CN105884782A - 一种吲哚二酮哌嗪类化合物的制备方法 - Google Patents

一种吲哚二酮哌嗪类化合物的制备方法 Download PDF

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CN105884782A
CN105884782A CN201610251501.6A CN201610251501A CN105884782A CN 105884782 A CN105884782 A CN 105884782A CN 201610251501 A CN201610251501 A CN 201610251501A CN 105884782 A CN105884782 A CN 105884782A
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李浩华
范震
章卫民
孙章华
刘洪新
叶伟
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Guangdong Detection Center of Microbiology of Guangdong Institute of Microbiology
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Abstract

本发明公开了一种吲哚二酮哌嗪类化合物的制备方法。本发明从深海真菌Dichotomom yces cejpii FS110发酵产物的乙酸乙酯提取物中分离到化合物1,2,3,4‑tetrahydro‑2‑methyl‑3‑methylene‑1,4‑dioxopyrazino[1,2‑a]indole。从而为化合物1,2,3,4‑tetrahydro‑2‑methyl‑3‑met hylene‑1,4‑dioxopyrazino[1,2‑a]indole的制备提供了一条途径。

Description

一种吲哚二酮哌嗪类化合物的制备方法
技术领域
本发明属于生物和医药领域，具体涉及利用南海深海沉积物的真菌Dichotomomyces cejpiiFS110制备化合物1,2,3,4-tetrahydro-2-methyl-3-methy lene-1,4-dioxopyrazino[1,2-a]indole的方法。
背景技术：
海洋拥有特殊的环境，像高盐、弱碱性、低营养、缺氧等，栖息于海洋环境的海洋微生物为了适应这些特殊环境，产生了独特的代谢途径，由此能够产生结构特异、生物活性特殊的次级代谢产物。近年来从海洋微生物中发现了大量结构新颖、活性显著的化合物，如生物碱类、萜类、聚酮类等(Blunt J.W.et al.2015；Yang J.G.et al.2013)。目前，海洋微生物已经成为天然产物研究的重要资源。与其它海洋微生物相比，海洋真菌来源的次生代谢产物不仅数量占到整个海洋微生物的一半左右，还具有产量大、结构和活性多样等特点，目前已经成为海洋微生物天然产物的研究热点(Bugni T.S.et al.2013；Saleem M.et al.2013；Rateb M.E.2011；Blunt J.W.et al.2013)。
本发明的前期研究表明，深海真菌Dichotomomyces cejpii FS110的发酵液乙酸乙酯粗提物具有很好的细胞毒和抗菌活性，因此我们对该深海真菌次级代谢产物进行了深入的研究。
化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole，其结构如式(I)所示，其公开于文献“Wan-Ling Liang,Xiu Le,Hou-Jin Li,et al.Exploring thechemodiversity and biological activities of the secondary metabolites from the marine fungusNeosartorya pseudofischeri[J].Mar.Drugs,2014,12(11):5657-5676.”中。
发明内容：
本发明的第一个目的是提供化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole的制备方法。
一种化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole的制备方法，其特征在于，所述的化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole是从深海真菌Dichotomomyces cejpii FS110的发酵培养物中制备得到。
优选，具体步骤如下：
制备Dichotomomyces cejpii FS110的发酵培养物，将该发酵培养物的发酵液和菌丝体分离，发酵液经乙酸乙酯萃取，乙酸乙酯层经浓缩后得到浸膏；将浸膏过硅胶柱，先用石油醚-乙酸乙酯从30:1,20:1,10:1,7:1,9:2,3:1,2:1,1:1,1:2v/v梯度洗脱，收集浸膏被石油醚:乙酸乙酯＝1:1v/v洗脱的馏分F13组分，F13组份过Sephadex LH-20，以二氯甲烷:甲醇＝1:1v/v洗脱，收集洗脱的馏分，再经纯化后得到化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole。
所述的经纯化后得到化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxo pyrazino[1,2-a]indole优选是将洗脱的馏分过正相制备HPLC(YMC柱，流动相：体积比70:30的n-hexane/EtOAc，流速10ml/min)，于保留时间tR＝16min处得到化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxo pyrazino[1,2-a]indole。
本发明的第二个目的是提供Dichotomomyces cejpii FS110在制备化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole中的应用。
本发明从Dichotomomyces cejpii FS110发酵培养物中分离得一个吲哚二酮哌嗪类化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole。从而为化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole的制备提供了一条途径。
本发明所涉及的深海真菌Dichotomomyces cejpii FS110公开于文献：杨小岚,陈玉婵,李浩华,章卫民.23株海洋真菌的分子鉴定及其抗植物病原真菌和细胞毒活性研究2014,(8):132-137。该菌株本申请人也持有，并保证自申请日起20年内向公众提供。
附图说明：
图1是化合物1的1H-NMR谱；
图2是化合物1的13C-NMR谱；
图3是化合物1的质谱。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。
实施例1：
将活化的Dichotomomyces cejpii FS110接入含质量分数1.5％海盐的马铃薯葡萄糖(PD)液体培养基(即在每升PD培养基中含有15g的海盐)中，28℃，120rpm，培养5d制得种子液10L，将种子液以体积比10％的接种量接入含质量分数1.5％海盐的PD液体培养基中，28℃，120rpm，振荡培养7d，而制得发酵培养物100L。将该发酵培养物的发酵液和菌丝体分离，发酵液经乙酸乙酯萃取，乙酸乙酯层经浓缩后得到浸膏。将浸膏过硅胶柱，先用石油醚-乙酸乙酯从30:1,20:1,10:1,7:1,9:2,3:1,2:1,1:1,1:2(v/v)梯度洗脱，再用乙酸乙酯洗脱，最后用二氯甲烷:甲醇＝5:1(v/v)洗脱；收集浸膏被石油醚:乙酸乙酯＝1:1洗脱的馏分F13，该馏分过Sephadex LH-20柱，以二氯甲烷:甲醇＝1:1(v/v)洗脱，收集洗脱的馏分，然后过正相制备HPLC(YMC柱，n-hexane/EtOAc，70:30，流速10ml/min)，于tR＝16min得到化合物1(化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole 3.2mg,)。
化合物的H-NMR谱、13C-NMR谱和质谱分别如图1、2和3所示，经质谱和核磁共振波谱分析，其结构鉴定如下：
化合物1具有以下理化和波谱特性：白色固体；ESIMS m/z 475[2M+Na]+；1H-NMR(500MHz,DMSO-d6)δH:8.39(1H,dt,J＝8.3,1.0Hz,H-6),7.83(1H,dt,J＝8.0,1.0Hz,H-9),7.56(1H,ddd,J＝8.3,7.2,1.0Hz,H-7),7.53(1H,t,J＝0.5Hz,H-10),7.44(1H,ddd,J＝8.0,7.2,1.0Hz,H-8),5.95(1H,d,J＝1.7Hz,H-3a),5.45(1H,d,J＝1.7Hz,H-3a),3.31(3H,s,H-2a).13CNMR(125MHz,CDCl3)δH:155.2(C-4),154.7(C-1),138.0(C-3),135.9(C-9a),129.2(C-5a),128.4(C-7),127.9(C-10a),125.8(C-8),123.1(C-9),117.3(C-6),115.6(C-10),106.3(C-12),29.9(C-2a)。经文献检索，该化合物波谱数据为与文献(Wan-Ling Liang,Xiu Le,Hou-Jin Li,etal.2014)报道化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyra zino[1,2-a]indole的一致，故鉴定化合物1为化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole。
经过上述方法分离的目标化合物1为1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole，其结构式如式(Ⅰ)所示：

