Inhibition of prostaglandin E2 production by synthetic minor prenylated chalcones and flavonoids: Synthesis, biological activity, crystal structure, and in silico evaluation

• Main Authors: Abas, F. (Author), Abdul Bahari, M.N (Author), Ahmad, S. (Author), Ismail, N.H (Author), Jantan, I. (Author), Mohd Aluwi, M.F.F (Author), Rullah, K. (Author), Wai, L.K (Author), Wei, L.S (Author), Yamin, B.M (Author)
• Format: Article
• Language: English
• Published: Elsevier Ltd 2014
• Subjects: ADMET prediction; alkylation; animal; animal cell; Animals; antagonists and inhibitors; Article; binding site; Binding Sites; biosynthesis; carbon nuclear magnetic resonance; cell death; cell line; Cell Line; cell survival; Cell Survival; cell viability; chalcone derivative; Chalcones; chemical structure; chemistry; chromatography; computer model; controlled study; COX-2 inhibitor; crystal structure; cyclooxygenase 2; Cyclooxygenase 2; Dinoprostone; dose response; Dose-Response Relationship, Drug; drug binding site; drug cytotoxicity; drug determination; drug effects; drug screening; drug structure; drug synthesis; flavonoid; Flavonoids; human; Humans; hydrogen; hydrogen bond; IC50; Intramolecular Oxidoreductases; isomerase; lipopolysaccharide; Lipopolysaccharides; macrophage; metabolism; Mice; Minor flavonoids; Models, Molecular; molecular docking; Molecular Structure; mouse; MTT assay; Murinae; n (2 cyclohexyloxy 4 nitrophenyl)methanesulfonamide; nonhuman; Prenylated chalcone; prostaglandin E synthase; prostaglandin E2; prostaglandin inhibitor; prostaglandin synthesis inhibition; proton nuclear magnetic resonance; Single-crystal XRD; structure activity relation; Structure-Activity Relationship; Suzuki reaction; synthesis; X ray diffraction
• Online Access: View Fulltext in Publisher; View in Scopus
• ISBN: 0960894X (ISSN)
• DOI: 10.1016/j.bmcl.2014.06.061

The discovery of potent inhibitors of prostaglandin E2 (PGE 2) synthesis in recent years has been proven to be an important game changer in pharmaceutical industry. It is known that excessive production of PGE2 triggers a vast array of biological signals and physiological events that contributes to inflammatory diseases such as rheumatoid arthritis, atherosclerosis, cancer, and pain. In this Letter, we report the synthesis of a series of minor prenylated chalcones and flavonoids which was found to be significantly active in suppressing the PGE2 production secreted by lipopolysaccharide-induced mouse macrophage cells (RAW 264.7). Among the compounds tested, 14b showed a dose-response inhibition of PGE2 production with an IC50 value of 2.1 μM. The suppression upon PGE2 secretion was not due to cell death since 14b did not reduce the cell viability in close proximity to the PGE2 inhibition concentration. The obtained atomic coordinates for the single-crystal XRD of 14b was then applied in the docking simulation to determine the potential important binding interactions with murine COX-2 and mPGES-1 putative binding sites. © 2014 Elsevier Ltd. All rights reserved.