Organometallic palladium reagents for cysteine bioconjugation.
Organometallic palladium reagents for cysteine bioconjugation.
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DOI：
10.1038/nature15739
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发表时间：
2015-10-29
期刊：
影响因子：
64.8
通讯作者：
Buchwald SL
中科院分区：
文献类型：
--
作者：
Vinogradova EV;Zhang C;Spokoyny AM;Pentelute BL;Buchwald SL
基于过渡金属的反应已在有机合成中得到广泛应用，并且经常用于使小分子官能化。然而，使用基于过渡金属的反应来修饰复杂的生物分子的报道很少，这是由于需要严格的反应条件（例如，水性介质、低温和温和的pH）以及在生物聚合物中存在多个反应性官能团。在这里，我们报告，钯（II）配合物可用于高效和高选择性的半胱氨酸共轭反应。生物缀合反应在一系列生物相容性反应条件下快速且稳健。钯试剂从不同的和容易获得的芳基卤化物和三氟甲磺酸酯前体的直接合成使得该方法非常实用，为蛋白质修饰提供了大的结构空间。所得芳基生物缀合物对酸、碱、氧化剂和外部硫醇亲核试剂是稳定的。新型钉合肽和抗体-药物缀合物的合成进一步证实了新生物缀合平台的广泛用途。这些钯配合物显示出作为一组新的台式试剂用于多种生物缀合应用的潜力。
Transition-metal based reactions have found wide use in organic synthesis and are used frequently to functionalize small molecules. However, there are very few reports of using transition-metal based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature, and mild pH) and the existence of multiple, reactive functional groups found in biopolymers. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation reactions. The bioconjugation reaction is rapid and robust under a range of biocompatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants, and external thiol nucleophiles. The broad utility of the new bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody-drug conjugates. These palladium complexes show potential as a new set of benchtop reagents for diverse bioconjugation applications.