Design and synthesis of dual functional NBD-fluorophore-incorporated naphthalene diimide derivatives as G-quadruplex ligands

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-07-23 DOI:10.1016/j.bmcl.2024.129903

Xinhang Zhang , Yashu Li , Yuchen Chen , Ziqi Liu , Zijin Li , Ziyin Wang , Yu Wang , Mingzhe Liu

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Abstract

Nitrobenzoxadiazole (NBD)-incorporated naphthalene diimide derivatives were designed and synthesized as candidates of antitumor agents with cytotoxicity against human pancreatic cancer cell MIA PaCa-2. Among these, compounds 1NND and 3NND exhibited fluorescent “turn-off” property toward human telomeric G-quadruplex (G4), which allows the direct measurement of dissociation constant (K_d) of ligands against G4 by fluorescence titration method. Notably, the compound 1NND not only exhibited great cytotoxic activity against MIA PaCa-2 with a half maximal inhibitory concentration (IC₅₀) of 77.9 nM, but also exhibited high affinity against G4 with K_d of 1.72 μM. Furthermore, the target binding properties were investigated by circular dichroism (CD) spectra and further studied by molecular docking methods.

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设计和合成具有双重功能的 NBD-荧光团并入的萘二亚胺衍生物作为 G-四链配体。

设计并合成了硝基苯并噁二唑（NBD）掺杂的萘二亚胺衍生物，作为对人类胰腺癌细胞 MIA PaCa-2 具有细胞毒性的抗肿瘤候选药物。其中，化合物 1NND 和 3NND 对人类端粒 G-四叉体（G4）具有荧光 "关闭 "特性，可通过荧光滴定法直接测量配体对 G4 的解离常数（Kd）。值得注意的是，化合物 1NND 不仅对 MIA PaCa-2 具有很强的细胞毒性，半数最大抑制浓度（IC50）为 77.9 nM，而且对 G4 具有很高的亲和力，Kd 为 1.72 μM。此外，还通过圆二色性光谱（CD）研究了目标结合特性，并通过分子对接方法进行了进一步研究。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.