Development of novel protein phosphatase inhibitors based on fostriecin

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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.