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Antiviral Structure-Activity Studies on Marine Natural Product Eudistomin Related Compounds

海洋天然产物Eudistomin相关化合物的抗病毒构效研究

基本信息

批准号：
03671021
负责人：
KURIHARA Takushi
金额：
$ 1.09万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1991
资助国家：
日本
起止时间：
1991 至 1992
项目状态：
已结题

项目摘要

Tetracyclic eudistomin (1), Which were isolated out of the colonial tunicate Eudistomin olivaceum, possessed very potent antiviral and antitumor activities.Upon oxidation of azetopyridoindoles (2, 3), which were synthesized from tryptamine via several steps, with MCPBA, oxazepinopyridoindoles (4, 5) were obtained by Meisenheimer rearrangement of the corresponding N-oxides. The framework of these oxazepines correspond to that of 12-carba-analog of eudistomin (1). Thus, synthesis of 12-carbaeudistomin analogs (6-9) is attractive from the point of the study of the structure-activity relationship.Dihydro derivative (6,alpha-isomer) of 4 was hydrolyzed with AlBr_3-EtSH to the corresponding carboxylic acid, which could be converted to alpha-amino derivative (7) via Curtius decomposition. Similarly, beta-amino derivative (7) was synthesized from beta-isomer of ester (6). In order to obtain the unsubstituted derivatives (9) on indole nitrogen atom, the phenylsulfonyl group, which could be removed by reduction with Mg-MeOH, was suitable as a protective group. Thus, oxazepine (5) was converted to alpha-and beta-amino derivatives (9) according to the similar method for the preparation of N-methyl derivatives (7).Antiviral activity of four compounds synthesized was evaluated. Among them, only beta-amino derivatives possessed activity. It is of interest that especially beta-amino derivative of 9, which is considered to be 12-carbaeudistomin, was the strongest.

四环eudistomin(1)是一种从蜂群被囊动物eudistomin olivaceum中分离得到的具有很强抗病毒和抗肿瘤活性的物质。由色胺经几个步骤合成的氮杂吡啶多哚（2,3）与MCPBA氧化后，通过相应的n -氧化物的Meisenheimer重排得到了恶氮杂吡啶多哚（4,5）。这些oxazepine的结构与12-碳类似物eudistomin相对应(1)。因此，从构效关系的研究角度来看，合成12- carbaeudisstomin类似物（6-9）是很有吸引力的。4的二氢衍生物（6，α -异构体）用AlBr_3-EtSH水解得到相应的羧酸，羧酸通过Curtius分解转化为α -氨基衍生物(7)。同样，由酯(6)的β -异构体合成β -氨基衍生物(7)。为了得到吲哚氮原子上的未取代衍生物(9)，可以用Mg-MeOH还原去除苯基磺酰基作为保护基团。因此，根据制备n -甲基衍生物(7)的类似方法，将恶氮平(5)转化为α和β -氨基衍生物(9)。对合成的四种化合物进行抗病毒活性评价。其中，只有-氨基衍生物具有活性。值得注意的是，9的β -氨基衍生物，被认为是12-carbaeudistomin，是最强的。