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July 6, 2026ACS Medicinal Chemistry Letters0 citations

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

Key Points

This research aims to develop and evaluate a norfloxacin-phenoxazine hybrid as a dual-function anticancer agent against breast tumors.
Synthetic approach to create norfloxacin-phenoxazine hybrids linked via alkyl, amide, and triazole linkers.
Photophysical studies to assess DNA intercalation and molecular docking analyses for interactions with topoisomerase II.
In vivo experiments demonstrated tumor regression in murine models with compounds 4 and 10.
Compound 4 showed an IC 50 of 3.55 ± 0.28 μM in MCF-7 cells, exceeding the efficacy of parent drugs and tamoxifen.
Observed G0/G1 cell cycle arrest and DNA damage indicated by γH2AX foci formation in treated cells.
Significant tumor regression was achieved with compounds 4 and 10 without liver or kidney toxicity.

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 (IC 50 = 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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