著者

どど 孝介 高橋 正人 山田 雄次 杉本 芳一 橋本 祐一 白井 隆一

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 42 (ISSN:24331856)

巻号頁・発行日

pp.667-672, 2000-10-01 (Released:2017-08-18)

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Dysidiolide (1), a novel sesterterpene from the Caribbean marine sponge Dysidea etheria de Laubenfels, inhibits the protein phophatase cdc25A (IC_<50>=9.4μM) that promotes the Gl/S transition of the cell cycle by dephosphorylation of the cyclin/CDK complex. Cdc25A is known to be oncogenic and overexpressed in a number of tumor cell lines. Therefore, cdc25A inhibitor dysidiolide is regarded as a novel candidate agent for the treatment of cancer and other proliferative diseases. Although some groups accomplished total synthesis of dysidiolide, a synthetic approach to its struture-activity relationship has not been reported yet. We developed an efficient synthetic route to dysidiolide and its analogs in order to investigate the structure-activity relationship. The retrosynthetic analysis is shown in scheme 1. The octalin framework was constructed by intermolecular Diels-Alder reaction of the chiral triene (5) with crotonaldehyde (scheme 3). Subsequently, the quaternary center at C6 was created by methylation of the exocyclic enolate (scheme 4). Finally, the γ-hydroxybutenolide residue was introduced by addition of 3-furyllithium to the aldehyde (2) and successive photochemical oxidation of the furan ring. A series of dysidiolide analogs were synthesized according to the same procedures. To investigate the structure-activity relationship of dysidiolide, dysidiolide and its analogs were examined for cdc25A/B inhibitory activity and antiproliferative activity (table1). Searching for simple and strong cdc25A inhibitors, we designed and synthesized novel cdc25A inhibitors using Windaus-Grundmann ketone derived from Vitamin D3 (figure 1, table 2). Finally, to comfirm the effect of cdc25A inhibitors on cell cycle progression, cell cycle analysis was performed (figure 2).

著者

チャンサカオ スニー 石川 勉 関 宏子 関根 啓子 岡田 峯明 樋口 義洋 チャイチャンティピュース チャイヨー

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集 42 (ISSN:24331856)

巻号頁・発行日

pp.49-54, 2000-10-01 (Released:2017-08-18)

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"Kwao Keur." which had been identified as Puraria mirifica (Leguminosae), has long been used in Thailand and Burma as a rejuvenating folk medicine and has a fascinating history. A potent estrogenic principle has been known to be an unusual phenol miroestrol (1). Although the possible presence of an alternative active component was suggested, there has been no isolation of any other powerful phytoestrogens. with further studies leading instead to the isolation of isoflavonoids. These situation made us re-investigate the estrogenic principles of P. mirifica. The bioassay-guided separation of the ethyl acetate extract of the tuberous roots of P. mirifica by chromatographic techniques resulted in the successful isolation of a new phytoestrogen. (+)-deoxymiroestrol (4). together with (+)-1 and (+)-isomiroestrol (7). The structure of (+)-1 had been determined by X-ray crystallographic analysis and its enantioselective total synthesis was recently reported. Thus. the structure of (+)-deoxymiroestrol (4) was established by comparison of its NMR data with those of (+)-1. The growth-promoting effect of them on MCF-7 human breast cancer cells showed the strongest activity with 4. Interestingly. 4 was easily converted into 1 and 7 by aerial oxidation. suggesting that 4 may be the actual phytoestrogen of P. mirifica. On the other hand daidzein (2), genistein (3), and coumestrol (6) belong to isoflavonoids were isolated as phytoestrogens with lower activity. In addition, it was found that kwakhurin (5). a characteristic isoflavonoid in this plant. also showed the same activity as 2.