Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors,The Journal of Organic Chemistry

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Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2023-05-20 , DOI: 10.1021/acs.joc.3c00126
Blazej A Wojtczak ₁ , Marcelina Bednarczyk _{1,

2} , Pawel J Sikorski ₁ , Anna Wojtczak ₂ , Piotr Surynt _{1,

2} , Joanna Kowalska ₂ , Jacek Jemielity ₁

Affiliation

Chemical modifications of the mRNA cap structure can enhance the stability, translational properties, and half-life of mRNAs, thereby altering the therapeutic properties of synthetic mRNA. However, cap structure modification is challenging because of the instability of the 5′-5′-triphosphate bridge and N7-methylguanosine. The Suzuki–Miyaura cross-coupling reaction between boronic acid and halogen compound is a mild, convenient, and potentially applicable approach for modifying biomolecules. Herein, we describe two methods to synthesize C8-modified cap structures using the Suzuki–Miyaura cross-coupling reaction. Both methods employed phosphorimidazolide chemistry to form the 5′,5′-triphosphate bridge. However, in the first method, the introduction of the modification via the Suzuki–Miyaura cross-coupling reaction at the C8 position occurs postsynthetically, at the dinucleotide level, whereas in the second method, the modification was introduced at the level of the nucleoside 5′-monophosphate, and later, the triphosphate bridge was formed. Both methods were successfully applied to incorporate six different groups (methyl, cyclopropyl, phenyl, 4-dimethylaminophenyl, 4-cyanophenyl, and 1-pyrene) into either the m⁷G or G moieties of the cap structure. Aromatic substituents at the C8-position of guanosine form a push–pull system that exhibits environment-sensitive fluorescence. We demonstrated that this phenomenon can be harnessed to study the interaction with cap-binding proteins, e.g., eIF4E, DcpS, Nudt16, and snurportin.

中文翻译：

通过 Suzuki-Miyaura 交叉偶联在 C8 位修饰的二鸟苷帽类似物的合成和评价：基于 7-甲基鸟苷的分子转子的发现

mRNA帽结构的化学修饰可以增强mRNA的稳定性、翻译特性和半衰期，从而改变合成mRNA的治疗特性。然而，由于 5'-5'-三磷酸桥和 N7-甲基鸟苷的不稳定，帽结构修饰具有挑战性。硼酸和卤素化合物之间的铃木-宫浦交叉偶联反应是一种温和、方便且具有潜在适用性的生物分子修饰方法。在此，我们描述了两种使用铃木-宫浦交叉偶联反应合成 C8 修饰帽结构的方法。两种方法均采用磷咪唑化学来形成 5',5'-三磷酸桥。然而，在第一种方法中，通过引入修改C8位置的Suzuki-Miyaura交叉偶联反应发生在合成后的二核苷酸水平上，而在第二种方法中，修饰是在核苷5'-单磷酸水平上引入的，随后形成了三磷酸桥。两种方法都成功地将六个不同的基团（甲基、环丙基、苯基、4-二甲基氨基苯基、4-氰基苯基和1-芘）并入帽结构的 m 7 G 或 G部分^。鸟苷 C8 位的芳香族取代基形成推拉系统，表现出环境敏感的荧光。我们证明，可以利用这种现象来研究与帽结合蛋白（例如，eIF4E、DcpS、Nudt16 和 snurportin ）的相互作用。

更新日期：2023-05-20

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