Reactive OFF-ON type alkylating agents for higher-ordered structures of nucleic acids
Reactive OFF-ON type alkylating agents for higher-ordered structures of nucleic acids
复制标题
用于核酸高阶结构的反应性OFF-ON型烷化剂
DOI：
10.1093/nar/gkz512
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发表时间：
2019
影响因子：
14.9
通讯作者：
Nagatsugi Fumi
中科院分区：
文献类型：
--
作者：
Onizuka Kazumitsu;Hazemi Madoka E;Sato Norihiro;Tsuji Gen-ichiro;Ishikawa Shunya;Ozawa Mamiko;Tanno Kousuke;Yamada Ken;Nagatsugi Fumi
核酸的高阶结构基序，如G-四链体（G-4），错配和凸起结构，是重要的研究目标，因为这些结构涉及遗传控制和疾病。由于烷化剂的化学不稳定性以及与单链或双链DNA和RNA的副反应，这些高级结构的选择性烷基化是具有挑战性的。我们现在报告的反应性关-开型烷基化剂，乙烯基喹唑啉酮（VQ）的前体与亚砜，噻吩基或硫甲基基团的关-开控制的乙烯基反应性。稳定的VQ前体与氨基吖啶结合，结合到G-4 DNA，选择性地与T碱基的G-4 DNA的单链和双链DNA相反。此外，VQ前体与AP位点、G-4 RNA和T-T错配结构中的T或U碱基反应。这些VQ前体将是核酸高级结构中T或U特异性烷基化的新候选者。
Higher-ordered structure motifs of nucleic acids, such as the G-quadruplex (G-4), mismatched and bulge structures, are significant research targets because these structures are involved in genetic control and diseases. Selective alkylation of these higher-order structures is challenging due to the chemical instability of the alkylating agent and side-reactions with the single- or double-strand DNA and RNA. We now report the reactive OFF-ON type alkylating agents, vinyl-quinazolinone (VQ) precursors with a sulfoxide, thiophenyl or thiomethyl group for the OFF-ON control of the vinyl reactivity. The stable VQ precursors conjugated with aminoacridine, which bind to the G-4 DNA, selectively reacted with a T base on the G-4 DNA in contrast to the single- and double-strand DNA. Additionally, the VQ precursor reacted with the T or U base in the AP-site, G-4 RNA and T-T mismatch structures. These VQ precursors would be a new candidate for the T or U specific alkylation in the higher-ordered structures of nucleic acids.