Development of novel protein phosphatase inhibitors based on fostriecin

我们已经成功地立体选择性合成了一种抗肿瘤抗生素fostriecin。我们的合成的一个特征是高度收敛，其中fostriecin被分成三个片段A（不饱和内酯部分），B（含有一系列立体中心的多元醇部分）和C（三烯部分）。由于该特征，该合成策略是高度通用的，并且不仅适用于合成Fostriecin，而且适用于合成Fostriecin家族的其他天然产物和各种非天然类似物。应用我们的合成，我们计划合成与fostriecin一样显示蛋白磷酸酶2A特异性抑制活性的leustroducsin B，以及一些类似物，如fostriecin和leustroducsin的杂合物，还计划研究蛋白磷酸酶抑制的结构-活性关系。关于leustroducsin B的全合成，我们成功地合成了具有leustroducsin B碳骨架的关键中间体。此外，还立体选择性地合成了磷曲菌素的三烯结构部分和leustroducsin B的氨乙基结构部分的类似物，并将其用于蛋白磷酸酶抑制活性的构效关系研究。因此，发现leustroducsin的氨乙基部分与活性无关，但三烯部分被认为在对蛋白磷酸酶2A的特异性抑制中起重要作用。

We have already succeeded to synthesize an antitumor antibiotic, fostriecin, stereoselectively. A characteristic feature of our synthesis is highly convergent, in which fostriecin was separated into three segments A (an unsaturated lactone moiety), B (a polyalcohol moiety containing a series of stereogenic centers) and C (a triene moiety). Because of the characteristic feature, this synthetic strategy is highly versatile and would be applicable to synthesize not only fostriecin but also other fostriecin family natural products and various unnatural analogues. Applying our synthesis, we planned to synthesize leustroducsin B which shows protein phosphatase 2A specific inhibitory activity, like fostriecin, and some analogues such as a hybrid of fostriecin and leustroducsin, and also planned to study a structure-activity relationship of protein phosphatase inhibition.Regarding the total synthesis of leustroducsin B, we have successfully synthesized a key intermediate having a carbon skeleton of leustroducsin B. Some analogues focusing on the triene moiety of fostriecin and on the aminoethyl substituent of leustroducsin B were also synthesized stereoselectively, and employed to study structure-activity relationship of protein phosphatase inhibition. As a consequence, it was found that the aminoethyl moiety of leustroducsin was not in relation with the activity, but the triene moiety was suggested to play a significant role in specific inhibition against protein phosphatase 2A.