Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing

J Med Chem. 2023 Apr 13;66(7):4565-4587. doi: 10.1021/acs.jmedchem.2c01408.

Perihan A Elzahhar ¹, Hisham A Nematalla ², Houssam Al-Koussa ³, Carla Abrahamian ⁴, Amira F El-Yazbi ⁵, Larry Bodgi ⁶ ⁷, Jolie Bou-Gharios ⁶ ⁷, Joyce Azzi ⁶ ⁷, Joelle Al Choboq ⁶ ⁷, Hala F Labib ⁸, Wassim Abou Kheir ⁷, Marwa M Abu-Serie ⁹, Mohamed A Elrewiny ¹⁰, Ahmed F El-Yazbi ³ ¹⁰ ¹¹, Ahmed S F Belal ¹

Affiliations

1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
2 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour 22516, Egypt.
3 Department of Pharmacology and Toxicology, American University of Beirut, Beirut 11072020, Lebanon.
4 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, 80336 Munich, Germany.
5 Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
6 Department of Radiation Oncology, American University of Beirut Medical Center, Beirut 11072020, Lebanon.
7 Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 11072020, Lebanon.
8 Department of Pharmaceutical Chemistry, College of Pharmacy, Arab Academy of Science Technology and Maritime Transport, Alexandria 21913, Egypt.
9 Medical Biotechnology Department, Genetic Engineering and Biotechnology Research Institute, City of Scientific Research and Technological Applications (SRTA-City), Alexandria 21934, Egypt.
10 Faculty of Pharmacy and the Research and Innovation Hub, Alamein International University, Alamein 5060335, Egypt.
11 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.

PMID: 36921275 DOI: 10.1021/acs.jmedchem.2c01408

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.

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