A Rationally Engineered Norfloxacin–Phenoxazine Hybrid as a Dual-Function Anticancer Agent: DNA Intercalation Synergizes with Topoisomerase II Inhibition against Murine Breast Tumor

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-08-13 Epub Date: 2026-07-04 DOI:10.1021/acsmedchemlett.6c00021

Rubi Roy, Tasnim Ria, Koyel Das, Vikram Patial, Gourab Das, Ugir Hossain Sk

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Abstract

Breast cancer therapy is compromised by acquired resistance and systemic toxicity, necessitating new therapeutic strategies. Herein, a series of hybrid molecules were synthesized by conjugating nononcogenic FDA-approved norfloxacin with DNA-targeting phenoxazine/phenothiazine through alkyl, amide, and triazole linkers. Photophysical studies demonstrated DNA intercalation, while molecular docking revealed stable interactions with topoisomerase II. The hybrids showed selective cytotoxicity against breast cancer cells, with compound 4 displaying superior potency (IC₅₀ = 3.55 ± 0.28 μM in MCF-7), surpassing the parent drugs and tamoxifen. Cellular studies demonstrated G0/G1 arrest, apoptosis, and DNA damage, as evidenced by γH2AX foci formation. Enzyme-based topoisomerase II inhibition, together with cellular TARDIS assays analysis, indicated stabilization of topo II–DNA cleavage complexes. In vivo, compounds 4 and 10 produced significant tumor regression without detectable hepatic or renal toxicity. Immunofluorescence analysis confirmed elevated cleaved caspase-3, γH2AX, favoring DNA damage-mediated apoptosis. These findings highlight the emergence of norfloxacin-based hybrids as promising anticancer agents.

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合理设计的诺氟沙星-苯恶嗪双功能抗癌剂：DNA嵌入与拓扑异构酶II协同抑制小鼠乳腺肿瘤

乳腺癌治疗受到获得性耐药和全身毒性的影响，需要新的治疗策略。本研究通过烷基、酰胺和三唑连接剂，将非致癌的fda批准的诺氟沙星与靶向dna的苯恶嗪/吩噻嗪偶联，合成了一系列杂化分子。光物理研究证明了DNA嵌入，而分子对接显示了与拓扑异构酶II的稳定相互作用。复合物对乳腺癌细胞具有选择性杀伤作用，化合物4在MCF-7中的IC50值为3.55±0.28 μM，优于母药和他莫昔芬。细胞研究证实了g0 /G1阻滞、凋亡和DNA损伤，如γH2AXfoci形成所证明的那样。基于酶的拓扑异构酶II抑制，结合细胞TARDIS分析，表明拓扑异构酶II - dna切割复合物稳定。在体内，化合物4和10产生了显著的肿瘤消退，没有检测到肝或肾毒性。免疫荧光分析证实了裂解caspase-3， γH2AX的升高，有利于DNA损伤介导的细胞凋亡。这些发现突出了以诺氟沙星为基础的混合物作为有希望的抗癌药物的出现。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.