海洋真菌Penicillium sp.HD-1-1次级代谢产物研究  

Study on secondary metabolites of marine-derived Penicillium sp.HD-1-1

作　　者：王聪 王玉妃 徐辉 许睿 兰建洲 孔凡栋 周丽曼 WANG Cong;WANG Yufei;XU Hui;XU Rui;LAN Jianzhou;KONG Fandong;ZHOU Liman(Key Laboratory of Universities in Guangxi for Excavation and Development of Ancient Ethnomedicinal Recipes,Guangxi Collaborative Innovation Center for Chemistry and Engineering of Forest Products,Guangxi Key Laboratory of Chemistry and Engineering of Forest Products,Key Laboratory of Chemistry and Engineering of Forest Products,State Ethnic Affairs Commission,School of Chemistry and Chemical Engineering,Guangxi Minzu University,Nanning 530006,China)

机构地区：[1]广西民族大学化学化工学院,林产化学与工程国家民委重点实验室,广西林产化学与工程重点实验室,广西林产化学与工程协同创新中心,广西高校少数民族医药古方挖掘与开发重点实验室,广西南宁530006

出　　处：《中草药》2024年第7期2142-2151,共10页Chinese Traditional and Herbal Drugs

基　　金：国家自然科学基金青年项目(82204276);国家自然科学基金资助项目(82360699);广西科技基地与人才专项(桂科AD22035018);广西高等学校千名中青年骨干教师培育计划;广西研究生教育创新计划项目(YCSW2023255);广西民族大学校级引进人才科研启动项目(2020KJQD09);广西民族大学相思湖青年创新团队(2021RSCXSHQN01)。

摘　　要：目的研究涠洲岛来源的海洋真菌Penicillium sp.HD-1-1产生的次级代谢产物及其生物活性。方法利用硅胶柱色谱和半制备液相等技术进行化合物的分离纯化,运用HRESIMS、NMR等方法对化合物的结构进行鉴定,使用CCK-8法评估化合物的细胞毒活性。结果从涠洲岛海洋真菌Penicillium sp.HD-1-1次级代谢产物中分离鉴定了1个新的霉酚酸类化合物以及16个已知化合物,分别为6-(5-甲氧羰基-3-甲基戊-2-烯)-7-羟基-3,5-双甲氧基-4-甲基苯酚-1-酮(1)、霉酚酸(2)、甲基麦考酚酸(3)、6-(5-甲氧羰基-3-甲基戊-2-烯)-3,7-二羟基-5-甲氧基-4-甲基苯酚-1-酮(4)、6-(5-羧基-3-甲基戊-2-烯)-3,7-二羟基-5-甲氧基-4-甲基苯酚-1-酮(5)、7-羟基-5-甲氧基-4-甲基-6-(3-甲基-4-氧代戊基)-二氢异苯并呋喃-l-酮(6)、6-(3-羧基丁酯)-7-羟基-5-甲氧基-4-甲基苯酞-1-酮(7)、breynivosamide A(8)、伞形香青酰胺(9)、N-(N’-苯甲酰基-S~*-苯丙氨酰基)-S~*-苯丙氨醇苯甲酸酯(10)、(3S,6R)-6-(对-羟苯基)-1,4-二甲基-3,6-二甲硫基哌嗪-2,5-二酮(11)、(3R,6R)-6-(对-羟苯基)-1,4-二甲基-3,6-二甲硫基哌嗪-2,5-二酮(12)、(+)-新海胆灵A(13)、(3R,8S)-5,7-二羟基-3-(1-羟乙基)苯酚(14)、5,7-二甲氧基-4-甲基异苯并呋喃-1(3H)-酮(15)、saccharonol A(16)、6,8-二羟基-3-羟甲基异香豆素(17)。细胞毒活性结果表明化合物2和3对人胃癌AGS细胞显示出强细胞毒活性,半数抑制浓度(median inhibition concentration,IC_(50))值分别是0.69、1.12μmol/L,此外化合物2对人非小细胞肺癌NCI-H1581细胞表现出中等程度的抑制活性,IC_(50)值为17.95μmol/L,化合物3对人结肠癌HT29细胞也显示出中等抑制活性,IC_(50)值为19.30μmol/L。结论化合物1为新的霉酚酸类化合物,命名为甲氧基霉酸酯。化合物2和3具有肿瘤细胞毒活性。Objective To study the secondary metabolites and biological activities of marine-derived Penicillium sp.HD-1-1 from Weizhou Island.Methods The compounds were isolated and purified by silica gel column chromatography and semi-preparative liquid chromatography.The structures of the compounds were identified by HRESIMS,NMR and other methods.The cytotoxicity of compounds was evaluated by CCK-8 method.Results A new mycophenolic acid compound and 16 known compounds were isolated and identified from the secondary metabolites of marine fungus Penicillium sp.HD-1-1 and identified as:6-(5-methoxycarbonyl-3-methylpent-2-enyl)-7-hydroxy-3,5-dimethoxy-4-methylphthalan-1-one(1),mycophenolic acid(2),methyl mycophenolic acid(3),6-(5-methoxycarbonyl-3-methylpent-2-enyl)-3,7-dihydroxy-5-methoxy-4-methylphthalan-1-one(4),6-(5-carboxy-3-methylpent-2-enyl)-3,7-dihydroxy-5-methoxy-4-methylphthalan-1-one(5),7-hydroxy-5-methoxy-4-methyl-6-(3-methyl-4-oxopentyl)-phthalan-l-one(6),6-(3-carboxybutyl)-7-hydroxy-5-methoxy-4-methylphthalan-1-one(7),breynivosamide A(8),anabellamide(9),N(N'-benzoyl-S*-phenylalaninyl)-S*-phenylalaninol benzoate(10),(3S,6R)-6-(p-hydroxybenzyl)-1,4-dimethyl3,6-bis(methylthio)piperazine-2,5-dione(11),(3R,6R)-6-(p-hydroxybenzyl)-1,4-dimethyl-3,6-bis(methylthio)piperazine-2,5-dione(12),(+)-neoechinulin A(13),(3R,8S)-5,7-dihydroxy-3-(1-hydroxyethyl)phthalide(14),5,7-dimethoxy-4-methylisobenzofuran1(3H)-one(15),saccharonol A(16)and 6,8-dihydroxy-3-hydroxymethylisocoumarin(17).The results of cytotoxic activity showed that compounds 2 and 3 showed strong cytotoxic activity against AGS cells,with IC_(50) values of 0.69μmol/L and 1.12μmol/L,respectively.Compound 2 showed moderate inhibitory activity against NCI-H1581 cells with IC_(50) value of 17.95μmol/L,and compound 3 also showed moderate inhibitory activity against HT29 cells with IC_(50) value of 19.30μmol/L.Conclusion Compound 1 is a new mycophenolic acid compound,named methoxy mycophenolate.Compounds 2 and 3 have tumor cytotoxic activities.

关 键 词：海洋真菌 青霉菌HD-1-1 霉酚酸衍生物 肿瘤细胞毒活性 甲氧基霉酸酯 霉酚酸 甲基麦考酚酸 

分 类 号：R284.1[医药卫生—中药学]