Cyclic Metabolites: Chemical and Biological Considerations

Abstract

Metabolism of xenobiotics can sometimes generate cyclic metabolites. Such metabolites are usually the result of intramolecular reactions occurring within a primary or secondary metabolite and this chemistry may lead to unexpected structures. Intramolecular chemistry is often driven by nucleophilic groups reacting with electrophilic atoms, often carbon, although radical processes also occur. Conjugation of xenobiotics or their metabolites with endogenous thiols, such as glutathione or cysteine, introduce a reactive amino group that can lead to the formation of cyclic structures. Less common than chemically driven cyclizations are enzymatically mediated ring-closures, although this may reflect our incomplete recognition of enzymatic involvement in this step of cyclic metabolite formation. While some cyclic metabolites are biologically inactive, others are biologically active. Thus, a cyclic metabolite may display desirable pharmacology, or, contribute to toxicology. When a cyclic metabolite is identified, it is important to consider the possibility that it is an artifact, i.e. metabonate, that was formed during processing of the sample, for example, through degradation or by chemical reactions with other components present in the matrix. From a medicinal chemistry perspective, a cyclic metabolite with a different chemical scaffold from the parent structure may lead to a new series of structurally novel, biologically active molecules with the same, or different, pharmacology from the parent. This review will cover a selection of cyclic metabolites from a mechanistic point of view, and when possible, discuss their biological relevance.

Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites

“…Enzymatically mediated fused ring formations are relatively uncommon, but have been observed for other drugs (Liu et al, 2007;Takahashi et al, 2015). The cyclization is proposed to be driven by enzymatic nucleophilic (hydroxyl group) attack to electrophilic atoms (iminium carbon) (Erve, 2008). In addition, chiral LC/MS analysis with synthetic standard also confirmed that M27 is one of the two synconfiguration stereoisomers.…”

Glycerolysis of Acyl Glucuronides as an Artifact of in Vitro Drug Metabolism Incubations

“…Several examples of this phenomenon exist in the scientific literature and include oximes (Beckett et al, 1971), imidazolines (Li et al, 2006), phenothiazones (Beckett and Navas, 1978), esters (Dickinson and King, 1989), and many entities arising from internal cyclization reactions (reviewed in Erve, 2008). In the course of the study of the glucuronidation of [ 14 C]benoxaprofen in human liver S-9 fraction, in addition to observation of the expected acyl glucuronide metabolite, an unusual drugrelated entity was also observed (Fig.…”

“…The term metabonate was coined by Beckett in 1971(Beckett et al, 1971 to describe drug-related chemical entities observed in work-ups or storage of biological samples that can be mistaken for drug metabolites. These entities can arise by intramolecular rearrangements of metabolites (e.g., cyclization) (Erve, 2008) or by reaction of metabolites with constituents of sample work-up such as solvents (e.g., methanol) King, 1989, 1991;Chabot and Gouyette, 1991). The objective of these studies was to characterize the formation of the glycerol ester of the carboxylic acid group of benoxaprofen, determine how this process arises, and determine whether other COOH-containing drugs can undergo this reaction and form metabonates.…”

Late-occurring and Long-circulating Metabolites of GABAAα2,3 Receptor Modulator AZD7325 Involving Metabolic Cyclization and Aromatization: Relevance to MIST Analysis and Application for Patient Compliance

“…However, it was unclear whether the dehydration occurred in the solution during the chromatography or in the gas phase of the MS ionization source. The metabolic cyclization of drug molecules by intramolecular nucleophilic attack of a primary or secondary amino group to an imine or iminium intermediate was previously reported in the formation of six-membered or fivemembered cyclic metabolites (Erve, 2008;Nagle et al, 2012). The intermediate 2 contains a cyclic substructure of dihydro pyrimidin-4-one, thus could be prone to metabolic aromatization to form a stable pyrimidin-4-one substructure of the tricyclic core of M9 (Scheme 1).…”