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首页> 外文期刊>Nucleic Acid Therapeutics >The Interaction of Telomere DNA G-Quadruplex with Three bis-Benzyltetrahydroisoquinoline Alkaloids
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The Interaction of Telomere DNA G-Quadruplex with Three bis-Benzyltetrahydroisoquinoline Alkaloids

机译：端粒DNA G-四链体与三种双苄基四氢异喹啉生物碱的相互作用

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摘要

Telomeres are important multifunctional nucleoprotein structures located at the ends of eukaryotic chromosomes. Telomerase regulates telomere elongation, and its activity is associated with tumorigenesis. Because the activity of telomerase can be inhibited by G-quadruplex (G4) formation (a four-stranded DNA with stacks of G-quartets formed by four guanines in a planar structure), the role of G4 in cancer therapy has attracted many research interests. We studied the effects of three natural alkaloids-tetrandrine, fangchinoline, and berbamine-on the stability and formation of telomere DNA G4 with circular dichroism melting spectroscopy (melting-CD), variable temperature ultraviolet (melting-UV), proton nuclear magnetic resonance spectroscopy ((1)H NMR), and molecular docking, and examined the relationships among the alkaloid structure and their activities. We further investigated their cytotoxicity with the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) and flow cytometry (FCM). The results demonstrated that alkaloids increased G4 stability and induced its formation, which added structure diversity of G4-ligands. The results showed that -OH at R(1), -OCH(3) at R(2), and H at R(3) had higher stability than other substituent groups for these alkaloids. We also found a transition of antiparallel to parallel G4 as the temperature increased. The result indicated the possible advantage of parallel G4 in adversity. In addition, the alkaloids demonstrated a moderate cytotoxicity and proved to be cell cycle blocker in the G(1) phase. These alkaloids have revealed promising potentials to be the agents for antitumor therapy.
机译：端粒是位于真核染色体末端的重要的多功能核蛋白结构。端粒酶调节端粒的伸长，其活性与肿瘤发生有关。由于端粒酶的活性可以被G-四链体（G4）的形成（由四个鸟嘌呤组成的四链DNA堆叠成一个平面结构的四链DNA）抑制，因此G4在癌症治疗中的作用吸引了许多研究兴趣。 。我们使用圆二色熔融光谱法（melting-CD），可变温度紫外光谱法（melting-UV），质子核磁共振光谱法研究了三种天然生物碱-粉防己碱，防己胆碱和苯巴明-对端粒DNA G4的稳定性和形成的影响（（1）H NMR）和分子对接，并检查了生物碱结构与其活性之间的关系。我们进一步研究了3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四唑溴化物测定（MTT）和流式细胞仪（FCM）的细胞毒性。结果表明生物碱提高了G4的稳定性并诱导其形成，从而增加了G4配体的结构多样性。结果表明，对于这些生物碱，R（1）的-OH，R（2）的-OCH（3）和R（3）的H具有比其他取代基更高的稳定性。我们还发现，随着温度升高，反平行G4向平行G4过渡。结果表明并行G4在逆境中的可能优势。此外，生物碱显示出中等的细胞毒性，并被证明是G（1）阶段的细胞周期阻滞剂。这些生物碱已显示出有望成为抗肿瘤治疗药物的潜力。

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