Shi Yun, Machida Kenzo, Kuzuya Akinori, Komiyama Makoto
Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
Bioconjug Chem. 2005 Mar-Apr;16(2):306-11. doi: 10.1021/bc049698m.
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.
由D-或L-苏糖醇和ω-氨基羧酸合成了带有9-氨基-6-氯-2-甲氧基吖啶的手性纯亚磷酰胺单体，并将其掺入寡核苷酸中。由于吖啶插入DNA/RNA异源双链体，这些吖啶-DNA缀合物与互补RNA形成了稳定的双链体。双链体的稳定性不太依赖于携带吖啶的中心碳原子的手性或侧链的长度。然而，吖啶前面的磷酸二酯键的位点选择性活化能力（其诱导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-苏糖醇和4-氨基丁酸制备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-硝基吖啶连接到这个优化的支架上，获得了一种用于位点选择性RNA断裂的相当有效的吖啶-DNA缀合物。
