Asymmetric synthesis of proteinphosphatase inhibitor dysidiolode and its potent analogs

蛋白磷酸酶抑制剂dysidiolode及其有效类似物的不对称合成

• 批准号: 10671984
• 负责人: SHIRAI Ryuichi
• 金额: $ 2.43万
• 依托单位: NARA INSTITUTE OF SCIENCE AND TECHNOLOGY (1999-2000)The University of Tokyo (1998)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671984/
• 关键词: dysidiolide; sesterterpene; cdc25A; dual phosphatase; cell cycle; asymmetric totalsynthesis; Diels-Alder reaction; structure-activity relationship; セスタテルペン

Dysidiolide is a novel inhibitor of the protein phosphatase cdc25A that promotes the G1/S transition of the cell cycle by dephosphorylation of the cyclin-cyclin dependent kinase complex. Asymmetric synthesis of dysidiolide was achieved via intennolecular Diels-Alder reaction of the chiral triene with crotonaldehyde and successive methylation of the exocyclic aldehyde enolate. The unnatural stereoisomers of dysidiolide was also synthesized.Synthesis of the potent stereoisomers of dysidiolide and novel cdc25A inhibitors utilizing Vitamin D_3 framework was *so investigate. Some isomers exhibited stronger inhibitory activity against cdc25A dephosphorylation of 4-nitrophenol phosphate than dysidiolide. The beta-hydroxybutenolide moiety cuold be converted to simple carboxylic acid. The hydrophilic substructure of dysidiolide may have a property of the mimic of phosphate group. This research project opened the new possibility of cdc25A inhibitor by the fusion of hydrophobic substructures with hydrophilic phosphate mimics.

Dysidiolide 是一种新型蛋白磷酸酶 cdc25A 抑制剂，通过细胞周期蛋白-细胞周期蛋白依赖性激酶复合物的去磷酸化促进细胞周期的 G1/S 转变。通过手性三烯与巴豆醛的分子内Diels-Alder反应以及环外醛烯醇化物的连续甲基化实现了dysidiolide的不对称合成。还合成了 Dysidiolide 的非天然立体异构体。利用维生素 D_3 框架合成了 Dysidiolide 的有效立体异构体和新型 cdc25A 抑制剂。一些异构体对 4-硝基苯酚磷酸盐的 cdc25A 去磷酸化表现出比 Dysidiolide 更强的抑制活性。 β-羟基丁烯内酯部分可以转化为简单的羧酸。 Dysidiolide的亲水亚结构可能具有磷酸基团模拟物的性质。该研究项目通过疏水性亚结构与亲水性磷酸盐模拟物的融合，开启了 cdc25A 抑制剂的新可能性。

项目成果

Masato Takahashi: "Concise asymmetric synthesis of dysidiolide"Tetrahedron Letters. 41・3. 2111-2114 (2000)

Masato Takahashi：“dysidiolide 的简明不对称合成”Tetrahedron Letters 41・3（2000）。

Kosuke Dodo: "Synthesis of a novel class of cdc25A inhibitor from Vitamin D3"Bioorganic and Medicinal Chemistry Letters. 10-7. 615-617 (2000)

Kosuke Dodo：“从维生素 D3 合成一类新型 cdc25A 抑制剂”《生物有机和药物化学快报》。

Masato Takahashi: "Synthesis of a novel analogues of dysidiolide and their structure-activity relationship"Bioorganic & Medicinal Chemistry Letters. 10・22. 2571-2574 (2000)

高桥正人：“二硫代内酯的新型类似物的合成及其结构-活性关系”《生物有机与药物化学快报》10・22 2571-2574（2000）。

Masato Takahashi: "Synthesis of the novel analogs of dysidiolide as cdc25A inhibitor"Bioorganic and Medicinal Chemistry Letters. 10-22. 2571-2574 (2000)

Masato Takahashi：“作为 cdc25A 抑制剂的 Dysidiolide 的新型类似物的合成”《生物有机和药物化学快报》。

Kosuke Dodo: "Synthesis of a novel class of CDC25A inhibitors from vitamin D3"Bioorganic & Medicinal Chemistry Letters. 10・7. 615-617 (2000)

Kosuke Dodo：“从维生素 D3 合成一类新型 CDC25A 抑制剂”《生物有机与药物化学快报》10・7（2000 年）。