Abstract

Natural and synthetic small molecules targeting G-quadruplex are currently being studied. These peculiar DNA arrangements arise in guanine-rich sequences located in telomeres, oncogene promoters and in several viruses. Two semi-synthetic derivatives of osajin, a natural isoflavone from Maclura pomifera, were prepared and screened for their binding affinity towards G-quadruplex and double stranded DNA (dsDNA) using electrospray mass spectrometry (ESI-MS). Although an overall decrease in affinity for DNA was observed, one of the derivatives showed improved selectivity for G-quadruplex over dsDNA, retaining structure stabilization properties. Binding motif was studied by collision-induced dissociation (CID) assays and molecular docking, that suggested stacking as the preferential interaction pattern. Moreover, the compound selectively induced DNA damage on the G-quadruplex sequence upon UV irradiation, due to the presence of the photoreactive aryl tosylate group.

摘要

目前正在研究靶向 G-四链体的天然和合成小分子。这些特殊的 DNA 排列出现在位于端粒、癌基因启动子和几种病毒中的富含鸟嘌呤的序列中。osajin 的两种半合成衍生物，一种来自Maclura pomifera的天然异黄酮, 使用电喷雾质谱 (ESI-MS) 制备并筛选它们对 G-四链体和双链 DNA (dsDNA) 的结合亲和力。尽管观察到对 DNA 的亲和力总体下降，但其中一种衍生物显示出比 dsDNA 更好的 G-四链体选择性，保留了结构稳定特性。通过碰撞诱导解离 (CID) 分析和分子对接研究结合基序，这表明堆叠是优先相互作用模式。此外，由于存在光反应性甲苯磺酸芳基基团，该化合物在紫外线照射下选择性地诱导 G-四链体序列的 DNA 损伤。