据报道，在温和条件下，通过多米诺分子间 SNAr 和内部亲核试剂触发的分子内 SNAr 途径，前所未有地无金属合成了稠合喹喔啉 1,5-二取代-[1,4]-二氮杂杂合体。我们的策略通过使用合适的二胺尾来设计结构多样的支架，提供了在融合二氮杂卓部分的 N-1 位置引入多种功能的灵活性。使用 UV-vis 吸光度和 EtBr 置换测定研究了代表性喹喔啉二氮杂杂合体的 DNA 结合特性，发现其受 N-1 位的功能性控制。有趣的是，含有 N-1 苄基取代的化合物 11f 表现出显着的 DNA 结合（KBH ~ 2.15 ± 0.25 × 104 M-1 和 Ksv ~ 12.6 ± 1.41 × 103 M-1），并伴有红移（Δλ ~ 5 nm）。计算机研究表明，二氮杂杂 11f 可能与 ct-DNA 六聚体双链体中富含 GC 的主沟结合，并显示出与溴化乙锭相当的结合能。在不同细胞系中按给定顺序观察到化合物的抗增殖活性：（HeLa > HT29 > SKOV 3 > HCT116 > HEK293）。先导化合物 11f 在 HeLa 细胞系中表现出最大的细胞毒性（IC50 值为 13.30 μM），并且还在癌细胞系中引起早期凋亡介导的细胞死亡。我们设想我们的工作将为构建稠合喹喔啉 1,5-二取代-[1,4]-二氮杂类分子提供更新的方法。版权所有 © 2024 Elsevier Inc. 保留所有权利。

An unprecedented metal-free synthesis of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine hybrids have been reported under mild conditions through a domino intermolecular SNAr followed by an internal nucleophile-triggered intramolecular SNAr pathway. Our strategy offers the flexibility for the introduction of a broad variety of functionalities at the N-1 position of fused diazepine moiety by using suitable diamine tails to design structurally diverse scaffolds. The DNA binding properties of representative quinoxaline diazepine hybrids were studied using UV-vis absorbance and EtBr displacement assay and were found to be governed by the functionalities at the N-1 position. Interestingly, compound 11f containing the N-1 benzyl substitution demonstrated significant DNA binding (KBH ∼ 2.15 ± 0.25 × 104 M-1 and Ksv ∼ 12.6 ± 1.41 × 103 M-1) accompanied by a bathochromic shift (Δλ ∼ 5 nm). In silico studies indicated possible binding of diazepine hybrid 11f at the GC-rich major groove in the ct-DNA hexamer duplex and showed comparable binding energies to that of ethidium bromide. The antiproliferative activity of compounds was observed in the given order in different cell lines: (HeLa > HT29 > SKOV 3 > HCT116 > HEK293). Lead compound 11f demonstrated maximum cytotoxicity (IC50 value of 13.30 μM) in HeLa cell lines and also caused early apoptosis-mediated cell death in cancer cell lines. We envision that our work will offer newer methodologies for the construction of fused quinoxaline 1,5-disubstituted-[1,4]-diazepine class of molecules.Copyright © 2024 Elsevier Inc. All rights reserved.