Exploration of novel medicinal leads by use of natural products inhibiting nuclear export of proteins as scaffolds

Satoru Tamura, Nobutoshi Murakami

研究成果: Review article査読

抄録

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 nonantagonistic 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 stereocontrolled 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-HW lead with enhanced Rev-export inhibitory potency in comparison with 3 and 24 has been disclosed.

本文言語English
ページ(範囲)393-402
ページ数10
ジャーナルYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
69
4
DOI
出版ステータスPublished - 2011 4 1

ASJC Scopus subject areas

  • 有機化学

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