灰海参生物活性成分研究
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摘要
灰海参(Holothuria grisea Selenka),为棘皮动物门(Echinodermata)海参纲(Holothuroidea)海参科(Holothuriidae)海参属(Holothuria)的海洋动物。广泛分布在佛罗里达南部经巴哈马至巴西的广大海域,可供食用。日本学者曾于八十年代初对此种海参进行过初步研究,仅从中分离得到两个海参皂苷,holothurin A和holothurinA_1,为深入研究该种海参的的化学成分和药理活性,我们对其进行了进一步的研究。本研究以稻瘟霉模型作为活性监测手段,应用正相硅胶、反相硅胶、葡聚糖凝胶以及高效液相色谱等多种色谱分离技术,对灰海参活性成分进行了系统的分离纯化和生物活性研究,共分离得到12个单体化合物,应用现代波谱技术和化学手段鉴定了其中8个化合物的结构,均为海参皂苷类化合物,其中新化合物2个,另外有4个化合物为首次从该海参中分离获得。其余的4个化合物的化学结构正在鉴定中。
所确定的8个化合物的化学结构是通过~1HNMR、~(13)CNMR和二维核磁共振技术(DQCOSY、TOCSY、HMQC、HMBC和NOESY等)及电喷雾离子质谱并结合化学方法(水解,化学鉴别)确定的。这8个化合物的化学结构如下:HG-1:3β-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)→β-D-吡喃木糖-(4→1)-β-D-吡喃葡萄糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α-二醇(命名为griseaside A);HG-2:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸钠-β-D-吡喃木糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α,17α-三醇(holothurin A);HG-3:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸钠-β-D-吡喃木糖]-海参烷-9(11)-烯-22-羟基-3β,12α,17α-三醇(holothurin A_1);HG-4:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸钠-β-D-吡喃木糖]-海参烷-9(11)-烯-3β,12α,17α-三醇(echinoside A);HG-5:3β-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-β-D-吡喃木糖-(4→1)-β-D-吡喃葡萄糖]-海参烷-9(11)-烯-22-羟基-3β,12α-二醇(命名为griseaside B);HG-6:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸基-β-D-吡喃木糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α,17α-三醇(arenicolaside A);HG-7:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)4-O-硫酸钠-β-D-吡喃木糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α-二醇(fuscoineroside C);HG-8:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-β-D-吡喃木糖-(4→1)-β-D-吡喃葡萄糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α,17α-三醇(holothurinoside A),其中HG-1和HG-5为新化合物。
初步的药理活性筛选表明,海参皂苷HG-1～HG-8对稻瘟霉显示显著的生物活性;对BEL-7402人肝癌细胞、HL-60人白血病细胞、A-549人肺癌细胞和Molt-4人白血病细胞具有较强的细胞毒活性,除HG-5活性相对较弱外,其余7个化合物对四种肿瘤细胞株的抑制率均在10~(-5)-10~(-8)mol/L之间;HG-1～HG-8对白色念珠菌、新生隐球菌、克柔式念珠菌、光滑念珠菌和近平滑念珠菌均具有不同强度的抑制生长作用,其中化合物HG-1对白色念珠菌和新生隐球菌的MIC_(80)值均达到4.0μg/ml。
本课题对灰海参体内的化学成分特别是皂苷类成分进行了系统的分离,得到2个新的海参皂苷和6个已知海参皂苷,并对其药理活性进行了初步研究。研究结果为进一步研制开发新的抗肿瘤和抗真菌药物提供了一定的科学依据和有价值的先导化合物,同时也为海洋天然产物的研究积累了新的资料,本课题的研究对开发利用丰富的海参生物资源具有较重要的意义。
The sea cucumber Holothuria grisea Selenka abundantly distributed in the sea from South Florida through the Bahamas to Brazil.Two compounds holothurin A and holothurin A_1 have been isolated by Japanese scientists from this animal while the chemical constitutents and their pharmacological activitities of this sea cucumber still need to be further investegated.Guided by Pyricularia oryzae bioassay model,we isolated 12 compounds from Holothuria grisea Selenka using various chromatography methods including LPLC, MPLC,HPLC on silica gel,ODS RP C_(18) and Zorbax SBC_(18).
