Zhao, Yi-Shu; Qian, Xing-Kai; Guan, Xiao-Qing; Song, Pei-Fang; Song, Yun-Qing; He, Rong-Jing; Sun, Meng-Ru; Wang, Xiu-Yang; Zou, Li-Wei; Ge, Guang-Bo published the artcile< Discovery of natural alkaloids as potent and selective inhibitors against human carboxylesterase 2>, Name: (41S,7aR,13aR,13bR)-Dodecahydro-1H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10(41H)-one, the main research area is natural alkaloid screening carboxylesterase inhibitor structure; Alkaloids; Human carboxylesterase 2A (hCES2A); Inhibitor; Reserpine.
Human Carboxylesterase 2A (hCES2A), one of the most important serine hydrolases, plays crucial roles in the hydrolysis and the metabolic activation of a wide range of esters and amides. Increasing evidence has indicated that potent inhibition on intestinal hCES2A may reduce the excessive accumulation of SN-38 (the hydrolytic metabolite of irinotecan with potent cytotoxicity) in the intestinal tract and thereby alleviate the intestinal toxicity triggered by irinotecan. In this study, more than sixty natural alkaloids have been collected and their inhibitory effects against hCES2A are assayed using a fluorescence-based biochem. assay. Following preliminary screening, seventeen alkaloids are found with strong to moderate hCES2A inhibition activity. Primary structure-activity relationships (SAR) anal. of natural isoquinoline alkaloids reveal that the benzo-1,3-dioxole group and the aromatic pyridine structure are beneficial for hCES2A inhibition. Further investigations demonstrate that a steroidal alkaloid reserpine exhibits strong hCES2A inhibition activity (IC50 = 0.94μM) and high selectivity over other human serine hydrolases including hCES1A, dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin. Inhibition kinetic analyses demonstrated that reserpine acts as a non-competitive inhibitor against hCES2A-mediated FD hydrolysis. Mol. docking simulations demonstrated that the potent inhibition of hCES2A by reserpine could partially be attributed to its strong σ-π and S-π interactions between reserpine and hCES2A. Collectively, our findings suggest that reserpine is a potent and highly selective inhibitor of hCES2A, which can be served as a promising lead compound for the development of more efficacious and selective alkaloids-type hCES2A inhibitors for biomedical applications.
Bioorganic Chemistry published new progress about Alkaloids Role: PAC (Pharmacological Activity), THU (Therapeutic Use), BIOL (Biological Study), USES (Uses). 6882-68-4 belongs to class naphthyridine, and the molecular formula is C15H24N2O, Name: (41S,7aR,13aR,13bR)-Dodecahydro-1H-dipyrido[2,1-f:3′,2′,1′-ij][1,6]naphthyridin-10(41H)-one.
Referemce:
1,8-Naphthyridine – Wikipedia,
1,8-Naphthyridine | C8H6N2 – PubChem