The role of intramolecular self‐destruction of reactive metabolic intermediates in determining toxicity

Abstract

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.

Silicon switch: Carbon–silicon Bioisosteric replacement as a strategy to modulate the selectivity, physicochemical, and drug‐like properties in anticancer pharmacophores

“…This difference in bonding behavior allows for a novel chemical space and offers the unique possibility to develop bioisosteres that do not have stable carbon counterparts. Startlingly, some geminal silicon diols prepared as a mimic of their unstable hydrated carbon counterparts appeared to drastically influence the overall metabolic pathway of the resulting bioactive organosilicon molecule (Johansson et al, 2010; Juers et al, 2005; Kim et al, 2002; Kim & Sieburth, 2001, 2004; Svennebring, 2016). This can be eloquently illustrated by the study of the antipsychotic drug haloperidol ( 4 ), which displays neurotoxic side effects attributed to its metabolite (1‐methyl‐4‐phenylpyridinum) responsible for killing dopamine producing neurons in the brain and thus can induce Parkinson disease (Dauer & Przedborski, 2003; Subramanyam et al, 1990; Subramanyam, Pond, et al, 1991; Subramanyam, Woolf, & Castagnoli, 1991).…”

Quest for Novel Chemical Entities through Incorporation of Silicon in Drug Scaffolds

“…The corresponding silicon analog ( 4 ) follows a different metabolic pathway devoid of the dehydrated compound 5 and the toxic pyridinium metabolite. , N-Dealkylation and hydroxylative ring opening were found to be the major pathways leading to metabolites 6 – 8 (Figure ). The inherent stability of the Si–O bond and the instability of the SiC make the molecule adopt this alternative pathway.…”

Structural Insights into Neonicotinoids and N-Unsubstituted Metabolites on Human nAChRs by Molecular Docking, Dynamics Simulations, and Calcium Imaging

“…Generally, regulatory authorities emphasize the importance of including metabolites and metabolism in toxicological risk assessments. This is particularly crucial considering the fact that there are some cases in which metabolism leads to toxification [20][21][22]. It is assumed that other neonicotinoids may also result in more active metabolites, like descyano-thiacloprid (DCNT) and descyano-thiacloprid-olefin (DCNTO).…”