| 1. |
- Fagan, V., et al.
(author)
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COMPARE analysis of the toxicity of an iminoquinone derivative of the imidazo[5,4-f]benzimidazoles with NAD(P)H:quinone Oxidoreductase 1 (NQO1) activity and computational docking of quinones as NQO1 substrates
- 2012
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In: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 20:10, s. 3223-3232
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Journal article (peer-reviewed)abstract
- Synthesis and cytotoxicity of imidazo[5,4-f]benzimidazolequinones and iminoquinone derivatives is described, enabling structure-activity relationships to be obtained. The most promising compound (an iminoquinone derivative) has undergone National Cancer Institute (NCI) 60 cell line (single and five dose) screening, and using the NCI COMPARE program, has shown correlation to NQO1 activity and to other NQO1 substrates. Common structural features suggest that the iminoquinone moiety is significant with regard to NQO1 specificity. Computational docking into the active site of NQO1 was performed, and the first comprehensive mitomycin C (MMC)-NQO1 docking study is presented. Small distances for hydride reduction and high binding affinities are characteristic of MMC and of iminoquinones showing correlations with NQO1 via COMPARE analysis. Docking also indicated that the presence of a substituent capable of hydrogen bonding to the His194 residue is important in influencing the orientation of the substrate in the NQO1 active site, leading to more efficient reduction. (C) 2012 Elsevier Ltd. All rights reserved.
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| 2. |
- Cerecetto, Hugo, et al.
(author)
-
1, 2, 4-Triazine N-oxide derivatives : studies as potential hypoxic cytotoxins. Part III.
- 2004
-
In: Archiv der Pharmazie. - : Wiley. - 0365-6233 .- 1521-4184. ; 337:5, s. 271-80
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Journal article (peer-reviewed)abstract
- New 5-(2-arylethenyl)-1, 2, 4-triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The desired products were obtained when the 5-methyl heterocycle reacted with the corresponding iminium electrophiles. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than Tirapazamine, 3-aminobenzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 11, 6-methyl-5-[2-(5-nitrofuryl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective. Some derivatives were studied as DNA-binding agents in oxic conditions showing poor affinity for this biomolecule. This result showed that the cytotoxic activity in oxia is DNA damage not dependent. Electrochemical and ESR spectroscopy studies were performed in order to determine the ability of compounds to produce radicals and the relation of these in the mechanism of cytotoxicity.
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| 3. |
- Cerecetto, Hugo, et al.
(author)
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1, 2, 4-Triazine N-oxide derivatives : studies as potential hypoxic cytotoxins. Part II.
- 2004
-
In: Archiv der Pharmazie. - : Weinheim Verlag. - 0365-6233 .- 1521-4184. ; 337:5, s. 247-258
-
Journal article (peer-reviewed)abstract
- New 1, 2, 4-Triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The starting heterocycles have been prepared using a standard microwave oven in a clean and good-yielded process. The reactivity of methyl-1, 2, 4-triazine N(4)-oxide and N(1), N(4)-dioxide with different electrophilic agents has been studied. The desired products were obtained only when iminium electrophiles were employed. The regioselectivity of this process has been studied by means of experimental and theoretical (at ab initio level) procedures. Theoretically was expected that the most stable intermediates where the benzylic-like anion from position 5. A fact which agreed with the experimental observed regioselectivity. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than tirapazamine, 3-amino-benzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 19, 6-methyl-5-[2-(5-nitrothienyl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective.
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| 4. |
- Cerecetto, H, et al.
(author)
-
1,2,5-Oxadiazole N-oxide derivatives and related compounds as potential antitrypanosomal drugs : structure-activity relationships.
- 1999
-
In: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 42:11, s. 1941-50
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Journal article (peer-reviewed)abstract
- The syntheses of a new series of derivatives of 1,2,5-oxadiazole N-oxide, benzo[1,2-c]1,2,5-oxadiazole N-oxide, and quinoxaline di-N-oxide are described. In vitro antitrypanosomal activity of these compounds was tested against epimastigote forms of Trypanosoma cruzi. For the most effective drugs, derivatives IIIe and IIIf, the 50% inhibitory dose (ID50) was determined as well as their cytotoxicity against mammalian fibroblasts. Electrochemical studies and ESR spectroscopy show that the highest activities observed are associated with the facile monoelectronation of the N-oxide moiety. Lipophilic-hydrophilic balance of the compounds could also play an important role in their effectiveness as antichagasic drugs.