The structure of 8 compounds were elucidated by chemical and spectral analysis(IR, EI-MS,ESI-MS,HRESI-MS,~1HNMR,~(13)CNMR,~1H-~1H COSY,DQCOSY,TOCSY, HMQC,HMBC,NOESY,etc.),their chemical structures were:HG-1:3β-O-[β-D-3-O-methylglucopyranosyl (1→3)-β-D-glucopyranosyl(1→4)-β-D-quinovopyranosyl(1→2)-β-D-xylopyranosyl (4→1)-β-D-glucopyranosyl]-22,25-epoxy-holost-9-(11)-ene-3β,12α-diol(nam ed griseasideA);HG-2:3-O-[3-O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl -(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sodiumsulfate-β-D-xylopyranosyl]-22,25-epox y-holosta-9(11)-ene-3β,12α,17α-triol(holothurinA);HG-3:3-O-[3-O-methyl-β-D-glucopyranosyl -(1→3)-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sod iumsulfate-β-D-xylopyranosyl]-holosta-22-hydroxyholost-9(11)-ene-3β,12α,17α-triol(holo thurinA_1);HG-4:3- O-[3- O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl -(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sodiumsulfate-β-D-xylopyranosyl]-holosta-9(1 1)-ene-3β,12α,17α-triol(echinosideA);HG-5:3β-O-[β-D-3-O-methylglucopy-ranosyl (1→3)-β-D-glucopyranssyl(1→4)-β-D-quinovopyranosyl(1→2)-β-D-xylopyranosyl(4→1)-β-D-glucopyranosyl]-holosta-22-hydroxyholost-9(11)-ene-3β,12α-diol(named griseasideB); HG-6:3-O-[3- O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl -(1→2)-4-O-sulfato-β-D-xylopyranosyl]-22,25-epoxy-holosta-9(11)-ene-3β, 12α,17α-triol(arenicolasideA);HG-7:3-O-[3- O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl -(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sodiumsulfate-β-D-xylpyra nosyl]-22,25-epoxy-holosta-9(11)-ene-3β,12α-diol(fuscoinerosideC);HG-8:3β-O-[β-D-3-O-methylglucopyranosyl (1→3)-β-D- glucopyrano syl(1β4)-β-D-quinovopyranosyl(1→2)-β-D-xylopyranosyl (4→1)-β-D-glucopyranosyl]-22,25-epoxy-holosta-9(11)-ene-3β,12α,17α-tr iol(holothurinoside A).
All the triterpene glycosides HG-1～HG-8 showed activity against P.oryzae.The preliminary cytotoxic assay of these saponins indicated that HG-1～HG-8 exhibited significant cytot0xicity against BEL-740,HL-60,A-549 and Molt-4 cell lines.In the anti-fungus screen,eight tfiterpene glycosides were confirmed active against several fungus lines.
Our studies focused on the bioactive constituents of Holothuria grisea Selenka have established a foundation for the further research and development of this kind of sea cucumber with abundant resources,and provided important leading compounds for the development of new anti-cancer and anti-fungus drugs.
所确定的8个化合物的化学结构是通过~1HNMR、~(13)CNMR和二维核磁共振技术(DQCOSY、TOCSY、HMQC、HMBC和NOESY等)及电喷雾离子质谱并结合化学方法(水解,化学鉴别)确定的。这8个化合物的化学结构如下:HG-1:3β-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)→β-D-吡喃木糖-(4→1)-β-D-吡喃葡萄糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α-二醇(命名为griseaside A);HG-2:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸钠-β-D-吡喃木糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α,17α-三醇(holothurin A);HG-3:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸钠-β-D-吡喃木糖]-海参烷-9(11)-烯-22-羟基-3β,12α,17α-三醇(holothurin A_1);HG-4:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸钠-β-D-吡喃木糖]-海参烷-9(11)-烯-3β,12α,17α-三醇(echinoside A);HG-5:3β-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-β-D-吡喃木糖-(4→1)-β-D-吡喃葡萄糖]-海参烷-9(11)-烯-22-羟基-3β,12α-二醇(命名为griseaside B);HG-6:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-4-O-硫酸基-β-D-吡喃木糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α,17α-三醇(arenicolaside A);HG-7:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)4-O-硫酸钠-β-D-吡喃木糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α-二醇(fuscoineroside C);HG-8:3-O-[3-O-甲基-β-D-吡喃葡萄糖-(1→3)-β-D-吡喃葡萄糖-(1→4)-β-D-吡喃奎诺糖-(1→2)-β-D-吡喃木糖-(4→1)-β-D-吡喃葡萄糖]-22,25-环氧-海参烷-9(11)-烯-3β,12α,17α-三醇(holothurinoside A),其中HG-1和HG-5为新化合物。
