurane diterpenoids. Chemotaxonomy analysis of these plants was performed according to the chemical research.
本文对中国的五种苔类植物,包括采自广西的圆叶异萼苔、齿边广萼苔、延叶叶苔、透明叶苔和采自贵州的双齿异萼苔的化学成分进行了系统研究,采用MCI柱层析、硅胶柱层析、Sephadex LH-20柱层析、C1s反相硅胶柱层析以及HPLC等分离手段共分离了78个次级代谢产物。通过核磁共振、质谱、圆二色谱和X射线单晶衍射等方法确定了化合物的结构,包括60个二萜、4个三萜、6个甾体以及8个其他类化合物,其中新化合物41个。本文对圆叶异萼苔和延叶叶苔的成分研究尚属首次。
从圆叶异萼苔Heteroscyphus tener)中分离并鉴定了8个化合物,包括5个ent-半日花烷型(1-5)和3个壳梭孢烷型(6-8)二萜,其中1-4为新化合物。测定了化合物1-8对9种细胞株(PC3, DU145, K562, A549, NCI-H292, NCI-H1299, NCI-H446, HBE, RWPE1)的细胞毒性,结果显示化合物3和5有中等偏弱的活性。对化合物5在前列腺癌PC3和DU145细胞株中的细胞毒机制进行了进一步的研究,发现其通过诱导细胞内ROS水平的升高,引起DNA氧化损伤,进而诱导细胞周期阻滞在G0/G1期,从而诱发细胞凋亡。
从双齿异萼苔(H. coalitus)中分离并鉴定了16个化合物,骨架类型比较多,包括1个具有新颖骨架的香豆素类衍生物(9)、1个视黄烷型二萜(10)以及1个单萜查尔酮衍生物(11)等,其中10为首次从苔藓植物中分得的视黄烷型二萜类化合物。测定了化合物9-12对3株肿瘤细胞(PC3,DU145,HepG-2)的细胞毒活性,它们均表现出中等偏弱的活性。从化学分类学角度对异萼苔属植物进行了分析,发现所研究的这两种同属植物在化学上完全不同,而圆叶异萼苔有可能属于毛耳苔亚目。
从齿边广萼苔(Chandonanthus hirtellus)中分离并鉴定了7个西松烷型二萜(25-31)、1个壳梭孢烷型二萜(6)以及3个简单芳香化合物(32-34),其中25-29为新化合物。筛选了化合物25-31对6种肿瘤细胞株(PC3, A549, NCI-H292, NCI-H1299, A172, PC12)的细胞毒性,它们大都表现出较弱的活性。我们得到的西松烷型二萜可以作为该属植物的化学标记物。
从延叶叶苔(Jungermannia fauriana)中分离并鉴定了24个对映-贝壳杉烷型二萜化合物(35-58),其中35-54为新化合物。从透明叶苔(J. hyalina)中得到了23个相同骨架的化合物(56-78),其中59-70为新化合物。化学分类学分析表明这两种植物都富含对映-贝壳杉烷二萜化合物,这类化合物在叶苔属中较为常见,可以作为化学标记物。含有相同的3个化合物说明这两种植物可能有着一定的亲缘关系。另外,以甜菊苷为原料合成了3个相同类型的化合物80-82。系统筛选了所得化合物对24株人类细胞的细胞毒活性。发现该类化合物毒性比较大,对细胞种类的选择性差。系统的构效关系分析表明α,β不饱和酮的结构是活性的必需基团,18或19位的甲基羟基化后会降低活性,羧基化使活性进一步降低,但是羧基成酯或成酰胺会使活性大大增强。通过一种巯基荧光探针染色发现该类化合物进入细胞后显著降低了荧光强度,且没有明显的分布特点,这可能是其作用选择性差和毒性大的主要原因。化合物82具有碱性基团,对其作用的细胞巯基探针的荧光定量发现它进入细胞后只是部分降低了荧光强度。通过对溶酶体的染色发现,82作用于溶酶体,2h后就可以引起溶酶体明显的肿胀。这说明碱性基团修饰可能会使其选择性分布于溶酶体,从而改变了该类化合物在细胞内的分布和作用方式。
对化合物的作用机制研究中,发现化合物81可以引起ROS升高,还原剂NAC可以同时逆转ROS升高和细胞毒,但是VC为还原剂时虽能逆转升高的ROS,但是不能逆转细胞死亡。通过HPLC-MS/MS的方法研究发现,当将化合物81加入到含有NAC的培养基中后几乎检测不到化合物原型的存在,但却同时检测到了加成产物81-NAC。这说明NAC之所以会逆转细胞毒是因为与化合物发生反应,使之失去药效集团。所以很多学者在研究该类化合物时用NAC作为还原剂来证明ROS的作用是不准确的,ROS也可能不是引起细胞死亡的主要因素。
本论文对中国的五种苔类植物的系统化学成分研究得到了41个新结构化合物。抗肿瘤活性筛选发现了具有中等活性的半日花烷型二萜,并且报道了其中的化合物5通过ROS途径引起细胞周期G0/G1阻滞和凋亡,以及一批具有较好活性的对映-贝壳杉烷型二萜,并总结了其构效关系。首次采用一种小分子荧光探针来检测化合物在细胞内的分布,并针对分布特点特异性改造了化合物结构。首次采用液质联用方法证明了还原剂NAC与对映-贝壳杉烷型二萜类化合物发生反应而使其毒性消失。根据系统的化学成分研究总结了所研究植物的化学分类学规律。
The bryophytes are taxonomically placed between the algae and the pteridophytes. Morphologically, they are divided into three classes, liverworts, mosses, and hornworts. The bryophytes have been used as medicinal plants to cure cuts, burns, scalds, pneumonia, pulmonary tuberculosis, neurasthenia, convulsions, edema, and so on. Generally, almost all species of bryophytes are not attacked by insects, snails, and mammals, nor infected by bacteria, fungi, and viruses. In recent years, studies on bryophytes have revealed various diterpenoids and aromatic compounds with interesting chemical structures, many of which show significant biological activity.
