Wang Jia-Bao, Shen Yu, Yan Qing-Long, Kong Wei-Jun, Nian Yong, Shang Ming
Frontiers Science Center for Transformative Molecules, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai, 200240, People's Republic of China.
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
Angew Chem Int Ed Engl. 2025 Jan 27;64(5):e202418806. doi: 10.1002/anie.202418806. Epub 2024 Dec 9.
Chemically modified oligonucleotides have garnered significant attention in medicinal chemistry, chemical biology, and synthetic biology due to their enhanced stability in vivo compared to naturally occurring oligonucleotides. However, current methods for synthesizing modified nucleosides, particularly at the C2'-position, are limited in terms of efficiency, modularity, and selectivity. Herein, we report a new approach for the synthesis of highly functionalized C2'-α-aryl/alkenyl nucleosides via an electrochemical nickel-catalyzed cross-coupling of 2'-bromo nucleosides with a variety of (hetero)aryl and alkenyl iodides. This method affords a diverse array of C2'- α-aryl/alkenyl nucleosides with excellent stereoselectivity, broad substrate scope, and good functional group compatibility. We further synthesized oligonucleotides incorporating C2'-aryl-modified thymidine moieties and demonstrated that their annealed double-stranded DNAs exhibit decreased melting temperatures (Tm). Additionally, oligonucleotides with C2'-aryl modifications at the 3' end showed enhanced resistance to 3'-exonuclease degradation and C2'-aryl modifications did not impede the cellular uptake process, highlighting the potential of these modified oligonucleotides for therapeutic applications.
与天然存在的寡核苷酸相比，化学修饰的寡核苷酸因其在体内具有更高的稳定性而在药物化学、化学生物学和合成生物学领域受到了广泛关注。然而，目前合成修饰核苷的方法，特别是在C2'-位的修饰，在效率、模块化和选择性方面存在局限性。在此，我们报道了一种通过电化学镍催化2'-溴核苷与多种（杂）芳基和烯基碘化物的交叉偶联反应来合成高度官能化的C2'-α-芳基/烯基核苷的新方法。该方法能够提供一系列具有优异立体选择性、广泛底物范围和良好官能团兼容性的C2'-α-芳基/烯基核苷。我们进一步合成了包含C2'-芳基修饰胸苷部分的寡核苷酸，并证明其退火双链DNA的解链温度（Tm）降低。此外，3'端带有C2'-芳基修饰的寡核苷酸对3'-外切核酸酶降解的抗性增强，并且C2'-芳基修饰并不妨碍细胞摄取过程，这突出了这些修饰寡核苷酸在治疗应用中的潜力。
