端粒的3'端悬臂区具有形成高级别结构的潜力，被称为多聚G-四链体(G4s)，这些结构主要存在于端粒中，因此成为开发抗癌药物的有吸引力的靶点，且副作用较少。然而，仅有少量分子经过随机筛选具有选择性地结合到多聚G4s，这就意味着还有很大的改进空间。在本研究中，我们提出了一种可行的策略来设计具有可能对多聚G4s具有选择性的小分子配体，并通过将1,2,3-三唑环连接到喹噁啉骨架上来合成多芳基化合物的焦点库。其中，发现QTR-3是最有前途的选择性配体，可以结合在G4-G4界面处，进而稳定多聚G4s、导致端粒区域的DNA损伤，从而引起细胞周期停滞和凋亡。值得注意的是，QTR-3对乳腺癌细胞的抑制作用显著大于对正常乳腺细胞的作用。版权所有 © 2023 Elsevier B.V.发表。

The telomeric 3'-overhang had potential to form into higher-order structures termed multimeric G-quadruplexes (G4s), which may mainly exist in telomeres, representing an attractive drug target for development of anticancer agents with few side effects. However, only a few molecules that selectively bind to multimeric G4s have been found by random screening, which means a lot of room for improvement. In this study, we raised a feasible strategy to design small-molecule ligands with possible selectivity to multimeric G4s, and then synthesized a focused library of multi-aryl compounds by attaching triazole rings to the quinoxaline skeleton. Among them, QTR-3 was identified as the most promising selective ligand that may bind at the G4-G4 interface, which accordingly stabilized multimeric G4s and induced DNA damage in telomeric region, thereby leading to cell cycle arrest and apoptosis. Notably, QTR-3 showed more significant inhibition on breast cancer cells against normal mammary cells.Copyright © 2023. Published by Elsevier B.V.