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Transforming iodoquinol into broad spectrum anti-tumor leads: Repurposing to modulate redox homeostasis.

PMID: 34091287 (view PubMed database entry)
DOI: 10.1016/j.bioorg.2021.105035 (read at publisher's website )

Ibrahim Chaaban, Haidy Hafez, Ibrahim AlZaim, Cynthia Tannous, Hanan Ragab, Aly Hazzaa, Salma Ketat, Asser Ghoneim, Mohamed Katary, Mohammad M Abd-Alhaseeb, Fouad A Zouein, Amgad Albohy, Ahmed Noby Amer, Ahmed F El-Yazbi, Ahmed S F Belal,

We managed to repurpose the old drug iodoquinol to a series of novel anticancer 7-iodo-quinoline-5,8-diones. Twelve compounds were identified as inhibitors of moderate to high potency on an inhouse MCF-7 cell line, of which 2 compounds (5 and 6) were capable of reducing NAD level in MCF-7 cells in concentrations equivalent to half of their IC<sub>50</sub>s, potentially due to NAD(P)H quinone oxidoreductase (NQO1) inhibition. The same 2 compounds (5 and 6) were capable of reducing p53 expression and increasing reactive oxygen species levels, which further supports the NQO-1 inhibitory activity. Furthermore, 4 compounds (compounds 5-7 and 10) were qualified by the Development Therapeutic Program (DTP) division of the National Cancer Institute (NCI) for full panel five-dose in vitro assay to determine their GI<sub>50</sub> on the 60 cell lines. All five compounds showed broad spectrum sub-micromolar to single digit micromolar GI<sub>50</sub> against a wide range of cell lines. Cell cycle analysis and dual staining assays with annexin V-FITC/propidium iodide on MCF-7 cells confirmed the capability of the most active compound (compound 5) to induce cell cycle arrest at Pre-G1 and G2/M phases as well as apoptosis. Both cell cycle arrest and apoptosis were affirmed at the molecular level by the ability of compound 5 to enhance the expression levels of caspase-3 and Bax together with suppressing that of CDK1 and Bcl-2. Additionally, an anti-angiogenic effect was evident with compound 5 as supported by the decreased expression of VEGF. Interesting binding modes within NQO-1 active site had been identified and confirmed by both molecular docking and dymanic experiments.

Bioorg Chem (Bioorganic chemistry)
[2021, 113:105035]

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