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

Güngör, Tuğba; Yetiş, Gülden; Önder, Ferah Cömert; Tokay, Esra; Tok, Tuğba Taşkın; Çelik, Ayhan; Ay, Mehmet Oğuzhan; Köçkar, Feray

doi:10.2174/1573406413666171129224424

Cited by 13 publications

(6 citation statements)

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“…75 Molecular modeling studies may furthermore allow optimization of the prodrug for the NTR system, and cell viability studies with a series of nitro-substituted benzamide prodrugs have led to the discovery of novel prodrug candidates with promising kinetic and molecular docking profiles for NTR-based therapy. 76 Other PAGT approaches/systems…”

Section: Ntr Systemsmentioning

confidence: 99%

Prodrugs and prodrug-activated systems in gene therapy

2021

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The inclusion of genes that control cell fate (so-called suicide, or kill-switch, genes) into gene therapy vectors is based on a compelling rationale for the safe and selective elimination of aberrant transfected cells. Prodrug-activated systems were developed in the 1980s and 1990s and rely on the enzymatic conversion of non-active prodrugs to active metabolites that lead to cell death. Although considerable effort and ingenuity has gone into vector design for gene therapy, less attention has been directed at the efficacy or associated adverse effects of the prodrug systems employed. In this review, we discuss prodrug systems employed in clinical trials and consider their role in the field of gene therapy. We highlight potential drawbacks associated with the use of specific prodrugs, such as systemic toxicity of the activated compound, the paucity of data on biodistribution of prodrugs, bystander effects, and destruction of genetically modified cells, and how these can inform future advances in cell therapies. Prodrug-activated gene therapyEarly gene therapy trials carried out for monogenic diseases, such as severe combined immune deficiency (SCID) and alpha 1-antitypsin deficiency, initially focused on replacing a single deficient or mutated gene with a normal copy. However, the safety concerns inherent in cellular therapy were highlighted when 4 of 10 patients treated with gene therapy for SCID developed acute T cell lymphoblastic leukemia as the result of insertional mutagenesis into the host genome. 4 One strategy to mitigate potential adverse effects (AEs) caused by genetically modified cells is to include a cell-fate control system, such as a suicide gene, in the transfer vector; thus, a second transgene accompanies the gene of interest and acts as a suicide switch that allows transduced cells to be destroyed when exposed to a particular signal. 1,5 Several mechanisms can be used to control cell fate in this way (Figure 1). Prodrug-activated gene therapy (PAGT) strategies aim to enable the selective, on-demand destruction of transduced cells. A suicide transgene that encodes an enzyme is introduced into a target cell, and the transduced cell then becomes able to convert

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Section: Ntr Systemsmentioning

confidence: 99%

Prodrugs and prodrug-activated systems in gene therapy

2021

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“…Prodrug strategies based on NTR have been extensively studied and a library of different nitro-containing prodrugs has led to promising in vitro prodrug candidates [21]. In addition, the design and synthesis of nitro containing compounds as diagnosis of tumor cells have come to the fore in recent years [22][23][24][25][26], some nitro benzamides have special attention as anti-tumor agents due to their remarkable effects obtained from in vitro/in vivo studies and also from clinical trials during treatment of some cancers [27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of prodrugs for nitroreductase based HSP90 inhibitor BIIB021as potential anticancer agents

Peng

Deng

et al. 2023

Preprint

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A series of prodrugs for nitroreductase (NTR) on the basis of BIIB021 as potential anticancer agents have been synthesized and tested in vitro for their cytotoxic effects. The results indicated that compounds 1c and 2c displayed promising antitumor activity, with IC50 values of 0.72 and 1.12 μM, respectively. Moreover, the two compounds were also accompanied by lower toxicity to normal WI-38 cells in comparison with positive agent BIIB021(IC50=495.51 and 570.27μM vs 261 μM). Cell cycle analysis revealed that both the compounds induced cell cycle arrest in the G2/M phase with a concomitant decrease in the population of G0/G1 phase in HeLa cells, which were accompanied by apoptosis. Together, the initial studies suggest that compounds 1c and 2c have the potential to be developed as promising lead compound for further optimization in structure and as well as for in vivo validation studies.

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“…Thus, these prodrugs have been determined as effective candidates in PC3, Hep3B, and HT29 cancer cell lines and in HUVEC normal healthy cell line. [26][27][28][29] Computational approaches such as molecular docking and MD simulation studies have been widely used an important tool for discovery and design of drug candidates and are highly useful for understanding the interactions between ligand and protein. [30][31][32] The latest studies have shown that computational assessments with combined in vitro studies contribute to further studies such as in vivo and clinical translation.…”

Section: Introductionmentioning

confidence: 99%

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

Comert Onder,

Sahin,

Davutlar

et al. 2023

ChemistrySelect

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In this study, the concept of combined in vitro and in silico studies were utilized by using some synthesized nitro bearing compounds. The anticancer activities of the studied compounds were performed by using colony formation analysis, cell cytotoxicity, and migration. Nitro group containing two compounds were analyzed using Hoechst staining to indicate the morphological changes on the nuclei of cancer cells under fluorescence microscopy. Scanning electron microscopy (SEM) analysis was performed with N,N‐dibutyl‐nitro‐substituted compound. Nitro containing anticancer agents were shown the inhibition at 1.5 μM and 2 μM concentrations, and nuclear apoptosis was detected. In addition, cell‐to‐cell interaction on MDA‐MB‐231 cells was broken and observed morphologic changes following the treatment with N,N‐dibutyl‐nitro‐substituted compound at the effective doses. In general, the other nitro compounds showed cell cytotoxicity at 5 μM, 10 μM, and 20 μM. Two hits as anticancer agents were determined as potential interleukin‐1 receptor‐associated kinase 1 (IRAK1) and interleukin‐1 receptor‐associated kinase 4 (IRAK4) inhibitor candidates. Molecular docking and molecular dynamics (MD) simulations studies will provide that the binding patterns with specific residues such as Met265, Tyr284 of the IRAK family members, and these will contribute to further in vitro and in vivo studies for targeted breast cancer therapy.

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

Cited by 13 publications

References 0 publications

Prodrugs and prodrug-activated systems in gene therapy

Prodrugs and prodrug-activated systems in gene therapy

Synthesis and biological evaluation of prodrugs for nitroreductase based HSP90 inhibitor BIIB021as potential anticancer agents

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

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