Metabolite profiling of remibrutinib in rat and human liver microsomes using liquid chromatography combined with benchtop orbitrap high-resolution mass spectrometry.

Remibrutinib is a potent and highly selective covalent Bruton's tyrosine kinase inhibitor that is undergoing clinical development for the treatment of autoimmune diseases. The present study was undertaken to investigate the in vitro metabolism of remibrutinib and to propose its biotransformation pathways. The metabolites were generated by incubating remibrutinib (2 µm) with human and rat liver microsomes at 37°C for 30 min. Ultra-high-performance liquid chromatography combined with benchtop orbitrap high-resolution mass spectrometry was used to identify and characterize the metabolites of remibrutinib. Compound Discoverer software was employed to process the acquired data. In rat liver microsomes, a total of 18 metabolites have been identified and characterized among which three (M8, M12 and M13) were identified as the most abundant metabolites. In human liver microsomes, a total of 16 metabolites have been identified, and M8 and M12 were identified as the predominant metabolites. All the metabolites were nicotinamide adenine dinucleotide phosphate dependent. The major metabolic changes were found to be oxygenation, dealkylation, demethylation, epoxidation and hydrolysis. The present study comprehensively reports the in vitro metabolism of remibrutinib mentioning 20 metabolites. These findings will help investigation of remibrutinib disposition and safety evaluation.

Comparison of nutritional quality and volatile flavor compounds among bighead carp from three aquaculture systems.

To explore the differences in the nutritional quality of the muscles of bighead carp from different environments and aquaculture systems, we investigated three types of water bodies typically used for aquaculture: A common culture pond (NC), a natural lake (PY), and a cold water reservoir (XHK). Parameters affecting quality were evaluated, including muscle microstructure, fatty acid profiles, amino acid profiles, and volatile compounds. Fish from the XHK reservoir had the smallest muscle fiber diameter and the highest muscle fiber density (25.3 fibers/0.01 mm2), while muscle fiber density was lowest in fish from the NC pond (9.7 fibers/0.01 mm2). The bighead carp from the XHK reservoir had a much wider variety of unsaturated fatty acids, as well as higher levels of total polyunsaturated fatty acids. Eicosapentaenoic acid (EPA), docosahexenoic acid (DHA), and arachidonic acid (AA) were all significantly more abundant in the XHK group, increases of 7.48%, 12.12%, and 17.49%, respectively (P < 0.05). The bighead carp from NC contained more "fishy" volatile flavor substances, as well as hydrocarbons with higher threshold values. Fish from XHK and NC had a greater umami intensity due to the presence of abundant volatiles with special aromas, including 1-Octene-3ol, DL-Menthol, and 2-ethyl-.

Electronic and Optical Properties of van der Waals Heterostructures Based on Two-Dimensional Perovskite (PEA)2PbI4 and Black Phosphorus.

Combining two-dimensional (2D) perovskites with other 2D materials to form a van der Waals (vdW) heterostructure has emerged as an intriguing way of designing electronic and optoelectronic devices. The structural, electronic, and optical properties of the 2D (PEA)2PbI4/black phosphorus (BP) [PEA:(C4H9NH3)+] vdW heterostructure have been investigated using first-principles calculations. We found that the (PEA)2PbI4/BP heterostructure shows a high stability at room temperature. It is demonstrated that the (PEA)2PbI4/BP heterostructure exhibits a type-I band arrangement with high carrier mobility. Moreover, the band gap and band offset of (PEA)2PbI4/BP can be effectively modulated by an external electric field, and a transition from semiconductor to metal is observed. The band edges of (PEA)2PbI4 and BP in the (PEA)2PbI4/BP heterostructure, which show significant changes with the external electric field, provide further support. Furthermore, the BP layers can enhance the light absorption of the (PEA)2PbI4/BP heterostructures. Our results indicate that the 2D perovskite and BP vdW heterostructures are competitive candidates for the application of low-dimensional photovoltaic and optoelectronic devices.

NBGNU: a hypoxia-activated tripartite combi-nitrosourea prodrug overcoming AGT-mediated chemoresistance.

Aim: A hypoxia-activated combi-nitrosourea prodrug, N-(2-chloroethyl)-N'-2-(2-(4-nitrobenzylcarbamate)-O6-benzyl-9-guanine)ethyl-N-nitrosourea (NBGNU), was synthesized and evaluated for its hypoxic selectivity and anticancer activity in vitro. Results: The prodrug was designed as a tripartite molecule consisting of a chloroethylnitrosourea pharmacophore to induce DNA interstrand crosslinks (ICLs) and an O6-benzylguanine analog moiety masked by a 4-nitrobenzylcarbamate group to induce hypoxia-activated inhibition of O6-alkylguanine-DNA alkyltransferase. NBGNU was tested for hypoxic selectivity, cytotoxicity and DNA ICLs ability. The reduction product amounts, cell death rates and DNA ICL levels induced by NBGNU under hypoxic conditions were all significantly higher than those induced by NBGNU under normoxic conditions. Conclusion: The tripartite combi-nitrosourea prodrug exhibits desirable tumor-hypoxia targeting ability and abolished chemoresistance compared with the conventional chloroethylnitrosoureas.

Synthesis and Antitumor Activity Evaluation of a Novel Combi-nitrosourea Prodrug: BGCNU.

Chloroethylnitrosoureas (CENUs) are an important type of alkylating agent employed in the clinical treatment of cancer. However, the anticancer efficacy of CENUs is greatly decreased by a DNA repairing enzyme, O6-alkylguanine-DNA alkyltransferase (AGT), by preventing the formation of interstrand cross-links (ICLs). In this study, a combi-nitrosourea prodrug, namely, N-(2-chloroethyl)-N'-2-(O6-benzyl-9-guanine)ethyl-N-nitrosourea (BGCNU), which possesses an O6-benzylguanine (O6-BG) derivative and CENU pharmacophores simultaneously, was synthesized and evaluated for its ability to induce ICLs. The target compound is markedly more cytotoxic in human glioma cells than the clinically used CENU chemotherapies ACNU, BCNU, and their respective combinations with O6-BG. In the AGT-proficient cells, significantly higher levels of DNA ICLs were observed in the groups treated by BGCNU than those by ACNU and BCNU, which indicated that the activity of AGT was effectively inhibited by the O6-BG derivatives released from BGCNU.