Glutathione trapping of reactive drug metabolites produced by biomimetic metalloporphyrin catalysts

Lassila, Toni; Mattila, Sampo; Turpeinen, Miia; Tolonen, Ari

doi:10.1002/rcm.7129

Cited by 7 publications

(4 citation statements)

References 19 publications

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“…Electrophiles that occur during metabolism form conjugates with intracellular macromolecules and constituents of the antioxidant system (primarily with glutathione); this causes its depletion and contributes to hepatocytes necrosis. For these reasons, early drug development processes include strategies for the detection of reactive metabolites by means of trapping assays with glutathione [36,37,38].…”

Section: Resultsmentioning

confidence: 99%

Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity

et al. 2019

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Epilepsy is one of the most common neurological disorder in the world. Many antiepileptic drugs cause multiple adverse effects. Moreover, multidrug resistance is a serious problem in epilepsy treatment. In the present study we evaluated the safety profile of three (1–3) new chiral N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol demonstrating anticonvulsant activity. Our aim was also to determine differences between the enantiomeric compounds with respect to their safety profile. The results of the study indicated that compounds 1–3 are non-cytotoxic for astrocytes, although they exhibit cytotoxic activity against human glioblastoma cells. Moreover, 1–3 did not affect the viability of HepG2 cells and did not produce adducts with glutathione. Compounds 1–3 demonstrated no mutagenic activity either in the Salmonella typhimurium or in Vibrio harveyi tests. Additionally, the compounds displayed a strong or moderate antimutagenic effect. Finally, the P-glycoprotein (P-gp) ATPase assay demonstrated that both enantiomers are potent P-gp inhibitors. To sum up, our results indicate that the newly synthesized derivatives may be considered promising candidates for further research on anticonvulsant drug discovery and development. Our study indicated the similar safety profile of the enantiomeric N-aminoalkyl derivatives of trans-2-aminocyclohexan-1-ol, although in the previous studies both enantiomers differ in their biotransformation pathways and pharmacological activity.

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Section: Resultsmentioning

confidence: 99%

Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity

et al. 2019

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“…Based on structural similarity, synthetic metalloporphyrins can be used to mimic the monooxygenase or mixed-function oxidase activity of the CyP450 enzymes using organic peroxides or H 2 O 2 as oxygen donors. Due to the specific catalytic activity of monooxygenase, metalloporphyrin-catalyzed oxidations can generally be considered biomimetic oxidative systems [10][11][12][13][14], which can also be supported by the fact that these systems could directly and robustly generate oxidative metabolites from the parent compound. However, metalloporphyrin analogues were successfully used for biomimetic reactions in many cases.…”

Section: Effect Of Binding Linkers On the Efficiency And Metabolite P...mentioning

confidence: 99%

Effect of Binding Linkers on the Efficiency and Metabolite Profile of Biomimetic Reactions Catalyzed by Immobilized Metalloporphyrin

et al. 2022

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The investigation of liver-related metabolic stability of a drug candidate is a widely used key strategy in early-stage drug discovery. Metalloporphyrin-based biomimetic catalysts are good and well-described models of the function of CyP450 in hepatocytes. In this research, the immobilization of an iron porphyrin was performed on nanoporous silica particles via ionic interactions. The effect of the metalloporphyrin binding linkers was investigated on the catalytic efficiency and the metabolic profile of chloroquine as a model drug. The length of the amino-substituted linkers affects the chloroquine conversion as well as the ratio of human major and minor metabolites. While testing the immobilized catalysts in the continuous-flow reactor, results showed that the presented biomimetic system could be a promising alternative for the early-stage investigation of drug metabolites regarding analytical or synthetic goals as well.

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“…Clozapine is commonly used as a model compound that undergoes bioactivation to a nitrenium intermediate which, in turn, readily forms a glutathione conjugate. 28,29 A value of zero implies that no adduct was detected for the test compound while a value greater than one implies the sum of adduct peak areas for the test compound is greater than the area of the clozapine adduct peak. This implies that the compound has a higher potential for bioactivation than clozapine.…”

Section: Bioactivation Studies On Previously Synthesized Analoguesmentioning

confidence: 99%

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

Ongarora

Strydom

Wicht

et al. 2015

Bioorganic & Medicinal Chemistry

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A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogs, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10 mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. KEYWORDS: amodiaquine, benzoxazole, antiplasmodial activity, antimalarial activity, malaria, reactive metabolite, 4-aminoquinolines; bioactivation; structure-activity relationship; β-hematin; quinone imine. INTRODUCTIONMalaria remains a leading cause of morbidity and mortality globally. In 2012, there were an estimated 207 million cases of malaria and 627 000 deaths worldwide, with 90% of all malaria deaths occurring in sub-Saharan Africa. 1 One of the biggest challenges facing malaria chemotherapy is the rapid emergence of resistance to existing antimalarial drugs. 2 This challenge underscores the need for the continued search for new antimalarials.Chloroquine (1) (structure shown in Figure 1), was undoubtedly one of the most successful antimalarials ever owing to its good efficacy and low cost which made it affordable especially in the developing countries with high malaria endemicity. 3 Chloroquine was replaced as first line therapy by the sulfonamide antimalarials and, later on, artemisinin combination therapy (ACT), following the development of widespread resistance against the drug by Plasmodium falciparum. 4An aromatic side chain analogue of chloroquine, amodiaquine (2), however, retains activity against chloroquine-resistant Plasmodium strains. 5 Besides, it is an established fact that resistance against these 4-aminoquinolines is not a result of target modification but is caused by impaired accumulation of the drug at the target. 6,7 Consequently, amodiaquine is an attractive lead compound in the search for new antimalarials. Despite the desirable antimalarial efficacy of amodiaquine, chronic use especially during prophylaxis has been found to precipitate severe hepatotoxicity, myelotoxicity and agranulocytosis. 8,9 This toxicity has been attributed to the bioactivation of amodiaquine to reactive quinone imine (3) and aldehyde quinone imine (4) metabolites (figure 1) which covalently bind to cellular macromolecules causing drug-induced toxicity and cell damage di...

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Glutathione trapping of reactive drug metabolites produced by biomimetic metalloporphyrin catalysts

Cited by 7 publications

References 19 publications

Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity

Similar Safety Profile of the Enantiomeric N-Aminoalkyl Derivatives of Trans-2-Aminocyclohexan-1-ol Demonstrating Anticonvulsant Activity

Effect of Binding Linkers on the Efficiency and Metabolite Profile of Biomimetic Reactions Catalyzed by Immobilized Metalloporphyrin

Antimalarial benzoheterocyclic 4-aminoquinolines: Structure–activity relationship, in vivo evaluation, mechanistic and bioactivation studies

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