Late-stage guanine C8–H alkylation of nucleosides, nucleotides, and oligonucleotides via photo-mediated Minisci reaction

Ruoqian Xie, Wanlu Li, Yuhua Ge (), Yutong Zhou, Guolan Xiao, Qin Zhao, Yunxi Han, Yangyan Li and Gang Chen ()
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Ruoqian Xie: Southeast University
Wanlu Li: Southeast University
Yuhua Ge: Southeast University
Yutong Zhou: Shanghai Jiao Tong University
Guolan Xiao: Shanghai Jiao Tong University
Qin Zhao: Shanghai Jiao Tong University
Yunxi Han: Shanghai Jiao Tong University
Yangyan Li: Shanghai Jiao Tong University
Gang Chen: Shanghai Jiao Tong University

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Chemically modified nucleosi(ti)des and functional oligonucleotides (ONs, including therapeutic oligonucleotides, aptamer, nuclease, etc.) have been identified playing an essential role in the areas of medicinal chemistry, chemical biology, biotechnology, and nanotechnology. Introduction of functional groups into the nucleobases of ONs mostly relies on the laborious de novo chemical synthesis. Due to the importance of nucleosides modification and aforementioned limitations of functionalizing ONs, herein, we describe a highly efficient site-selective alkylation at the C8-position of guanines in guanosine (together with its analogues), GMP, GDP, and GTP, as well as late-stage functionalization of dinucleotides and single-strand ONs (including ssDNA and RNA) through photo-mediated Minisci reaction. Addition of catechol to assist the formation of alkyl radicals via in situ generated boronic acid catechol ester derivatives (BACED) markedly enhances the yields especially for the reaction of less stable primary alkyl radicals, and is the key to success for the post-synthetic alkylation of ONs. This method features excellent chemoselectivity, no necessity for pre-protection, wide range of substrate scope, various free radical precursors, and little strand lesion. Downstream applications in disease treatment and diagnosis, or as biochemical probes to study biological processes after linking with suitable fluorescent compounds are expected.

Date: 2024
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DOI: 10.1038/s41467-024-46671-4

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