27 新規発ガンプロモーター、trichothecinol A(口頭発表の部)

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Three novel trichothecene sesquiterpenes, trichothecinols A (1), B (2) and C (3) were isolated from the fungus Trichothecium roseum (TMI-32358) together with some known analogues such as trichothecin (4). They showed inhibitory effect on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and thus were classified as anti-tumor promoters in vitro. We focused on the potent activity of 1 and further examined its inhibitory effect on the tumor promotion in mouse skin in vivo. Surpprisingly, while 1 reduced both the rate of papilloma-bearing mice and the number of papillomas per mouse in the presence of TPA, 1 itself enhanced the tumor promotion in the absence of TPA and induced the formation of papillomas. In addition, malignant conversion of papillomas to carcinomas was caused after 20 weeks without 1. On the other hand, 1 did not enhance the tumor promotion in vitro in the absence of TPA at all. Accordingly, 1 was indicated to be a new class of tumor promoter that can be distinguished from TPA and teleocidin. In order to clarify the peculiar action of 1 in the tumor promotion, a structure-activity relationship was investigated with the natural products and compounds derived from 1 and 4. In anti-tumor promoting effect in vitro, it was found that the presence of the isocrotonyl ester and conjugated ketone was most important for increasing the activity. The presence of the 3-hydroxyl group was also effective when the ketone carbonyl group was reduced. Interestingly 4 did not enhance the tumor promotion neither in vitro nor in vivo at all although the structure of 4 differs from 1 only in the lack of 3-hydroxyl group and its antitumor promoting activity in vitro was comparable to that of 1. Therefore, it was strongly suggested that the 3-hydroxyl group plays a crutial role in the tumor promotion.
天然有機化合物討論会の論文
1997-07-20

27 新規発ガンプロモーター、trichothecinol A(口頭発表の部)

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