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The role of intramolecular self-destruction of reactive metabolic intermediates in determining toxicity
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2016 (English)In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 36, no 4, 483-500 p.Article, review/survey (Refereed) Published
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Abstract [en]

When reactive centers are formed in chemical conversions, intermolecular reactions tend to dominate over intramolecular alternatives whenever both alternatives are possible. Hence, when reactive metabolites are formed from xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may play an important role in reducing toxicity related to reactive intermediates. The phenomenon is likely to be particularly noticeable for toxicophores that are readily associated with a type of toxicity that is rarely caused by other structural motives. In two demonstrative investigations, it is concluded that nitrobenzenes for which the expected nitrosyl metabolite is likely to react with adjacent groups are less toxic than what is rationally expected, and that among aryl amine drugs allowing for the immediate quenching of the corresponding N-aryl hydroxylamine metabolite, the typical erythrocyte toxicity often seen with aryl amines is absent. The deliberate introduction of effective quenching groups nearby a toxicophoric moiety may present a potential strategy for reducing toxicity in the design of drugs and other man-made xenobiotics. Copyright (c) 2015 John Wiley & Sons, Ltd. Intermolecular reactions tend to dominate over intramolecular alternatives when both alternatives are possible. Consequently, for reactive metabolites of xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may reduce toxicity related to reactive intermediates. In two demonstrative cases, nitrobenzenes and aryl amine drugs, the toxicity characteristic of the toxicophore is absent for drugs that can undergo intramolecular quenching.

Place, publisher, year, edition, pages
2016. Vol. 36, no 4, 483-500 p.
Keyword [en]
drug design, medicinal chemistry, prescriptive toxicology, reactive intermediates, self-quenching
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-284639DOI: 10.1002/jat.3248ISI: 000370152900001PubMedID: 26542997OAI: oai:DiVA.org:uu-284639DiVA: diva2:920885
Available from: 2016-04-19 Created: 2016-04-19 Last updated: 2017-11-30Bibliographically approved

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