2. Academic Validation
  3. Prodrugs for nitroreductase-based cancer therapy-3: Antitumor activity of the novel dinitroaniline prodrugs/Ssap-NtrB enzyme suicide gene system: Synthesis, in vitro and in silico evaluation in prostate cancer

Prodrugs for nitroreductase-based cancer therapy-3: Antitumor activity of the novel dinitroaniline prodrugs/Ssap-NtrB enzyme suicide gene system: Synthesis, in vitro and in silico evaluation in prostate cancer

  • Eur J Med Chem. 2020 Feb 1:187:111937. doi: 10.1016/j.ejmech.2019.111937.
Esra Tokay 1,  Tuğba Güngör 2,  Nelin Hacıoğlu 1,  Ferah Cömert Önder 2,  Ünzile Güven Gülhan 3,  Tuğba Taşkın Tok 4,  Ayhan Çelik 3,  Mehmet Ay 5,  Feray Köçkar 6
Affiliations

Affiliations

  • 1 Department of Molecular Biology and Genetic, Faculty of Sciences and Arts, Balıkesir University, Balıkesir, 10145, Turkey.
  • 2 Department of Chemistry, Faculty of Sciences and Arts, Natural Products and Drug Research Laboratory, Çanakkale Onsekiz Mart University, Çanakkale, 17020, Turkey.
  • 3 Department of Chemistry, Faculty of Science, Gebze Technical University, Gebze-Kocaeli, 41400, Turkey.
  • 4 Department of Chemistry, Faculty of Sciences and Arts, Gaziantep University, Gaziantep, 27310, Turkey.
  • 5 Department of Chemistry, Faculty of Sciences and Arts, Natural Products and Drug Research Laboratory, Çanakkale Onsekiz Mart University, Çanakkale, 17020, Turkey. Electronic address: mehmetay06@comu.edu.tr.
  • 6 Department of Molecular Biology and Genetic, Faculty of Sciences and Arts, Balıkesir University, Balıkesir, 10145, Turkey. Electronic address: fkockar@balikesir.edu.tr.
PMID: 31841727 DOI: 10.1016/j.ejmech.2019.111937
Abstract

Prodrugs for targeted tumor therapies have been extensively studied in recent years due to not only maximising therapeutic effects on tumor cells but also reducing or eliminating serious side effects on healthy cells. This strategy uses prodrugs which are safe for normal cells and form toxic metabolites (drugs) after selective reduction by Enzymes in tumor tissues. In this study, prodrug candidates (1-36) containing nitro were designed, synthesized and characterized within the scope of chemical experiments. Drug-likeness properties of prodrug candidates were analyzed using DS 2018 to investigate undesired toxicity effects. In vitro cytotoxic effects of prodrug canditates were performed with MTT assay for human hepatoma cells (Hep3B) and prostate Cancer cells (PC3) and human umbilical vein endothelial cells (HUVEC) as healthy control. Non-toxic compounds (3, 5, 7, 10, 12, 15, 17, 19 and 21-23), and also compounds (1, 2, 5, 6, 9, 11, 14, 16, 20 and 24) which had low toxic effects, were selected to examine their suitability as prodrug canditates. The reduction profiles and kinetic studies of prodrug/Ssap-NtrB combinations were performed with biochemical analyses. Then, selected prodrug/Ssap-NtrB combinations were applied to prostate Cancer cells to determine toxicity. The results of theoretical, in vitro cytotoxic and biochemical studies suggest 14/Ssap-NtrB, 22/Ssap-NtrB and 24/Ssap-NtrB may be potential prodrug/Enzyme combinations for nitroreductase (Ntr)-based prostate Cancer therapy.

Keywords

Cytotoxicity; Dinitroaniline; Enzymatic activity; In silico studies; Nitroreductase; Prodrug; Prostate cancer; Ssap-NtrB.

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