A review of the synthesis, bioanalysis, and chemical reactivity of xenobiotic acyl-coenzyme a thioesters

AbstractIn this review, we describe current methodologies important for addressing the formation of xenobiotic acyl-coenzyme A-thioesters (acyl-CoAs). This includes the synthesis of reference standards of xenobiotic acyl-CoAs as an important tool in developing bioanalytical methods and for evaluating chemical reactivity. The review also describes current challenges and solutions for the LC-MS analysis of xenobiotic acyl-CoAs in biological samples. Reversed-phase chromatography is typically used, and the selection of mobile phases should be carefully considered. As acyl-CoAs are not excreted from cells and are thus not possible to measure directly in plasma or excreta, identification of acyl-CoA dependent metabolites such as amino acid conjugates, acyl carnitines, and metabolites formed through β-oxidation can provide insights into acyl-CoA formation and the possible roles in formation of reactive metabolites. Finally, the chemical reactivity, structure-reactivity relationships, and reactions of acyl-CoAs with proteins are reviewed. Acyl-CoA metabolites have been shown to be chemically mo re reactive than the corresponding acyl glucuronides, which can be an important consideration when metabolic activation of carboxylic acids and potential covalent binding to proteins is evaluated during drug discovery and development.

Source: Medicinal Chemistry Research - August 10, 2023 Category: Chemistry Source Type: research