Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
WuXi AppTec Co., Ltd, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
Nat Chem. 2016 Dec;8(12):1112-1119. doi: 10.1038/nchem.2635. Epub 2016 Oct 17.
The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been elusive. Here we describe a bioreversible linkage based on a quaternary ammonium that can be used to connect a broad array of tertiary and heteroaryl amines to a carrier protein. Using a concise, protecting-group-free synthesis we demonstrate the chemoselective modification of 12 complex molecules that contain a range of reactive functional groups. We also show the utility of this connection with both protease-cleavable and reductively cleavable antibody-drug conjugates that were effective and stable in vitro and in vivo. Studies with a tertiary-amine-containing antibiotic show that the resulting antibody-antibiotic conjugate provided appropriate stability and release characteristics and led to an unexpected improvement in activity over the conjugates previously connected via a carbamate.
小分子药物与载体的可逆连接可改善药代动力学和治疗指数。先前的研究报告了通过酰胺或氨基甲酸酯键传递含有伯胺和仲胺的分子;然而,能够使用含叔胺的生物活性分子的能力一直难以捉摸。在这里,我们描述了一种基于季铵的生物可逆连接,可用于将广泛的叔胺和杂芳基胺连接到载体蛋白上。使用简洁、无保护基的合成方法,我们证明了可对包含一系列反应性官能团的 12 种复杂分子进行化学选择性修饰。我们还展示了这种连接在蛋白酶可切割和还原可切割的抗体药物偶联物中的应用,它们在体外和体内均有效且稳定。含有叔胺的抗生素的研究表明,所得的抗体-抗生素缀合物提供了适当的稳定性和释放特性,并导致与先前通过氨基甲酸酯连接的缀合物相比,活性意外提高。
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