Metabolism‐Inspired Electrosynthesis

Abstract

Drug metabolism is a critical stage in the development of new chemical entities to understand how the drug will behave in the body and to reveal potential toxic metabolites. In this Review, we discuss how a renaissance in the applications of synthetic electrochemistry can be employed both to identify drug metabolites (and mechanisms) and enable electrosynthetic preparation of drug metabolites for further analysis. Recent advances in electro‐oxidative drug reactions are reviewed together with a perspective on the future use of electrosynthesis to diversify lead stage drug molecules to enable rapid testing of advanced analogues. A focus on the remarkable advances in the last decade with the inclusion of seminal papers for contextual analysis are reviewed.

Dialling‐In New Reactivity into the Shono‐Type Anodic Oxidation Reaction

“…Incredibly, controlling the current delivered an alternative final product, C − N bond cleavage vs dehydrogenative C − O cross‐coupling (Scheme 5). [43] …”

Development of an electrochemical flow‐through cell for the fast and easy generation of isotopically labeled metabolite standards

“…This top-down approach allows the fast, easy, and controlled synthesis of metabolites from their parent compounds, and the purely instrumental approach grants a simple implementation and clean-up procedure. 10,14,15 Due to the synthesis starting with the parent compound in this approach, isotopically labeled metabolite standards can easily be synthesized from isotopically labeled precursors, which are often already available for drug candidates. These isotopically labeled standards can then be used as internal standards for the quantification of metabolites in metabolic, toxicological, and pharmacokinetic studies.…”

“…Comprehensive overviews about oxidative metabolic phase I reactions and their mimicry by EC have been published by Jurva et al 11 and Johansson et al 12 Apart from the EC/MS setup, EC recently gained attention in electrosynthetic applications for the generation of metabolite standards. [13][14][15] Reference materials are needed for the quantification and identification of metabolites, for toxicological studies, and for the complete structure elucidation of the metabolites. 10,16 Conventionally, metabolite standards are either synthesized via an organic de novo synthesis in a bottom-up approach or by a top-down approach utilizing biomimetic systems like liver microsomes or enzymes on a preparative scale.…”

Electrically Driven N(sp2)–C(sp2/3) Bond Cleavage of Sulfonamides

“…9 The phase I metabolism of drug molecules containing alkylated heteroatoms (e.g., C−N) is an important clearance pathway in the body that determines drug dosing regimens and safety profiles and is of critical importance in drug development. 10,11 Recent attention has been devoted to the synthesis 12 and late stage functionalization 13 of sulfonamides, including their de novo electrochemical synthesis. 14,15 Intriguingly, no overoxidation of the electrochemically prepared sulfonamides was observed during their synthesis.…”