In this research, five Chinese liverworts, Heteroscyphus tener, Chandonanthus hirtellus, Jungermannia fauriana, and J. hyalina collected from Guangxi Zhuang Autonomous Region, and H. coalitus collected from Guizhou Province were phytochemically investigated. A total of78secondary metabolites,41of which were new compounds, including60diterpenoids, four triterpenoids, and six sterides, were obtained following separation and purification by column chromatography (CC) on silica gel, MCI, reversed-phase C18silica gel, and Sephadex LH-20, as well as by HPLC. Their structures were elucidated on the basis of NMR, MS, CD, and X-ray. This work represents the first phytochemical study on H. tener and J. fauriana.
Five ent-labdane diterpenoids (1-5), four of which were new ones (1-4), and three known fusicoccane-type diterpenoids (6-8) were isolated from the Chinese liverwort Heteroscyphus tener. The absolute configuration of compound1was defined by single-crystal X-ray diffraction using Cu Ka radiation. Cytotoxicity tests of compounds1-8revealed that compounds3and5exhibited weak activity against nine cell lines (PC3, DU145, K562, A549, NCI-H292, NCI-H1299, NCI-H446, HBE, and RWPE1). Further research found that the apoptotic effect of compound5was induced through ROS-mediated DNA damage and cell cycle arrest at the G0/G1phase in both DU145and PC3cells.
From the ether extract of the liverwort H. coalitu, sixteen compounds, including a new dihydroisocoumarin derivative, R-(-)-heteroscyphide (9) and a known retinane-type diterpenoid (10), which was the first one isolated from bryophytes. Cytotoxic test found that they exhibited moderate inhibitory activity to three human tumor cell lines (PC3, DU145, and HepG-2). Chemotaxonomy analysis of Heteroscyphus species found that H. tener and H. coalitus were different chemically, and the liverwort H. tener more like belongs to the suborder Jubulineae.
Seven cembrane-type diterpenoids (25-31), five of which were new ones (25-29), a known fusicoccane-type diterpenoid (6), and three aromatic compounds (32-34) were obtained from the liverwort Chandonanthus hirtellus. All isolated compounds were tested for their cytotoxic activities against six tumor cell lines (PC3, A549, NCI-H292, NCI-H1299, A172, and PC12). Unfortunately, they all exhibited week activity. Cembrane-type diterpenoid could be the chemical marker of the genus Chandonanthus.
Twenty-four ent-kaurane diterpenoids (35-58), twenty of which were new (35-54), were isolated from the liverwort Jungermannia fauriana, while twenty-three ent-kaurane diterpenoids (56-78), of which compounds59-70were new, were obtained from J. hyalina. Chemotaxonomy analysis found that these two plants were rich in ent-kaurane diterpenoids, which could be used as the chemical marker of the genus Jungermannia. Containing three same compounds demonstrated they may have a certain kinship. Three ent-kaurane derivatives (80-82) were prepared from stevioside. All of the compounds were tested for their cytotoxic activities against twenty-four human cell lines, suggesting that these compounds have relatively potent toxicity and poor selectivity of cell types. We performed a systematic structure-activity relationship analysis and found that the a,(3-unsaturated carbonyl function is a structural requirement for cytotoxicity in these compounds. The mercapto group was detected by a fluorescent probe. The fluorescence intensity of PC3cells treated with these compounds was significantly reduced, which indicated that these compounds were widely distributed in the cells. However, compound82with a basic group, only partially reduced the intensity of the fluorescence. The lysosomal staining found that82could act on lysosomes, which were observed to be swelled after2h. The basic group modified compound may selectively locate in lysosomes. This modification changed the cell distribution and mode of action of this kind compound.
To investigate whether ROS are involved in apoptosis, we measured cellular changes in the ROS levels using a ROS-sensitive fluorometric probe, DCFH-DA. Our results found that compound81could elevate the ROS levels of treated cells. NAC, a ROS scavenger, blocked the cell death induced by81. However, another antioxidant VC could not reverse the cytotoxicity, although could reverse the rise of ROS. By HPLC-MS/MS method, we found that when compound81was added to the medium containing NAC, the prototype compound was hardly detected, but the detection of the addition product81-NAC. These results showed that the reason for the reversal of cytotoxic of NAC was not scavenging ROS, but reacting with compounds, so that loss of efficacy group. Therefore, it is not accurate that many scholars use NAC as a reducing agent to prove the role of ROS. ROS are probably not the major factor causing cell death.
In this manuscript, phytochemical investigation of five Chinese liverworts led to41new compounds. Cytotoxic test found a group of ent-labdane diterpenoids, of which compound5induced cell cycle arrest at G0/G1and apoptosis through ROS pathway, and ent-kaurane ones, the structure-activity relationships of which were summarized. It is the first report to use a small molecule fluorescent probe to detect the intracellular distribution of these compounds. By HPLC-MS/MS method we proved that the reason for the reversal of cytotoxic of NAC was not scavenging ROS, but reacting with ent-kaurane diterpenoids. Chemotaxonomy analysis of these plants was performed according to the chemical research.
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