P-12 NES含有蛋白核外移行阻害物質valtrateのアナログ合成と生物活性(ポスター発表の部)
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概要
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Previously, we isolated valtrate (2) as an inhibitor for nuclear export of NES (nuclear export signal) possessing proteins such as Rev and MEK from the medicinal plant, Valerianae Radix. Furthermore, this principle was shown to exhibit anti-HIV and selective cytotoxic activity against MEK activated tumor cells, respectively. Because of acyl groups instable in serum, valtrate (2) was presumed to show little efficacy in vivo. In addition, preparation for a deacylated derivative of 2 was revealed to be difficult due to a labile hemi-vinyl acetal moiety. In this context, establishment of total synthetic protocol of 2 or its analog with similar biological activity seems essential to exploration for medicinal leads with in vivo potency. With the aid of molecular orbital calculation by PM3, we designed 5,6-dihydroanalog (3) as an isostere of 2. By use of asymmetric Diels-Alder reaction and intramolecular acetal cyclization of 17 as key steps, a methyl-vinyl acetal 18 with iridoid skeleton was prepared. Successive construction of exo-olefin, 1-O-valely1 portion, and an acetoxymethyl function from 18 provided an allyl alcohol 29 by a combination of moderate chemical conversions. Stereoselective epoxidation of exo-olefin in 29 followed by Mitsunobu reaction furnished the desired 5,6-dihydroanalog (3). Since 5,6-dihydroanalog (3) exhibited nearly the same biological activity as valtrate (2), the analogs of 3 with different acyl groups were also synthesized to clarify their steric effect. As a result of synthesis of the three analogs (3a-3c) according to the synthetic route of 3 and evaluation for biological activity, 1-O-acetylanalog (3b) was shown to display more potent activity than valtrate (2).
- 天然有機化合物討論会の論文
- 2007-08-24
著者
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田村 理
阪大院薬
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清水 伸泰
Presto
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藤原 克明
阪大院薬
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藤堂 慎吾
阪大院薬
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村上 啓寿
阪大院薬
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MURAKAMI Nobutoshi
Kyoto Pharmaceutical University
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村上 啓寿
阪大院薬:presto
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Matsumura N
Res. Foundation Itsuu Lab. Tokyo Jpn
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