Claims (4)

1.一种化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole的制备方法，其特征在于，所述的化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole是从深海真菌Dichotomomyces cejpii FS110的发酵培养物中制备得到的。
2.根据权利要求1所述的制备方法，其特征在于，具体步骤如下：
制备Dichotomomyces cejpii FS110的发酵培养物，将该发酵培养物的发酵液和菌丝体分离，发酵液经乙酸乙酯萃取，乙酸乙酯层经浓缩后得到浸膏；将浸膏过硅胶柱，先用石油醚-乙酸乙酯从30:1,20:1,10:1,7:1,9:2,3:1,2:1,1:1,1:2v/v梯度洗脱，收集浸膏被石油醚:乙酸乙酯＝1:1v/v洗脱的馏分F13组分，F13组份过Sephadex LH-20柱，以二氯甲烷:甲醇＝1:1v/v洗脱，收集洗脱的馏分，再经纯化后得到化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxo pyrazino[1,2-a]indole。
3.根据权利要求2所述的制备方法，其特征在于，所述的经纯化后得到化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxo pyrazino[1,2-a]indole是将洗脱的馏分过正相制备HPLC(YMC柱，流动相：体积比70:30的正己烷/乙酸乙酯，流速10ml/min)，于保留时间tR＝16min处得到化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxo pyrazino[1,2-a]indole。
4.真菌Dichotomomyces cejpii FS110在制备化合物1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole中的应用。
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