Design of phosphoramidite monomer for optimal incorporation of functional intercalator to main chain of oligonucleotide
Design of phosphoramidite monomer for optimal incorporation of functional intercalator to main chain of oligonucleotide
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DOI：
10.1021/bc049698m
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发表时间：
2005-03-01
影响因子：
4.7
通讯作者：
Komiyama, M
中科院分区：
文献类型：
--
作者：
Shi, Y;Machida, K;Komiyama, M
以D-或L-苏氨醇和ω-氨基羧酸为原料合成了手性纯的含9-氨基-6-氯-2-甲氧基吖啶的亚磷酰胺单体，并将其掺入寡核苷酸中。这些吖啶-DNA缀合物形成稳定的双链体与互补的RNA，因为插入的吖啶到DNA/RNA异源双链体。双链体的稳定性不是很依赖于承载吖啶的中心碳的手性或侧链的长度。然而，在吖啶前面的磷酸二酯键的位点选择性激活的能力，诱导Lu（III）促进的RNA断裂，强烈依赖于这两个因素。当单体单元由L-苏氨醇和4-氨基丁酸制备并且吖啶与氨基结合时，实现了最大的活化。通过将酸性更强的9-氨基-2-甲氧基-6-硝基吖啶连接到这种优化的支架上，获得了一种非常有效的吖啶-DNA偶联物用于RNA的位点选择性切割。
Chirally pure phosphoramidite monomers bearing 9-amino-6-chloro-2-methoxyacridine were synthesized from D- or L-threoninol and omega-aminocarboxylic acid, and incorporated into oligonucleotides. These acridine-DNA conjugates formed stable duplexes with complementary RNA because of intercalation of the acridine to DNA/RNA heteroduplexes. The stability of duplexes was not very dependent on either the chirality of the central carbon bearing the acridine or the length of the side chain. However, the ability for site-selective activation of the phosphodiester linkage in front of the acridine, which induced Lu(III)-promoted RNA scission, was strongly dependent on these two factors. The largest activation was achieved when the monomer unit was prepared from L-threoninol and 4-aminobutyric acid and the acridine was bound to the amino group. By attaching the more acidic 9-amino-2-methoxy-6-nitroacridine to this optimized scaffold, a quite effective acridine-DNA conjugate for site-selective RNA scission was obtained.