New, Highly Active Nonbenzoquinone Geldanamycin Derivatives by Using Mutasynthesis
New, Highly Active Nonbenzoquinone Geldanamycin Derivatives by Using Mutasynthesis
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DOI：
10.1002/cbic.200900246
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发表时间：
2009-07-20
期刊：
影响因子：
3.2
通讯作者：
Kirschning, Andreas
中科院分区：
文献类型：
--
作者：
Eichner, Simone;Floss, Heinz G.;Kirschning, Andreas
自从 Rinehart 和 Gottlieb [1] 发明以来，突变生物合成（“mutasynthesis”[2]）已成为合成天然产物化学家 [3] 的一个有用工具，用于制备具有药物潜力的复杂天然产物衍生物。 [4]突变合成需要产生生产生物体的突变体，这些突变体在最终产品的生物合成构件的形成中被阻断。对被阻断的突变体施用突变合成子会产生新的代谢物。 [5]适合突变合成研究的天然产物是格尔德霉素（1，方案 1），它是一种潜在的抗肿瘤药物 [6]，可与热休克蛋白 90 (Hsp90) 的 N 端 ATP 结合域结合并抑制其 ATP 依赖性分子伴侣活性。 [7]迄今为止报道的大多数格尔德霉素衍生物都是17-胺化化合物，并且是通过半合成获得的。 [8]最近，两个研究小组利用格尔德霉素微生物来源的封闭突变体制备了几种新的衍生物。[9-11] 含苯醌的 Hsp90 抑制剂依赖于 NAD (P) H/醌氧化还原酶 1 (NQO1) 对氢醌的还原激活。[12-15] 由于该酶在不同患者中的活性存在差异，因此与 Hsp90 的 ATP 结合袋结合的衍生物无需非常需要 NQO1 激活。此外，格尔德霉素的醌部分会产生不良副作用（例如肝毒性）。谷胱甘肽的硫醇部分与醌的迈克尔加成被认为是问题的根源之一。 [16]与格尔德霉素 1 相关的是 reblastatin 2，它在 C4-C5 上饱和，并具有苯发色团而不是苯醌或氢醌部分。 [17]重要的是，reblastatin 显示出比格尔德霉素更低的细胞毒性，但对 Hsp90 具有更高的亲和力。 [17]
Since its invention by Rinehart and Gottlieb,[1] mutational biosynthesis (“mutasynthesis”[2]) has become a useful tool in the portfolio of the synthetic natural product chemist [3] for the preparation of complex natural product derivatives with pharmaceutical potential.[4] Mutasynthesis requires the generation of mutants of a producer organism that are blocked in the formation of a biosynthetic building block of the end-product. Administration of mutasynthons to the blocked mutant results in new metabolites.[5] A natural product suitable for mutasynthetic investigations is geldanamycin (1, Scheme 1), a potential antitumor drug [6] that binds to the N-terminal ATP-binding domain of heat shock protein 90 (Hsp90) and inhibits its ATP-dependent chaperone activities.[7] Most geldanamycin derivatives reported to date are 17-aminated compounds and were obtained by semisynthesis.[8] Recently, two groups have utilized blocked mutants of the microbial source of geldanamycin to prepare several new derivatives.[9–11] Benzoquinone-containing Hsp90 inhibitors depend on reductive activation to the hydroquinone by the enzyme NAD (P) H/quinone oxidoreductase 1 (NQO1).[12–15] As the activity of this enzyme in different patients is variable, derivatives that show binding to the ATP binding pocket of Hsp90 without the need for activation by NQO1 are highly desirable. Additionally, the quinone moiety of geldanamycin is held responsible for undesired side effects (for example, hepatotoxicity). The Michael addition of the thiol moiety of glutathione to the quinone is regarded as one source of problems.[16] Related to geldanamycin 1 is reblastatin 2, which is saturated across C4–C5 and has a benzene chromophore instead of a benzoquinone or a hydroquinone moiety.[17] Importantly, reblastatin shows lower cytotoxicity than geldanamycin but has a higher affinity for Hsp90.[17]