无金属内部亲核试剂触发的多米诺反应路径合成融合喹氧嗪[1,4]-二唑杂化物及其DNA结合性能的评价

Metal-free internal nucleophile-triggered domino route for synthesis of fused quinoxaline [1,4]-diazepine hybrids and the evaluation of their DNA binding properties

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BIOORGANIC CHEMISTRY

影响因子:4.7

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

DOI: 10.1016/j.bioorg.2024.107694

keywords: Cascade/domino reaction; DNA binding properties; Fused 1,4-Diazepine; Nucleophilic substitution reaction; Quinoxaline

摘要

在温和条件下通过多米诺分子间SNAr反应结合内部亲核试剂诱导的分子内SNAr途径，首次报道了一种无金属合成融合喹氧嗪1,5-二取代-[1,4]-二唑杂化物的方法。我们的方法提供了在融合二唑基团的N-1位置引入多种官能团的灵活性，可利用适宜的二胺尾部设计结构多样的骨架。采用UV-Vis吸收和EtBr置换实验研究了代表性喹氧嗪二唑杂化物的DNA结合性能，发现其行为受N-1位置官能团的调控。有趣的是，含N-1苄基取代的化合物11f表现出显著的DNA结合能力（KBH 约为2.15 ± 0.25 × 10^4 M^-1，Ksv 约为12.6 ± 1.41 × 10^3 M^-1），伴随着吸收波长的红移（Δλ 约为5 nm）。分子模拟研究表明，二唑杂化物11f可能在ct-DNA六聚体的GC丰富的主要沟槽中结合，其结合能与乙啶溴化物相当。该化合物在不同细胞系中的抗增殖活性依次为：HeLa > HT29 > SKOV3 > HCT116 > HEK293。领先化合物11f在HeLa细胞系中表现出最大细胞毒性（IC50为13.30 μM），并引起癌细胞的早期凋亡。我们相信，此研究将为合成新型融合喹氧嗪1,5-二取代-[1,4]-二唑类化合物提供新的方法学。

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.