10 効率的なエポラクタエン及び誘導体の合成と分子プローブの合成(口頭発表の部)

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Epolactaene (1), which was isolated from fungal strain Penicillium sp. BM1689-P by Osada et al., possesses a potent neurite outgrowth activity in a human neuroblastoma cell line SH-SY5Y. The characteristic features of epolactaene include the highly functionalized α,β-epoxy-γ-lactam and the conjugated triene moiety in the side chain. The significant biological activity as well as the structural complexity of epolactaene has stimulated intensive synthetic interests, culminating in the total syntheses and determination of its absolute stereochemistry by two groups. We have accomplished the total synthesis of epolactaene by an application of the bridgehead oxiranyl anion strategy. We first successfully performed an aldol-type condensation of the epoxylactone with a series of aldehydes by a two-step procedure via the trimethylsilyl epoxylactone. Then the methodology was applied to the total synthesis of epolactaene. The present approach provides the first example of the generation and reaction of the highly reactive bridgehead oxiranyl anion derived from the epoxylactone. The most significant feature of the present approach is that the trimethylsilylated epoxylactone serves as a potential intermediate for the synthesis of various substituted epolactaene analogs. Several analogs were also prepared by the coupling of the silylated epoxylactone with aldehydes. Biological studies on the α,β-epoxy-γ-lactam derivatives as well as the synthetic intermediates were investigated. As a result, we observed that the synthetic (+)-epolactaene and α,β-epoxy-γ-lactam derivatives inhibited the activities of mammalian DNA polymerase α,β and human DNA topoisomerase II. We also found that they induced apotosis in BALL-1 cells. In order to investigate further biological studies, we prepared fluorescent and biotinylated derivatives. The biologcal studies using the synthetic probes are now undergoing.
天然有機化合物討論会の論文
2003-09-01

10 効率的なエポラクタエン及び誘導体の合成と分子プローブの合成(口頭発表の部)

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