Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation.
PLoS One. 2011;6(11):e27151. doi: 10.1371/journal.pone.0027151. Epub 2011 Nov 15.
Linear heteroareneanthracenediones have been shown to interfere with DNA functions, thereby causing death of human tumor cells and their drug resistant counterparts. Here we report the interaction of our novel antiproliferative agent 4,11-bis[(2-{[acetimido]amino}ethyl)amino]anthra[2,3-b]thiophene-5,10-dione with telomeric DNA structures studied by isothermal titration calorimetry, circular dichroism and UV absorption spectroscopy. New compound demonstrated a high affinity (K(ass)∼10⁶ M⁻¹) for human telomeric antiparallel quadruplex d(TTAGGG)₄ and duplex d(TTAGGG)₄∶d(CCCTAA)₄. Importantly, a ∼100-fold higher affinity was determined for the ligand binding to an unordered oligonucleotide d(TTAGGG TTAGAG TTAGGG TTAGGG unable to form quadruplex structures. Moreover, in the presence of Na+ the compound caused dramatic conformational perturbation of the telomeric G-quadruplex, namely, almost complete disordering of G-quartets. Disorganization of a portion of G-quartets in the presence of K+ was also detected. Molecular dynamics simulations were performed to illustrate how the binding of one molecule of the ligand might disrupt the G-quartet adjacent to the diagonal loop of telomeric G-quadruplex. Our results provide evidence for a non-trivial mode of alteration of G-quadruplex structure by tentative antiproliferative drugs.
线性杂芳蒽二酮已被证明能干扰 DNA 功能，从而导致人类肿瘤细胞及其耐药对应物的死亡。在这里，我们报告了我们新的抗增殖剂 4,11-双[(2-({[乙酰氨基]氨基}乙基)氨基]蒽[2,3-b]噻吩-5,10-二酮与端粒 DNA 结构的相互作用，该作用通过等温滴定量热法、圆二色性和紫外吸收光谱研究。新化合物与人端粒反平行四聚体 d(TTAGGG)₄和双链体 d(TTAGGG)₄∶d(CCCTAA)₄表现出高亲和力（K(ass)∼10⁶ M⁻¹）。重要的是，确定配体与不能形成四聚体结构的无规寡核苷酸 d(TTAGGG TTAGAG TTAGGG TTAGGG 的结合具有约 100 倍的高亲和力。此外，在 Na+存在下，该化合物导致端粒 G-四链体发生剧烈的构象扰动，即 G-四联体几乎完全无序。在 K+存在下，还检测到部分 G-四联体的去组织化。进行了分子动力学模拟，以说明配体的一个分子的结合如何可能破坏端粒 G-四链体中与对角线环相邻的 G-四联体。我们的结果为试探性抗增殖药物改变 G-四链体结构的非平凡模式提供了证据。
