Palladium-Mediated Incorporation of Carboranes into Small Molecules, Peptides, and Proteins.
Palladium-Mediated Incorporation of Carboranes into Small Molecules, Peptides, and Proteins.
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DOI：
10.1021/jacs.2c01932
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发表时间：
2022-05-04
影响因子：
15
通讯作者：
Pentelute BL
中科院分区：
文献类型：
--
作者：
Gazvoda M;Dhanjee HH;Rodriguez J;Brown JS;Farquhar CE;Truex NL;Loas A;Buchwald SL;Pentelute BL
碳硼烷代表一类具有增加的治疗潜力的化合物。然而，很少有容易地将碳硼烷嵌入小分子、肽和蛋白质中的通用方法可用。我们报告了一种基于钯介导的C-X（X = C，S和N）键形成的策略，用于将含碳硼烷的部分安装到小分子和肽上。我们证明了具有适当配体的Pd基试剂克服碳硼烷基团的高疏水性并使半胱氨酸残基在室温下在水性缓冲液中的化学选择性缀合的能力。因此，碳硼烷可以有效地安装在蛋白质上，通过采用一种组合的双磺化联芳基膦连接的钯试剂在一种含水的组氨酸缓冲液。该方法已成功应用于纳米抗体（一种完全合成的抗体）和抗体治疗剂曲妥珠单抗和西妥昔单抗。抗体ZHER 2和曲妥珠单抗抗体的缀合物保留与其靶抗原的结合。在HER 2阳性BT-474细胞系中，缀合蛋白在基于细胞的功能测定中保持其活性。这种方法能够将碳硼烷部分快速掺入小分子、肽和蛋白质中，以进一步探索硼中子捕获治疗，这需要靶向递送硼密集基团。
Carboranes represent a class of compounds with increasing therapeutic potential. However, few general approaches to readily embed carboranes into small molecules, peptides, and proteins are available. We report a strategy based on palladium-mediated C–X (X = C, S, and N) bond formation for the installation of carborane-containing moieties onto small molecules and peptides. We demonstrate the ability of Pd-based reagents with appropriate ligands to overcome the high hydrophobicity of the carborane group and enable chemoselective conjugation of cysteine residues at room temperature in aqueous buffer. Accordingly, carboranes can be efficiently installed on proteins by employing a combination of a bis-sulfonated biarylphosphine-ligated Pd reagent in an aqueous histidine buffer. This method is successfully employed on nanobodies, a fully synthetic affibody, and the antibody therapeutics trastuzumab and cetuximab. The conjugates of the affibody ZHER2 and the trastuzumab antibody retained binding to their target antigens. Conjugated proteins maintain their activity in cell-based functional assays in HER2-positive BT-474 cell lines. This approach enables the rapid incorporation of carborane moieties into small molecules, peptides, and proteins for further exploration in boron neutron capture therapy, which requires the targeted delivery of boron-dense groups.
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影响因子：
15
作者：
Dhanjee HH;Saebi A;Buslov I;Loftis AR;Buchwald SL;Pentelute BL
通讯作者：
Pentelute BL
HER2结合分子分子（Z（HER2∶342））₂增加了SKBR-3细胞的放射敏性。
影响因子：
3.7
作者：
Ekerljung L;Lennartsson J;Gedda L
通讯作者：
Gedda L
影响因子：
15
作者：
Dennis JM;White NA;Liu RY;Buchwald SL
通讯作者：
Buchwald SL
影响因子：
12.8
作者：
Frejd FY;Kim KT
通讯作者：
Kim KT
影响因子：
5.6
作者：
Feldwisch, Joachim;Tolmachev, Vladimir;Abrahmsen, Lars
通讯作者：
Abrahmsen, Lars