Structures and Synthesis of Natural Antitumor/Carcinogenic Substances.

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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.