Total synthesis as a resource in the discovery of potentially valuable antitumor agents: cycloproparadicicol.
Total synthesis as a resource in the discovery of potentially valuable antitumor agents: cycloproparadicicol.
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DOI：
10.1002/anie.200390329
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发表时间：
2003-03
影响因子：
--
通讯作者：
Kana Yamamoto;R. Garbaccio;S. Stachel;D. Solit;G. Chiosis;N. Rosen;S. Danishefsky
中科院分区：
文献类型：
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作者：
Kana Yamamoto;R. Garbaccio;S. Stachel;D. Solit;G. Chiosis;N. Rosen;S. Danishefsky
热休克蛋白90是一种分子伴侣，在暴露于环境压力的细胞中蛋白质的重折叠所需的。它控制着在调节有丝分裂信号转导和细胞存活中起关键作用的一组蛋白质的构象成熟。[1]这些客户蛋白包括类固醇受体、转录因子、突变型p53、Hif 1a、可溶性激酶如Akt、Raf-1、跨膜激酶如HER 2以及cdk 4蛋白激酶。热休克蛋白90在其氨基末端含有一个ATP结合口袋。几种天然产物，包括格尔德霉素、除草霉素A和根赤霉素结合到该口袋并抑制其分子伴侣功能。这种抑制反映在Hsp 90客户蛋白的增强的细胞内蛋白酶体降解中。这种效应的一个令人鼓舞的结果是癌细胞增殖的减弱。在动物模型中，格尔德霉素同系物在无毒剂量下表现出抗肿瘤活性。[2]格尔德霉素相关药物的新的作用机制以及它们在原则上具有可利用的体内治疗指数的证明，已经提高了对Hsp 90作为肿瘤学靶点的兴趣。[3，4]Radicicol（1），[5]最初从M. Bonorden对Hsp 90具有高亲和力（Kd= 20 nm），并且在抑制其功能方面特别有效。[6]然而，尚未完成将根赤霉素和根赤霉素肟的非常有希望的体外特征转化为体内领域，[7]显然是由于不利的药理学和非特异性毒性。
Hsp90 is a molecular chaperone required for the refolding of proteins in cells exposed to environmental stress. It governs the conformational maturation of a subset of proteins critical in regulating mitotic signal transduction and cellular survival.[1] These client proteins include steroid receptors, transcription factors, mutant p53, Hif1a, soluble kinases such as Akt, Raf-1, transmembrane kinases such as HER2, as well as cdk4 protein kinases. Hsp90 contains an ATP-binding pocket in its amino terminus. Several natural products, including geldanamycin, herbimycinA, and radicicol bind to this pocket and inhibit its chaperone function. This inhibition is mirrored in enhanced intracellular proteasomal degradation of Hsp90 client proteins. An encouraging consequence of this effect is an attenuation in the proliferation of cancer cells. In animal models, geldanamycin congeners exhibit antitumor activity at nontoxic doses.[2] The novel mechanism of action of geldanamycin-related drugs and the demonstration that they have, in principle, exploitable in vivo therapeutic indices have served to heighten interest in Hsp90 as a target for oncology.[3, 4]Radicicol (1),[5] originally isolated from M. bonorden, has a high affinity for Hsp90 (Kd= 20 nm) and is particularly potent in inhibiting its functions.[6] However, translation of the very promising in vitro profiles of radicicol and radicicol oxime to the in vivo realm has not been accomplished,[7] apparently as a result of unfavorable pharmakokinetics and nonspecific toxicities.