初步的药理活性筛选表明,海参皂苷HG-1～HG-8对稻瘟霉显示显著的生物活性;对BEL-7402人肝癌细胞、HL-60人白血病细胞、A-549人肺癌细胞和Molt-4人白血病细胞具有较强的细胞毒活性,除HG-5活性相对较弱外,其余7个化合物对四种肿瘤细胞株的抑制率均在10~(-5)-10~(-8)mol/L之间;HG-1～HG-8对白色念珠菌、新生隐球菌、克柔式念珠菌、光滑念珠菌和近平滑念珠菌均具有不同强度的抑制生长作用,其中化合物HG-1对白色念珠菌和新生隐球菌的MIC_(80)值均达到4.0μg/ml。
本课题对灰海参体内的化学成分特别是皂苷类成分进行了系统的分离,得到2个新的海参皂苷和6个已知海参皂苷,并对其药理活性进行了初步研究。研究结果为进一步研制开发新的抗肿瘤和抗真菌药物提供了一定的科学依据和有价值的先导化合物,同时也为海洋天然产物的研究积累了新的资料,本课题的研究对开发利用丰富的海参生物资源具有较重要的意义。
The sea cucumber Holothuria grisea Selenka abundantly distributed in the sea from South Florida through the Bahamas to Brazil.Two compounds holothurin A and holothurin A_1 have been isolated by Japanese scientists from this animal while the chemical constitutents and their pharmacological activitities of this sea cucumber still need to be further investegated.Guided by Pyricularia oryzae bioassay model,we isolated 12 compounds from Holothuria grisea Selenka using various chromatography methods including LPLC, MPLC,HPLC on silica gel,ODS RP C_(18) and Zorbax SBC_(18).
The structure of 8 compounds were elucidated by chemical and spectral analysis(IR, EI-MS,ESI-MS,HRESI-MS,~1HNMR,~(13)CNMR,~1H-~1H COSY,DQCOSY,TOCSY, HMQC,HMBC,NOESY,etc.),their chemical structures were:HG-1:3β-O-[β-D-3-O-methylglucopyranosyl (1→3)-β-D-glucopyranosyl(1→4)-β-D-quinovopyranosyl(1→2)-β-D-xylopyranosyl (4→1)-β-D-glucopyranosyl]-22,25-epoxy-holost-9-(11)-ene-3β,12α-diol(nam ed griseasideA);HG-2:3-O-[3-O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl -(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sodiumsulfate-β-D-xylopyranosyl]-22,25-epox y-holosta-9(11)-ene-3β,12α,17α-triol(holothurinA);HG-3:3-O-[3-O-methyl-β-D-glucopyranosyl -(1→3)-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sod iumsulfate-β-D-xylopyranosyl]-holosta-22-hydroxyholost-9(11)-ene-3β,12α,17α-triol(holo thurinA_1);HG-4:3- O-[3- O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl -(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sodiumsulfate-β-D-xylopyranosyl]-holosta-9(1 1)-ene-3β,12α,17α-triol(echinosideA);HG-5:3β-O-[β-D-3-O-methylglucopy-ranosyl (1→3)-β-D-glucopyranssyl(1→4)-β-D-quinovopyranosyl(1→2)-β-D-xylopyranosyl(4→1)-β-D-glucopyranosyl]-holosta-22-hydroxyholost-9(11)-ene-3β,12α-diol(named griseasideB); HG-6:3-O-[3- O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl-(1→4)-β-D-quinovopyranosyl -(1→2)-4-O-sulfato-β-D-xylopyranosyl]-22,25-epoxy-holosta-9(11)-ene-3β, 12α,17α-triol(arenicolasideA);HG-7:3-O-[3- O-methyl-β-D-glucopyranosyl-(1→3)-β-D-glucopyranosyl -(1→4)-β-D-quinovopyranosyl-(1→2)-4-O-sodiumsulfate-β-D-xylpyra nosyl]-22,25-epoxy-holosta-9(11)-ene-3β,12α-diol(fuscoinerosideC);HG-8:3β-O-[β-D-3-O-methylglucopyranosyl (1→3)-β-D- glucopyrano syl(1β4)-β-D-quinovopyranosyl(1→2)-β-D-xylopyranosyl (4→1)-β-D-glucopyranosyl]-22,25-epoxy-holosta-9(11)-ene-3β,12α,17α-tr iol(holothurinoside A).