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| 5. |
- Engström, Niklas, 1985, et al.
(author)
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Towards Celiac-safe foods: Decreasing the affinity of transglutaminase 2 for gliadin by addition of ascorbyl palmitate and ZnCl2 as detoxifiers
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 7:77
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Journal article (peer-reviewed)abstract
- Initiation of celiac disease is triggered in the gastrointestinal tract by transglutaminase 2 (TG2) assisted deamidation of gluten peptides. Deamidation is a side-reaction to transamidation and occurs if primary amines are absent. In contrast to deamidation, transamidation does not trigger an immune response. The aim of the study was to identify a suitable food additive that interacts with TG2 binding motives in gluten-derived peptides to prevent deamidation/transamidation. Homology modelling of alpha 2-gliadin and computational screening of compounds for their binding affinity to a common TG2 binding motive (P) QLP were done by using computational approaches followed by experimental testing of TG2 activity. A database containing 1174 potential food grade ligands was screened against the model of alpha 2-gliadin (27 out of 33 aa). Out of the five best ligands, ascorbyl palmitate, was observed to decrease TG2 transamidation of gliadin by 82% +/- 2%. To completely silence the transamidation, we added zinc chloride (ZnCl2), and thereby reached a 99% +/- 1% inhibition of TG2 activity. In addition, we conducted a pilot experiment in which ascorbyl palmitate was observed to decrease TG2 deamidation of gliadin completely. We propose ascorbyl palmitate in combination with ZnCl2 with the future perspective to become an additive in celiac-safe foods.
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| 6. |
- Saenz Mendez, Patricia
(author)
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Chapter 14 - Multi-Target Drugs as Master Keys to Complex Diseases: Inverse Docking Strategies and Opportunities
- 2021
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In: Molecular Docking for Computer-Aided Drug Design. - : Academic Press. - 9780128223123 - 9780128223130 ; , s. 295-311
-
Book chapter (other academic/artistic)abstract
- This chapter discusses the change in the paradigm of drug discovery, shifting from the “magic bullet” concept to the “magic shotgun” or “silver bullet” approach, i.e., one-compound—multiple-target model. The concept of polypharmacology and its aspects related to drug discovery and development, such as drug attrition and drug repurposing are presented. Computational multi-target drug design strategies are discussed, particularly focusing on docking approaches (forward and inverse) and by presenting relevant examples available in the literature.
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| 7. |
- Sjögren, Erik, et al.
(author)
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Assessment of Free Drug Concentration in Cyclodextrin Formulations Is Essential to Determine Drug Potency in Functional In Vitro Assays
- 2016
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In: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 105:9, s. 2913-2920
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Journal article (peer-reviewed)abstract
- Cyclodextrins (CD) have the ability to form inclusion complexes with drugs and can be used as excipients to enhance solubility of poorly soluble drugs. To make accurate estimations of the potency of the drug, knowledge of the free drug concentration is important. The aim of this study was to evaluate the applicability of calculated free drug concentrations toward response measurements in a transient receptor potential vanilloid receptor-1 cell-based in vitro assay. This included accounting for potential competitive CD binding of 2 transient receptor potential vanilloid receptor-1 active entities: 1 antagonist, and 1 agonist (capsaicin). Solubility of the CD-drug complexes was measured, and the ligand to substrate affinity in CD formulations was determined according to the phase-solubility technique. The total concentration of antagonist, agonist, CD, and the binding constants between ligands and CD were used to calculate the free concentration of CD ligands. For capsaicin and 2 of the 3 investigated model drugs, the calculated free drug concentration was consistent with the experimental in vitro data while it was overestimated for one of the compounds. In conclusion, the suggested approach can be used to calculate free drug concentration and competitive binding in CD formulations for the application of cell-based drug functionality assays. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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