Moving Pd-Mediated Protein Cross Coupling to Living Systems
Moving Pd-Mediated Protein Cross Coupling to Living Systems
复制标题
将钯介导的蛋白质交叉偶联转移到生命系统中。
DOI：
10.1002/cbic.201200353
复制
发表时间：
2012-08-13
期刊：
影响因子：
3.2
通讯作者：
Chen, Peng R.
中科院分区：
文献类型：
--
作者：
Li, Jie;Chen, Peng R.
生物正交反应极大地提高了我们在天然细胞环境中修饰和操纵生物分子的能力。[1]CuI催化的叠氮-炔环加成(CuAAC)，通常被称为“点击”反应，[2]已经成为应用最广泛的生物正交连接反应之一，具有从生物材料结合[3]到活细胞成像的广泛应用。铜(I)催化剂的细胞毒性阻碍了该反应在生命系统中的普遍适用性。[5]虽然已经成功地开发了“无铜”点击反应，以避免使用有毒的铜(I)离子，从而允许这种反应在细胞内进行，但最近发现，环辛型分子可能具有与细胞内蛋白质上的游离硫醇或半胱氨酸残基发生非特异性反应的倾向。[6]最近发展的反向电子需求Diels-Alder反应，具有反应速度快和转化效率高的特点，为解决这一挑战开辟了一条新的途径，[7]但是四嗪或反式环辛烯化合物的复杂合成在现阶段阻碍了它的广泛应用。[8]这些问题促使化学家寻找合适的催化剂或稳定的配体来减轻铜(I)离子的毒性。[9]同时，人们开始探索过渡金属介导的配位化学方法来进行额外的生物正交反应。新出现的例子是钯催化的蛋白质选择性化学修饰反应[10]，蛋白质是细胞内含量最丰富的生物分子。钯介导的碳-碳键形成反应因其在促进有机合成方面的革命性作用而获得2010年诺贝尔化学奖。[11]其中一些反应，特别是铃木-宫浦交叉偶联反应，被证明与类似于细胞环境中的“温和条件”相兼容，即水介质、环境温度和近中性的pH。Bradley等人最近证明了这种反应与活细胞内条件的兼容性，他们合成了一种生物相容的载体系统，将Pd催化剂输送到HeLa细胞中，从而触发小分子之间的交叉偶联反应。据我们所知，这是第一个在细胞内进行的Pd介导的反应的例子。此外，通过Pd络合物修饰蛋白质也已经实现，如Francis实验室的Pd催化的酪氨酸选择性蛋白质烷基化反应所表明的那样。[13]然而，将Pd介导的交叉偶联反应扩展到生物系统仍处于起步阶段，尚未实现对蛋白质等生物分子的体内操纵。
Bioorthogonal reactions have dramatically enhanced our ability to modify and manipulate biomolecules within their native cellular context.[1] The CuI-catalysed azide–alkyne cycloaddition (CuAAC), commonly referred as the “click” reaction,[2] has become one of the most widely utilised bioorthogonal ligation reactions with broad applications ranging from biomaterial conjugation [3] to live-cell imaging.[4] However, the cytotoxicity of copper (I) catalysts has hindered the general applicability of this reaction in living systems.[5] Although the “copper-free” click reaction has been developed successfully to avoid the usage of toxic copper (I) ions and thus allowed such reactions to be performed within cells, it was recently found that molecules of the cyclooctyne type can have a tendency to react nonspecifically with free thiols or the cysteine residues the on proteins inside cells.[6] The recently developed inverse-electron-demand Diels–Alder reaction, featuring high reaction speed and high conversion efficiency, has opened up a new avenue for addressing this challenge,[7] but the complicated synthesis of tetrazine or trans-cyclooctene compounds can hinder its broad usage at the current stage.[8] These issues prompted chemists to look for suitable catalysts or stabilising ligands to alleviate the toxicity from copper (I) ions.[9] At the same time, people started to explore the repertoire of transition-metal-mediated ligation chemistry for additional bioorthogonal reactions. Emerging examples are Palladium-catalysed reactions for the selective chemical modification of proteins,[10] the most abundant biomolecules within a cell. Palladium-mediated carbon–carbon bond formation reactions were recognised with the Nobel Prize in Chemistry in 2010 owing to their revolutionary role in advancing organic synthesis.[11] Some of these reactions, the Suzuki–Miyaura cross-coupling reaction in particular, were shown to be compatible with “mild conditions” resembling those met in cellular environment, that is, aqueous medium, ambient temperature and near-neutral pH. The compatibility of such reactions to the conditions inside living cells has recently been demonstrated by Bradley et al., who synthesised a biocompatible carrier system to transport Pd catalysts into HeLa cells so as to trigger cross-coupling reactions between small molecules.[12] This represents the first example, to our knowledge, of a Pd-mediated reaction conducted within a cell. In addition, modifications of proteins via Pd complexes have also been realised, as shown by the Pd-catalysed tyrosine-selective protein alkylation from Francis’ laboratory.[13] Nevertheless, expanding Pd-mediated cross-coupling reactions into biological systems is still in its infancy and the in vivo manipulation of biomolecules such as proteins have yet to be realised.