Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing
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American Chemical Society
Abstract
Structural modifications of the antibacterial drug nitrofurantoin were envisioned, employing drug repurposing and biology-oriented drug synthesis, to serve as possible anticancer agents. Eleven compounds showed superior safety in non-cancerous human cells. Their antitumor efficacy was assessed on colorectal, breast, cervical, and liver cancer cells. Three compounds induced oxidative DNA damage in cancer cells with subsequent cellular apoptosis. They also upregulated the expression of Bax while downregulated that of Bcl-2 along with activating caspase 3/7. The DNA damage induced by these compounds, demonstrated by pATM nuclear shuttling, was comparable in both MCF7 and MDA-MB-231 (p53 mutant) cell lines. Mechanistic studies confirmed the dependence of these compounds on p53-mediated pathways as they suppressed the p53-MDM2 interaction. Indeed, exposure of radiosensitive prostatic cancer cells to low non-cytotoxic concentrations of compound 1 enhanced the cytotoxic response to radiation indicating a possible synergistic effect. In vivo antitumor activity was verified in an MCF7-xenograft animal model. © 2023 American Chemical Society.
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Animals, Antineoplastic agents, Apoptosis, Biology, Breast neoplasms, Cell line, tumor, Cell proliferation, Drug repositioning, Female, Humans, Nitrofurantoin, Tumor suppressor protein p53, 1 [[(5 nitrofuran 2 yl)methylene]amino] 3 (2 oxo 2 phenylethyl)imidazolidine 2,4 dione, 1 [[(5 nitrofuran 2 yl)methylene]amino] 3 [(1 phenyl 1h 1,2,3 triazol 4 yl)methyl]imidazolidine 2,4 dione, 1 [[(5 nitrofuran 2 yl)methylene]amino] 3 [2 oxo 2 (4 tolyl)ethyl]imidazolidine 2,4 dione, 1 [[(5 nitrofuran 2 yl)methylene]amino] 3 [[1 (4 nitrophenyl) 1h 1,2,3 triazol 4 yl]methyl]imidazolidine 2,4 dione, 1 [[(5 nitrofuran 2 yl)methylene]amino] 3 [[1 (4 tolyl) 1h 1,2,3 triazol 4 yl]methyl]imidazolidine 2,4 dione, 3 (4 bromobenzyl) 1 [[(5 nitrofuran 2 yl)methylene]amino]imidazolidine 2,4 dione, 3 (4 nitrobenzyl) 1 [[(5 nitrofuran 2 yl)methylene]amino]imidazolidine 2,4 dione, 3 benzyl 1 [[(5 nitrofuran 2 yl)methylene]amino]imidazolidine 2,4 dione, 3 [2 (4 bromophenyl) 2 oxoethyl] 1 [[(5 nitrofuran 2 yl)methylene]amino]imidazolidine 2,4 dione, 3 [2 (4 chlorophenyl) 2 oxoethyl] 1 [[(5 nitrofuran 2 yl)methylene]amino]imidazolidine 2,4 dione, 3 [2 (4 methoxyphenyl) 2 oxoethyl] 1 [[(5 nitrofuran 2 yl)methylene]amino]imidazolidine 2,4 dione, 3 [[1 (4 chlorophenyl) 1h 1,2,3 triazol 4 yl]methyl]1 [[(5 nitrofuran 2 yl)methylene]amino]imidazolidine 2,4 dione, 4 [4 [[3 [[(5 nitrofuran 2 yl)methylene]amino] 2,5 dioxoimidazolidin 1 yl]methyl] 1h 1,2,3 triazol 1 yl] n (thiazol 2 yl)benzenesulfonamide, 4 [4 [[3 [[(5 nitrofuran 2 yl)methylene]amino] 2,5 dioxoimidazolidin 1 yl]methyl] 1h 1,2,3 triazol 1 yl]benzenesulfonamide, Antineoplastic agent, Caspase 3, Caspase 7, Fluorouracil, Mouse double minute 2 homolog, Protein bax, Protein bcl 2, Protein p53, Unclassified drug, Adult, Animal experiment, Animal model, Antineoplastic activity, Article, Cancer chemotherapy, Controlled study, Cytotoxicity, Dna damage, Drug efficacy, Drug synthesis, Enzyme activity, Human, Human cell, In vivo study, Male, Malignant neoplasm, Mcf-7 cell line, Mda-mb-231 cell line, Nonhuman, Nucleocytoplasmic transport, Oxidation, Protein expression, Tumor volume, Upregulation, Animal, Breast tumor, Chemistry, Genetics, Tumor cell line