Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Bioorg Med Chem. 2009 Oct 1;17(19):6803-10. doi: 10.1016/j.bmc.2009.08.040. Epub 2009 Aug 22.
We have previously developed W-shaped nucleoside analogs (WNA) for recognition of TA and CG interrupting sites, which are the intrinsic limitation for the formation of a stable triplex DNA by the natural triplex-forming oligonucleotide (TFO). However, the stabilization effect of WNA is dependent on the neighboring nucleobases at both sides of the WNA analogs within the TFO. Considering that the base is located at the hindered site constructed of three bases of the target duplex and the TFO, it was expected that replacement of the pyrimidine base of the WNA analog with a smaller pyrazole ring might avoid steric repulsion to produce a greater stability for the triplex. In this study, the new WNA analogs bearing the pyrazole ring, 3-aminopyrazole (AP), and 4-methyl-3-pyrazole-5-on (MP) were synthesized, incorporated into the TFOs, then their stabilizing effects on the triplexes were evaluated. A remarkable success was illustrated by the fact that the TFO containing WNA-betaAP in the 3'G-WNA-G-5' sequence formed a stable triplex with selectivity to the CG interrupting site where the previous WNA-betaC did not induce the triplex formation.
我们之前开发了 W 型核苷类似物 (WNA) 来识别 TA 和 CG 中断位点，这是天然三链形成寡核苷酸 (TFO) 形成稳定三链 DNA 的固有限制。然而，WNA 的稳定作用取决于 TFO 中 WNA 类似物两侧的相邻碱基。考虑到碱基位于由靶双链体和 TFO 的三个碱基构成的受阻部位，预计用更小的吡唑环替代 WNA 类似物中的嘧啶碱基可能会避免空间排斥，从而产生更稳定的三链体。在这项研究中，合成了带有吡唑环的新型 WNA 类似物 3-氨基吡唑 (AP) 和 4-甲基-3-吡唑-5-酮 (MP)，并将其掺入 TFO 中，然后评估它们对三链体的稳定作用。事实证明了一个显著的成功，即含有 3'G-WNA-G-5'序列中的 WNA-betaAP 的 TFO 形成了一个对 CG 中断位点具有选择性的稳定三链体，而之前的 WNA-betaC 不会诱导三链体形成。
