Prodrugs for nitroreductase based cancer therapy-4: Towards prostate cancer targeting: Synthesis of N-heterocyclic nitro prodrugs, Ssap-NtrB enzymatic activation and anticancer evaluation.

Autor: Güngör T; Department of Chemistry, Faculty of Sciences and Arts, Natural Products and Drug Research Laboratory, Çanakkale Onsekiz Mart University, Çanakkale 17020, Turkey., Tokay E; Department of Molecular Biology and Genetic, Faculty of Sciences and Arts, Balıkesir University, Balıkesir 10145, Turkey., Güven Gülhan Ü; Department of Chemistry, Faculty of Science, Gebze Technical University, Gebze-Kocaeli 41400, Turkey., Hacıoğlu N; Department of Molecular Biology and Genetic, Faculty of Sciences and Arts, Balıkesir University, Balıkesir 10145, Turkey., Çelik A; Department of Chemistry, Faculty of Science, Gebze Technical University, Gebze-Kocaeli 41400, Turkey., Köçkar F; Department of Molecular Biology and Genetic, Faculty of Sciences and Arts, Balıkesir University, Balıkesir 10145, Turkey. Electronic address: fkockar@balikesir.edu.tr., Ay M; 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.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Dec; Vol. 105, pp. 104450. Date of Electronic Publication: 2020 Nov 04.
DOI: 10.1016/j.bioorg.2020.104450
Abstrakt: In this study, various N-heterocyclic nitro prodrugs (NHN1-16) containing pyrimidine, triazine and piperazine rings were designed and synthesized. The final compounds were identified using FT-IR, 1 H NMR, 13 C NMR as well as elemental analyses. Enzymatic activities of compounds were conducted by using HPLC analysis to investigate the interaction of substrates with Ssap-NtrB nitroreductase enzyme. MTT assay was performed to evaluate the toxic effect of compounds against Hep3B and PC3 cancer cell lines and healthy HUVEC cell. It was observed that synthesized compounds NHN1-16 exhibited different cytotoxic profiles. Pyrimidine derivative NHN3 and triazine derivative NHN5 can be good drug candidates for prostate cancer with IC 50 values of 54.75 µM and 48.9 µM, respectively. Compounds NHN6, NHN10, NHN12, NHN14 and NHN16 were selected as prodrug candidates because of non-toxic properties against three different cell models. The NHN prodrugs and Ssap-NtrB combinations were applied to SRB assay to reveal the prodrug capabilities of these selected compounds. SRB screening results showed that the metabolites of all selected non-toxic compounds showed remarkable cytotoxicity with IC 50 values in the range of 1.71-4.72 nM on prostate cancer. Among the tested compounds, especially piperazine derivatives NHN12 and NHN14 showed significant toxic effect with IC 50 values of 1.75 nM and 1.79 nM against PC3 cell compared with standart prodrug CB1954 (IC 50 : 1.71 nM). Novel compounds NHN12 and NHN14 can be considered as promising prodrug candidates for nitroreductase-prodrug based prostate cancer therapy.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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