Prodrugs for Nitroreductase Based Cancer Therapy-1: Metabolite Profile, Cell Cytotoxicity and Molecular Modeling Interactions of Nitro Benzamides with Ssap-NtrB

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dc.authoridComert Onder, Ferah/0000-0002-4037-1979
dc.authoridAY, Mehmet/0000-0002-1095-1614
dc.authoridGungor, Tugba/0000-0001-5261-1856
dc.authoridTASKIN-TOK, Tugba/0000-0002-0064-8400
dc.authoridCelik, Ayhan/0000-0003-1355-9252
dc.contributor.authorGungor, Tugba
dc.contributor.authorYetis, Gulden
dc.contributor.authorOnder, Ferah C.
dc.contributor.authorTokay, Esra
dc.contributor.authorTok, Tugba T.
dc.contributor.authorCelik, Ayhan
dc.contributor.authorAy, Mehmet
dc.date.accessioned2025-01-27T20:29:13Z
dc.date.available2025-01-27T20:29:13Z
dc.date.issued2018
dc.departmentÇanakkale Onsekiz Mart Üniversitesi
dc.description.abstractBackground: Directed Enzyme Prodrug Therapy (DEPT) as an alternative method against conventional cancer treatments, in which the non-toxic prodrug is converted to highly cytotoxic derivative, has attracted an ample attentions in recent years for cancer therapy studies. Objective: The metabolite profile, cell cytotoxicity and molecular modeling interactions of a series of nitro benzamides with Ssap-NtrB were investigated in this study. Method: A series of nitro-substituted benzamide prodrugs (1-4) were synthesized and firstly investigated their enzymatic reduction by Ssap-NtrB (S. saprophyticus Nitroreductase B) using HPLC analysis. Resulting metabolites were analyzed by LC-MS/MS. Molecular docking studies were performed with the aim of the investigating the relationship between nitro benzamide structures (prodrugs 1-4) and Ssap-NtrB at molecular level. Cell viability assay on two cancer cell lines, hepatoma (Hep3B) and colon (HT-29) cancer models and healthy cell model HUVEC. Upon the reduction of benzamide prodrugs by Ssap-NtrB, the corresponding amine effectors were tested in a cell line panel comprising PC-3, Hep3B and HUVEC cells and were compared with the established NTR substrates, CB1954 (an aziridinyl dinitrobenzamide). Results: Cell viability assay resulted in while prodrugs 1, 2 and 3 had no remarkable cytotoxic effects, prodrug 4 showed the differential effect, showing moderate cytotoxicity with Hep3B and HUVEC. The metabolites that obtained from the reduction of nitro benzamide prodrugs (1-4) by Ssap-NtrB, showed differential cytotoxic effects, with none toxic for HUVEC cells, moderate toxic for Hep3B cells, but highly toxic for PC3 cells. Conclusion: Amongst all metabolites of prodrugs after Ssap-NtrB reduction, N-(2,4-dinitrophenyl)-4-nitrobenzamide (3) was efficient and toxic in PC3 cells as comparable as CB1954. Kinetic parameters, molecular docking and HPLC results also confirm that prodrug 3 is better for Ssap-NtrB than 1, 2 and 4 or known cancer prodrugs of CB1954 and SN23862, demonstrating that prodrug 3 is an efficient candidate for NTR based cancer therapy
dc.description.sponsorshipScientific and Technological Research Council of Turkey-TUBITAK [110T754, 113Z706]; TUBITAK-BIDEB
dc.description.sponsorshipWe are grateful to the Scientific and Technological Research Council of Turkey-TUBITAK for their generous financial support (TUBITAK, Grant No. 110T754 and 113Z706). Tugba GONGOR and Gulden YETIS also thank TUBITAK-BIDEB for postgraduate scholarships.
dc.identifier.doi10.2174/1573406413666171129224424
dc.identifier.endpage507
dc.identifier.issn1573-4064
dc.identifier.issn1875-6638
dc.identifier.issue5
dc.identifier.pmid29189173
dc.identifier.scopus2-s2.0-85049868859
dc.identifier.scopusqualityQ3
dc.identifier.startpage495
dc.identifier.urihttps://doi.org/10.2174/1573406413666171129224424
dc.identifier.urihttps://hdl.handle.net/20.500.12428/22869
dc.identifier.volume14
dc.identifier.wosWOS:000438116000008
dc.identifier.wosqualityQ3
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherBentham Science Publ Ltd
dc.relation.ispartofMedicinal Chemistry
dc.relation.publicationcategoryinfo:eu-repo/semantics/openAccess
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_WoS_20250125
dc.subjectSsap-NtrB
dc.subjectcancer therapy
dc.subjectcell cytotoxicity
dc.subjectprodrugs
dc.subjectquantum chemical parameter
dc.subjectmolecular docking
dc.titleProdrugs for Nitroreductase Based Cancer Therapy-1: Metabolite Profile, Cell Cytotoxicity and Molecular Modeling Interactions of Nitro Benzamides with Ssap-NtrB
dc.typeArticle

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