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

Abstract

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.

Roles of 5‐lipoxygenase and cyclooxygenase‐2 in the biosynthesis of hemiketals E2and D2by activated human leukocytes

“…Curcumin, the main bioactive ingredient in turmeric extract, inhibits the activities of 5‐LOX and COX‐2 but not COX‐1 (35, 36). In addition, it inhibits expression of COX‐2 in monocytes by down‐regulating NF‐κB activity (37, 38).…”

The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites

“…Although in this study curcumin ( 1 ) was unfortunately not used as a control, Mohd Aluwi et al found it to act with an IC 50 value of ca. 16 µM . Therefore, it seems that hexahydrocurcumin ( 1a ) is more potent in this regard than its parent compound, although no direct comparison was made in this case.…”

“…16 µM. 74 Therefore, it seems that hexahydrocurcumin (1a) is more potent in this regard than its parent compound, although no direct comparison was made in this case. A broad range of further bioactivities of hexahydrocurcumin (1a) shows that this compound is a potent bioactive metabolite of curcumin (1) and this has been recently reviewed by Huang et al 75 A number of studies demonstrated that the in vitro antioxidant activity of 1a is at least comparable to that of curcumin as scavenger of DPPH, • NO, and • OH radicals, and as inhibitor of AAPH-induced linoleic oxidation and hemolysis.…”

Design and synthesis of novel pyrazolo[4,3-d]pyrimidines as potential therapeutic agents for acute lung injury

“…Nitric oxide (NO) is an important pro-inflammatory mediator, relating to several inflammatory diseases, such as rheumatoid arthritis, chronic hepatitis and ALI 22,23 . Therefore, inhibition of its overproduction may provide a useful therapy for inflammatory diseases 24 . Treatment of RAW 264.7 cells with LPS stimulated NF-jB signaling pathway, resulting in the production of cytokines including NO, IL-6 and TNF-a.…”