112(P-40) cdc25A阻害剤dysidiolideの全合成と構造活性相関(ポスター発表の部)

• どど 孝介

  奈良先端大物質科学セ:東大分生研

• 高橋 正人

  東大分生研

• 山田 雄次

  大鵬薬品第一がん研

• 杉本 芳一

  大鵬薬品第一がん研

• 橋本 祐一

  東大分生研

• 白井 隆一

  奈良先端大物質科学セ

書誌事項

タイトル別名

• 112(P-40) Total Synthesis and Structure-Activity Relationship of cdc25A Inhibitor Dysidiolide

抄録

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).

収録刊行物

• 天然有機化合物討論会講演要旨集

  天然有機化合物討論会講演要旨集 42 (0), 667-672, 2000

  天然有機化合物討論会実行委員会

詳細情報

• CRID: 1390282681055145088
• NII論文ID: 110006682014
• DOI: 10.24496/tennenyuki.42.0_667
• ISSN: 24331856
• 本文言語コード: ja
• データソース種別:
  • JaLC
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可