書誌事項
- タイトル別名
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- Exploration of Novel Medicinal Leads by Use of Natural Products Inhibiting Nuclear Export of Proteins as Scaffolds
- タンパクカク ガイ イコウ ソガイ テンネンブツ オ シーズ ト スル シンキ イヤクヒン リード カゴウブツ ノ ソウセイ
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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.
収録刊行物
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- 有機合成化学協会誌
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有機合成化学協会誌 69 (4), 393-402, 2011
公益社団法人 有機合成化学協会
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詳細情報 詳細情報について
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- CRID
- 1390282680288933376
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- NII論文ID
- 10028125487
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- NII書誌ID
- AN0024521X
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- COI
- 1:CAS:528:DC%2BC3MXkvFGlsb8%3D
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- ISSN
- 18836526
- 00379980
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- NDL書誌ID
- 11079620
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- 本文言語コード
- ja
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- データソース種別
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- JaLC
- NDL
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- 使用不可