タンパク核外移行阻害天然物をシーズとする新規医薬品リード化合物の創製

概要

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Nuclear export signal (NES)-mediated export of MEK and Rev from the nucleus to the cytoplasm is revealed to be essential for proliferation of tumor cells and viral multiplication of HIV. In this context, we have been engaged in explore medicinal leads by using medicinal plant originated natural products with inhibitory potency for nuclear export of NES-containing proteins as seed principles. By use of the bioassay monitoring MEK directly, the unprecedented NES non-antagonistic MEK-export inhibitor, peumusolide A (5), was disclosed. Furthermore, this principle was shown to act in the NES non-antagonistic mode by the synthesized probe and display selective cytotoxicity for MEK-activated tumor cells. Additionally, we developed the stereo-controlled synthesis of the core structure of 5, presenting all four stereoisomers from the common starting material. By application of this procedure, the first total synthesis of 5 as well as exploration of the antitumor leads with the novel mechanism of action has been accomplished. With respect to Rev-export inhibitor valtrate (3), the synthesis of 5,6-dihydroanalog (24), rationally designed with the aid of MO calculation, presented the alternative bioisosteric seed principle. By utilizing this bioisotere as the scaffold, the new anti-HIV lead with enhanced Rev-export inhibitory potency in comparison with 3 and 24 has been disclosed.