Effects of Novel Diarylpentanoid Analogues of Curcumin on Secretory Phospholipase A2, Cyclooxygenases, Lipo-oxygenase, and Microsomal Prostaglandin E Synthase-1

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Abstract

Arachidonic acid and its metabolites have generated a heightened interest due to their significant role in inflammation. Inhibiting the enzymes involved in arachidonic acid metabolism has been considered as the synergistic anti-inflammatory effect. A series of novel curcumin diarylpentanoid analogues were synthesized and evaluated for their inhibitory effects on activity of secretory phospholipase A2, cyclooxygenases, soybean lipo-oxygenase as well as microsomal prostaglandin E synthase-1. Among the curcumin analogues, compounds 3, 6, 9, 12, and 17 exhibited strong inhibition of secretory phospholipase A2 activity, with IC50 values ranging from 5.89 to 11.02 μm. Seven curcumin analogues 1, 3, 6, 7, 9, 11, and 12 showed inhibition of cyclooxygenases-2 with IC50 values in the range of 46.11 to 94.86 μm, which were lower than that of curcumin. Compounds 3, 6, 7, 12, and 17 showed strong inhibition of lipo-oxygenase enzyme activity. Preliminary screening of diarylpentanoid curcumin analogues for microsomal prostaglandin E synthase-1 activity revealed that four diarylpentanoid curcumin analogues 5, 6, 7, and 13 demonstrated higher inhibition of microsomal prostaglandin E synthase-1 activity with IC50 ranging from 2.41 to 4.48 μm, which was less than that of curcumin. The present results suggest that some of these diarylpentanoid analogues were able to inhibit the activity of these enzymes. This raises the possibility that diarylpentanoid analogues of curcumin might serve as useful starting point for the design of improved anti-inflammatory agents.

A series of novel diarylpentanoid analogues of curcumin was synthesized by direct coupling of the appropriate aromatic aldehyde with three ketones, namely cyclohexanone, acetone, and cyclopentanone, under base-catalyzed Claisen–Schmidt condensation reaction. These analogues were screened for their inhibitory effects on the activity of secretory phospholipase A2 (sPLA2), cyclooxygenases, soybean lipo-oxygenase as well as microsomal prostaglandin E synthase-1 using in vitro assays.

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