Gusev Artem Evgenievich, Ivanov Vladimir Nikolaevich, Dmitriev Nikolai Andreevich, Kholstov Aleksandr Viktorovich, Vasilichin Vladislav Aleksandrovich, Kofiadi Ilya Andreevich, Khaitov Musa Rakhimovich
NRC Institute of Immunology FMBA of Russia, 115552 Moscow, Russia.
Molecules. 2024 Dec 17;29(24):5959. doi: 10.3390/molecules29245959.
N-Acetylgalactosamine (GalNAc) is an efficient and multifunctional delivery tool in the development and synthesis of chemically modified oligonucleotide therapeutics (conjugates). Such therapeutics demonstrate improved potency in vivo due to the selective and efficient delivery to hepatocytes in the liver via receptor-mediated endocytosis, which is what drives the high interest in this molecule. The ways to synthesize such structures are relatively new and have not been optimized in terms of the yields and stages both in lab and large-scale synthesis. Another significant criterion, especially in large-scale synthesis, is to match ecological norms and perform the synthesis in accordance with the Green Chemistry approach, i.e., to control and minimize the amounts of reagents and resources consumed and the waste generated. Here, we provide a robust and resource effective pot-economy method for the synthesis of triantennary GalNAc and GalNAc phosphoramidite/CPG optimized for laboratory scales.
N-乙酰半乳糖胺（GalNAc）是化学修饰寡核苷酸疗法（缀合物）开发和合成中一种高效且多功能的递送工具。由于通过受体介导的内吞作用选择性且高效地递送至肝脏中的肝细胞，此类疗法在体内显示出更高的效力，这也是该分子备受关注的原因。合成此类结构的方法相对较新，在实验室和大规模合成的产率及步骤方面尚未得到优化。另一个重要标准，尤其是在大规模合成中，是要符合生态规范并按照绿色化学方法进行合成，即控制并尽量减少所消耗的试剂和资源量以及产生的废物量。在此，我们提供了一种稳健且资源高效的一锅法经济方法，用于合成针对实验室规模优化的三分支GalNAc和GalNAc亚磷酰胺/CPG。
