无金属内部核定触发的多米诺蛋白途径，用于合成融合二氧素[1,4] - 二氮杂杂种及其DNA结合特性的评估
Metal-free internal nucleophile-triggered domino route for synthesis of fused quinoxaline [1,4]-diazepine hybrids and the evaluation of their DNA binding properties
影响因子:4.70000
分区:医学2区 / 有机化学1区 生化与分子生物学2区
发表日期:2024 Oct
作者:
Bhim Majhi, Achyut Bora, Subhadeep Palit, Samrat Dev, Papiya Majumdar, Sanjay Dutta
摘要
在轻度条件下通过多米诺分子间鼻涕，据报道了融合二氮蛋白融合1,5-脱氧甲素1,5-二氮氮卓类杂种的前所未有的无金属合成。我们的策略为通过使用合适的直径尾部设计结构上多样化的脚手架来引入融合地西班平部分的N-1位置的广泛功能提供了灵活性。使用UV-VIS吸光度和ETBR位移测定法研究了代表性的奎诺克林地西班皮杂种的DNA结合特性，并被发现受N-1位置的功能控制。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），伴随着脊髓移位（δλ〜5 nm）。在计算机研究中，在CT-DNA己酯双链体中GC富主要凹槽处的地西班皮杂交11F可能结合，并显示出与溴化乙锭的结合能相当的结合能。化合物的抗增殖活性在给定的顺序中以不同的细胞系观察到：（HELA> HT29> SKOV 3> HCT116> HEK293）。铅化合物11F在HeLa细胞系中表现出最大的细胞毒性（IC50值13.30μm），并且还引起了癌细胞系中早期凋亡介导的细胞死亡。我们设想，我们的工作将为融合二氧甲素1,5-取代 - [1,4] - 二氮卓类分子类别提供更新的方法。
Abstract
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.