Asymmetric synthesis of proteinphosphatase inhibitor dysidiolode and its potent analogs

Dysidiolide是一种新的蛋白磷酸酶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间Diels-Alder反应和外环醛烯酸酯的连续甲基化，实现了不对称合成。还合成了异二醇酯的非天然立体异构体。本文研究了利用维生素D_3框架合成二苯二甲酸酯立体异构体和新型cdc25A抑制剂。一些异构体对cdc25A对4-硝基苯酚磷酸去磷酸化的抑制作用强于二硫氰酸酯。-羟基丁烯内酯部分可以转化为简单的羧酸。二硫氰酸酯的亲水亚结构可能具有类似磷酸基团的性质。本研究为利用疏水亚结构与亲水性磷酸盐模拟物融合制备cdc25A抑制剂开辟了新的可能性。

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.