Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships.
Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships.
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DOI：
10.1021/jm8007486
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发表时间：
2008-10-23
影响因子：
7.3
通讯作者：
Blagg BS
中科院分区：
文献类型：
--
作者：
Brandt GE;Schmidt MD;Prisinzano TE;Blagg BS
葛杜宁(Gedunin，1)是从印楝树(Azadirachta Indica)中分离得到的一种四元三萜类化合物，最近被证明通过抑制90 kDa热休克蛋白(Hsp90)折叠机制显示出抗癌活性，并与其他Hsp90抑制剂类似地诱导依赖于Hsp90的客户蛋白的降解。Gedunin诱导客户蛋白降解的作用机制尚不确定，然而，先前的研究表明，它不与ATP竞争性结合。为了进一步探讨其作用机制，我们合成了19个半合成的吉都宁衍生物，并测定了它们对MCF-7和SkBr3乳腺癌细胞的抗增殖活性。虽然没有发现化合物表现出比天然产物更有效的抗增殖活性，但已经确定了对抗增殖活性至关重要的功能。
Gedunin (1), a tetranortriterpenoid isolated from the Indian neem tree (Azadirachta indica), was recently shown to manifest anticancer activity via inhibition of the 90 kDa heat shock protein (Hsp90) folding machinery and to induce the degradation of Hsp90-dependent client proteins similar to other Hsp90 inhibitors. The mechanism of action by which gedunin induces client protein degradation remains undetermined, however, prior studies have demonstrated that it does not bind competitively versus ATP. In an effort to further probe the mechanism of action, 19 semisynthetic derivatives of gedunin were prepared and their antiproliferative activity against MCF-7 and SkBr3 breast cancer cells determined. Although no compound was found to exhibit antiproliferative activity more effective than the natural product, functionalities critical for antiproliferative activity have been identified.
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影响因子：
50.3
作者：
Isaacs, JS;Xu, WP;Neckers, L
通讯作者：
Neckers, L
影响因子：
5.1
作者：
KHALID, SA;DUDDECK, H;GONZALEZSIERRA, M
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GONZALEZSIERRA, M
影响因子：
50.3
作者：
Hieronymus, Haley;Lamb, Justin;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
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作者：
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通讯作者：
Neckers, Len
影响因子：
4.1
作者：
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通讯作者：
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