Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action.
Thiol Probes To Detect Electrophilic Natural Products Based on Their Mechanism of Action.
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DOI：
10.1021/acschembio.5b00924
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发表时间：
2016-08-19
影响因子：
4
通讯作者：
Hughes CC
中科院分区：
文献类型：
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作者：
Castro-Falcón G;Hahn D;Reimer D;Hughes CC
迫切需要新的方法来寻找新的天然产物，作为开发治疗癌症和多重耐药细菌感染等新疾病的新药的结构性先导。在这里，我们介绍了一种以反应性为导向的药物发现方法，用于亲电天然产物，这是一类与治疗相关的天然产物，在粗提物中以共价修饰其细胞靶标。使用精心设计的卤代芳香族试剂，该工艺提供了具有紫外线活性的衍生物，并通过同位素独特的溴或氯标签通过质谱分析获得高度显眼的衍生物。除了鉴定高价值的代谢物外，该过程还通过提供为X射线晶体分析准备的衍生品，简化了结构鉴定的困难任务。我们发现半胱氨酸探针可以有效地、化学地选择性地标记基于烯酮、β-内酰胺和β-内酯的亲电天然产物(巴特内酯、穿心莲内酯、Wortmannin、青霉素G、盐孢酰胺)，而硫酚探针则优先标记基于环氧化物的亲电天然产物(雷公藤甲素、环氧维菌素、依诺霉素、环瓜素、盐酸酰胺)。利用优化的方法，我们能够检测和分离盐生孢子菌中含有环氧化物的天然产物tiranalydigin，从而将一个孤儿基因簇连接到它的基因产物上。
New methods are urgently needed to find novel natural products as structural leads for the development of new drugs against emerging diseases such as cancer and multiresistant bacterial infections. Here we introduce a reactivity-guided drug discovery approach for electrophilic natural products, a therapeutically relevant class of natural products that covalently modify their cellular targets, in crude extracts. Using carefully designed halogenated aromatic reagents, the process furnishes derivatives that are UV-active and highly conspicuous via mass spectrometry by virtue of an isotopically unique bromine or chlorine tag. In addition to the identification of high-value metabolites, the process facilitates the difficult task of structure elucidation by providing derivatives that are primed for X-ray crystallographic analysis. We show that a cysteine probe efficiently and chemoselectively labels enone-, β-lactam-, and β-lactone-based electrophilic natural products (parthenolide, andrographolide, wortmannin, penicillin G, salinosporamide), while a thiophenol probe preferentially labels epoxide-based electrophilic natural products (triptolide, epoxomicin, eponemycin, cyclomarin, salinamide). Using the optimized method, we were able to detect and isolate the epoxide-bearing natural product tirandalydigin from Salinispora and thereby link an orphan gene cluster to its gene product.
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影响因子：
16.6
作者：
He, Qing-Li;Titov, Denis V.;Li, Jing;Tan, Minjia;Ye, Zhaohui;Zhao, Yingming;Romo, Daniel;Liu, Jun O.
通讯作者：
Liu, Jun O.
影响因子：
15
作者：
Brady, SF;Bondi, SM;Clardy, J
通讯作者：
Clardy, J
影响因子：
16.6
作者：
Feling, RH;Buchanan, GO;Fenical, W
通讯作者：
Fenical, W
影响因子：
4
作者：
Cox, Courtney L.;Tietz, Jonathan I.;Sokolowski, Karol;Melby, Joel O.;Doroghazi, James R.;Mitchell, Douglas A.
通讯作者：
Mitchell, Douglas A.
DOI：
10.1038/ja.2014.122
发表时间：
2015-03
期刊：
The Journal of antibiotics
影响因子：
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作者：
通讯作者：
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