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

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Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-03-15 , 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

Affiliation

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

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.

中文翻译：

通过生物导向合成和药物再利用将呋喃妥因纳入癌症化疗领域

设想了抗菌药物呋喃妥因的结构修饰，采用药物再利用和以生物学为导向的药物合成，以作为可能的抗癌剂。11 种化合物在非癌性人类细胞中表现出优异的安全性。他们对结直肠癌、乳腺癌、宫颈癌和肝癌细胞的抗肿瘤功效进行了评估。三种化合物在癌细胞中诱导氧化性 DNA 损伤，随后发生细胞凋亡。他们还上调了 Bax 的表达，同时下调了 Bcl-2 的表达以及激活半胱天冬酶 3/7。通过 pATM 核穿梭证明，这些化合物诱导的 DNA 损伤在 MCF7 和 MDA-MB-231（p53 突变体）细胞系中具有可比性。机理研究证实了这些化合物对 p53 介导途径的依赖性，因为它们抑制了 p53-MDM2 相互作用。的确，1增强了对辐射的细胞毒性反应，表明可能存在协同作用。在 MCF7 异种移植动物模型中验证了体内抗肿瘤活性。

更新日期：2023-03-15

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