In Vitro Metabolism Study of Seongsanamide A in Human Liver Microsomes Using Non-Targeted Metabolomics and Feature-Based Molecular Networking

Abstract

Seongsanamide A is a bicyclic peptide with an isodityrosine residue discovered in Bacillus safensis KCTC 12796BP which exhibits anti-allergic activity in vitro and in vivo without significant cytotoxicity. The purpose of this study was to elucidate the in vitro metabolic pathway and potential for drug interactions of seongsanamide A in human liver microsomes using non-targeted metabolomics and feature-based molecular networking (FBMN) techniques. We identified four metabolites, and their structures were elucidated by interpretation of high-resolution tandem mass spectra. The primary metabolic pathway associated with seongsanamide A metabolism was hydroxylation and oxidative hydrolysis. A reaction phenotyping study was also performed using recombinant cytochrome P450 isoforms. CYP3A4 and CYP3A5 were identified as the major metabolic enzymes responsible for metabolite formation. Seongsanamide A did not inhibit the cytochrome P450 isoforms commonly involved in drug metabolism (IC50 > 10 µM). These results will contribute to further understanding the metabolism and drug interaction potential of various bicyclic peptides.

Antimetastatic activity of seongsanamide B in γ-irradiated human lung cancer

“…The diaryl ether is functional scaffold that are considered fundamental fragment of a variety of medicinal drugs as well as their bioisosteres [ 33 , 34 ]. Due to the potential structural diversity of seongsanamdies, it is thought that it will be applied to various drugs, but its bioactive properties have not yet been well studied [ 21 ].…”

“…1 A) is a bicyclic peptide isolated from Bacillus safensis KCTC 12796BP [ 20 ]. Its bicyclic structure is considered to confer high conformational rigidity and metabolic stability to the compound [ 21 ]. These features are generally associated with high target specificity and resistance to enzymatic digestion, suggesting the high therapeutic potential of the compound [ 22 , 23 ].…”