Structures and Synthesis of Natural Antitumor/Carcinogenic Substances.

对天然抗肿瘤/致癌物质的结构和合成进行了研究.抗肿瘤物质。本文用核磁共振波谱分析法和有机合成法测定了从海兔黑尾海兔中分离出的抗肿瘤活性物质--黑尾海兔碱A的绝对立体结构。实现了对映体选择性全合成阿龙宁A。从海兔中分离出同源物阿曲洛宁B和C，并建立了它们的结构：通过比较阿曲洛宁A、B和C的细胞毒性，阐明了阿曲洛宁A中三甲基丝氨酸基团对细胞毒性的作用。细胞毒性物质。从海兔Dolabella auricularia新的细胞毒性物质，如多拉司他汀C，D，E，和doliculide分离，其结构随后被确定。这些细胞毒性物质的结构通过合成明确证实。Doliculide的大规模合成足以对其抗肿瘤活性进行评价.致癌物质。从蕨菜致癌物质Ptaquiloside中提取的最终致癌物与DNA发生反应，最终致癌物与DNA发生烷基化反应，随后发生DNA断裂，详细阐明了DNA断裂的分子机理。合成了天然终极致癌物的简单类似物，其DNA切割活性与天然终极致癌物相当。

Studies on the structures and synthesis of natural antitumor/carcinogenic substances have been made.1. Antitumor substances. Absolute stereostructure of aplyronine A,a potent antitumor substance isolated as a minute constituent of the sea hare Aplysia kurodai was determined by NMR spectral analysis any by organic synthetic method. The enantioselective total synthesis of aplyronine A was achieved. The congeners aplyronines B and C were isolated from the sea hare and their structures were established : the role of the trimethylserine group in aplyronine A with respect to the cytotoxicity was clarified by comparison of the cytotoxicity of aplyronine A,B,and C.2. Cytotoxic substances. From the sea hare Dolabella auricularia new cytotoxic substances such as dolastatins C,D,E,and doliculide were isolated, the structures of which were subsequently determined. The structures of these cytotoxic substances were confirmed by the synthesis unambiguously. Doliculide was synthesized on a large scale sufficient for the evaluation of its antitumor activity.3. Carcinogenic substances. The ultimate carcinogen derived from ptaquiloside, a potent bracken carcinogenic substance was allowed to react with DNA.Thus, the alkylation of DNA with the ultimate carcinogen took place and subsequently cleavage of DNA occurred : the molecular mechanism of DNA cleavage was clarified in details. The simple analogue of the natural ultimate carcinogen was synthesized, which was shown to have the DNA cleaving activity comparable to that of natural ultimate carcinogen.