Synthesis of unsymmetrical monocarbonyl curcumin analogues with potent inhibition on prostaglandin E2 production in LPS-induced murine and human macrophages cell lines

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 10; pp. 2531 - 2538
• Main Authors: Mohd Aluwi, Mohd Fadhlizil Fasihi, Rullah, Kamal, Yamin, Bohari M., Leong, Sze Wei, Abdul Bahari, Mohd Nazri, Lim, Sock Jin, Mohd Faudzi, Siti Munirah, Jalil, Juriyati, Abas, Faridah, Mohd Fauzi, Norsyahida, Ismail, Nor Hadiani, Jantan, Ibrahim, Lam, Kok Wai
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.05.2016
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Cell Line; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Curcumin - analogs & derivatives; Curcumin - chemistry; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - chemical synthesis; Cyclooxygenase 2 Inhibitors - chemistry; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2; Dinoprostone - antagonists & inhibitors; Dinoprostone - metabolism; Humans; I-kappa B Kinase - chemistry; I-kappa B Kinase - metabolism; Inhibitory Concentration 50; Lipopolysaccharides - pharmacology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mitogen-Activated Protein Kinase 9 - chemistry; Mitogen-Activated Protein Kinase 9 - metabolism; Molecular Docking Simulation; Prostaglandin E2; RAW264.7; Single-crystal XRD; U937; Unsymmetrical curcumin analogues; Prostaglandin E2; Unsymmetrical curcumin analogues; Single-crystal XRD; Cyclooxygenase-2; RAW264.7; U937; Prostaglandin E
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2016.03.092

[Display omitted] The syntheses and bioactivities of symmetrical curcumin and its analogues have been the subject of interest by many medicinal chemists and pharmacologists over the years. To improve our understanding, we have synthesized a series of unsymmetrical monocarbonyl curcumin analogues and evaluated their effects on prostaglandin E2 production in lipopolysaccharide-induced RAW264.7 and U937 cells. Initially, compounds 8b and 8c exhibited strong inhibition on the production of PGE2 in both LPS-stimulated RAW264.7 (8b, IC50=12.01μM and 8c, IC50=4.86μM) and U937 (8b, IC50=3.44μM and 8c, IC50=1.65μM) cells. Placing vanillin at position Ar2 further improved the potency when both compounds 15a and 15b significantly lowered the PGE2 secretion level (RAW264.7: 15a, IC50=0.78μM and 15b, IC50=1.9μM while U937: 15a, IC50=0.95μM and 15b, IC50=0.92μM). Further experiment showed that compounds 8b, 8c, 15a and 15b did not target the activity of downstream inflammatory COX-2 mediator. Finally, docking simulation on protein targets COX-2, IKK-β, ERK, JNK2, p38α and p38β were performed using the conformation of 15a determined by single-crystal XRD.