All the triterpene glycosides HG-1～HG-8 showed activity against P.oryzae.The preliminary cytotoxic assay of these saponins indicated that HG-1～HG-8 exhibited significant cytot0xicity against BEL-740,HL-60,A-549 and Molt-4 cell lines.In the anti-fungus screen,eight tfiterpene glycosides were confirmed active against several fungus lines.
Our studies focused on the bioactive constituents of Holothuria grisea Selenka have established a foundation for the further research and development of this kind of sea cucumber with abundant resources,and provided important leading compounds for the development of new anti-cancer and anti-fungus drugs.
引文
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[11]Tomofumi Migamoto,Kenichi Togawa,Ryuichi Higuchi,and et al.Structures of four new triterpenoid oligoglycosides:DS-penaustrosides A,B,C,and D from the sea cucumber Pentacta austratis.J.Nat.Prod.1992,55(7):940-946.
[12]Avilov SA,Kalinovsky JA,Kalinin VI,et al.Koreoside A,a new nonholostane triterpene glycoside from the sea cucumber Cucumber Koraiensis.J.Nat.Prod.1997,60(8):808-810.
[13]Avilov SA,Kalinin VI,Makarieva TN,et al.Structure of cucumarioside G2,a novel nonholostane glycoside from the sea cucumber Eupentacta fraudatrix.J.Nat.Prod.1994,57(8):1166-1171
[14]邹峥嵘,易杨华,李玲等.海参皂苷的研究进展.中国海洋药物,2004,23(1):46-53.
[15]Tomofumi Migamoto,Kenichi Togawa,Ryuichi Higuchi,and et al.Six newly identified biologically active triterpenoid glycoside sulfates from the sea cucumber Cucumber echinata.Liebigs.Ann.Chem.1990:453-460.
[16]周清凯,杨惠英,蔡云见,等.玉足海参素的抗真菌作用及其临床应用.海洋药物.1985,(4):43-44.
[17]Kalinin VI,Prokofieva NG,Likhatskaya GN,and et al.Hemolytic activities of triterpene glycosides from the holothurian order Dendrochirotida:some trends in the evolution of this group of toxins.Toxicon.1996,34(2):475-478.
[18]Oleinikova GK,Kuznetsova TA,Ivanova NS,et al.Glycosides of marine invertebrates.XV.A new triterpene glycoside-Holothurin A_1-From Caribbean holothurians of the family Holothuriidae[J].Chemistry of Natural Compounds.1983.18(4),430-434.
[19]于德泉(Yu DQ),杨峻山(Yang JS).分析化学手册(第2版),核磁共振波谱解析[M].北京:化学工业出版社,1999:495.
[20]Chulidl HD,Muniain CC,Seldes AM,et al.Cytotoxic and antifungal triterpene glycosides from the Patagonian sea cucumber Hemoiedma spectabilis[J].J Nat Prod,2002,65(6):860-865.
[21]Kitagawa I,Kobayashi M,Inamoto T,et al.Marine natural products ⅩⅣ structural of echinosides A and B,antifungal lanostane-oligosides from the sea cucumber Actinopyga echinites(Jaeger).Chem Pharm Bull,1985,33(2):5214 5224.
[22]翁怡毅(Weng YY),易杨华(Yi YH),李玲(Li L),等.沙海参中的三个海参皂苷[J],中国天然药物(Chin J Nat Med),2007,5(2):96-100.
[23]Rodriguez J,Castro R and Riguera R.Holothurinosides:new antitumor non sulphated triterpenoid glycosides from the sea cucumber Holothuria forskalii[J].Tetrahedron.1991,47(26),4753-4762.
[24]Shu-Yu Zhang,Yang-Hua Yi,et al.Bioactive Triterpene Glycosides from the Sea Cucumber Holothuria fuscocinerea.J.Nat.Prod,2006,69(10):1492-1495.