Microbial-Catalyzed Baeyer-Villiger Oxidation for 3,4--Triterpenoids as Potential HMGB1 Inhibitors.

Pentacyclic triterpenoids are considered to be the potential HMGB1 inhibitors, but due to the limited number of hydrogen bond donors and the number of rotatable bonds in the rigid skeletons, their further chemical biology research with this target was restricted. To improve these profiles, microbial-catalyzed Baeyer-Villiger oxidation of the primary ursane and oleanane-type triterpenoids including uvaol (), erythrodiol (), oleanolic acid (), and ursolic acid () was performed by CICC 23628. As a result, ten new and one known A-ring cleaved metabolites were obtained and the possible biogenetic pathways were also discussed based on the HPLC-MS analysis. Furthermore, the direct interactions between compounds , , and HMGB1 were observed by the biolayer interferometry technique. Molecular docking revealed that the newly introduced vicinal diol at C-4, C-24, and the hydroxyl group at C-21 of compound are crucial for binding with HMGB1. The cellular assay showed that co-treatment of could significantly block HMGB1-activated nitric oxide release with an IC value of 9.37 μM on RAW 264.7 cells. Altogether, our research provides some insights into 3,4--triterpenes as potential anti-inflammatory candidates for the discovery of novel HMGB1 inhibitors.