127(P-70) トリコテシノール類の発がんプロモーター活性と合成研究(ポスター発表の部)

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Trichothecinol A (TA) is a potent tumor promoting trichothecene isolated from the fungus Trichothecium roseum. In order to clarify its property as a tumor promoter, we examined biological activities of TA. TA was negative to protein kinase C activation. Furthermore, TA was also negative to ornithine decarboxylase induction in mouse skin. Therefore, TA is classified as a non-TPA type tumor promoter that is close to thapsigargin. Further investigation showed that TA induces a morphological change of the nucleus in the Raji cell and that TA causes no point mutation in a Ha-ras gene. An extensive structure-activity relationship study is required to understand the mode of action of TA as a tumor promoter. This allowed us to start synthetic studies toward trichothecenes in addition to biochemical research on TA. Thus we synthesized the optically pure cis-AB ring 1, which is the known synthetic intermediate of calonectrin, a natural trichothecene that can be transformed into trichothecinols. Our synthetic approach to the cis-AB ring 1 originated with a chiral lactone 2 derived from D-mannnitol. The successful scheme involved the formation of the A ring by the ring closing olefin metathesis reaction. The second ring can be appended by a Lewis acid catalyzed deprotection of the methoxymethyl group and a concomitant stereoselective cyclization reaction to the desired cis-fused tetrahedrochromane skeleton that corresponds to the trichothecene AB ring system. This bicyclic intermediate 15 was transformed into the known intermediate 1, resulting in the success of a formal total synthesis of the trichothecene.
2000-10-01

127(P-70) トリコテシノール類の発がんプロモーター活性と合成研究(ポスター発表の部)

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