Identification of HDACs Inhibitor E14 Metabolites Appeared in Rat Plasma, Feces and Urine by UPLC-QTOF-MS/MS

Abstract

Background: The activation or overexpression of histone deacetylases (HDACs) are associated with the development of numerous cancers. The importance of HDACs in new anticancer therapeutic strategies has led researchers to develop promising anticancer drugs, design, and synthesis of novel HDACs inhibitors are also in progress. E14 was synthesized and acted as a selective inhibitor of HDACs I. Methods: We develop a sensitive UPLC-QTOF-MS/MS method to discover the new phase Ⅰ and Ⅱ metabolites of E14 from complex biological matrices in plasma, feces and urine of rats. Then a strategy comparing samples after administration with blank samples was applied to distinguish metabolites. The accurate measurements of the product ions obtained by high-resolution mass spectrometry, the structure of the parent drug and its detected metabolites are used to verify its fragmentation pathway and to obtain the proposed structure of the metabolites. Results: Fourteen metabolites were tentatively identified, including twelve metabolites in urine, five in plasma and one metabolite in feces. Hydroxylation, oxidation, methylation, N-demethylation, dehydration, glucuronidation, dehydroxylation and hydrolysis were the main metabolic pathways of E14. Conclusion: E14 is a drug with a variety of metabolites and metabolic pathways. E14 metabolites was excreted most in urine, indicating the main metabolic organ was kidney.