Synthesis, Biological Evaluation, and Molecular Docking Study of 3-Amino and 3-Hydroxy-seco A Derivatives of α-Amyrin and 3-Epilupeol as Inhibitors of COX-2 Activity and NF-kB Activation

Abstract

In this study, a series of novel 3-seco-A derivatives of the natural triterpenes α-amyrin (1) and 3-epilupeol (2) were synthesized by a one-pot radical scission−oxidation procedure and evaluated in vitro and in vivo for their capacity to inhibit the inflammatory process. For the in vitro studies, the trans-4-hydroxy-L-proline methyl ester derivatives (1f and 2f) were consistently effective in inhibiting NO, IL-6, and TNF-α secretion, as well as inhibition of NF-κB activation, in RAW cells stimulated by LPS. The further in vivo anti-inflammatory study revealed that the trans-4-hydroxy-L-proline methyl ester derivatives (1f and 2f), together with 1g, were the most effective in inhibiting TPA-induced edema. Interestingly, the α-amyrin derivatives were the most potent inhibitors of COX-2, but inhibited COX-1 only to some extent. The hydroxyl derivative (1c) was selective for COX-2 inhibition (66.3 ± 1.1% at 17.5 μM) without affecting the COX-1 isoform and did not present toxicity. Molecular docking studies revealed that these compounds bind with their polar region in the cavity over Arg-120, and their lipophilic part is orientated to the HEM cofactor similarly to the natural substrate arachidonic acid in the catalytic site of COX-2. These results indicated that seco-A ursane derivatives could be considered promising candidates for the future development of selective NF-κB and COX-2 inhibitors.

Autophagy activation alleviates the LPS‐induced inflammatory response in endometrial epithelial cells in dairy cows

“…NF-κB is a vital transcription factor that affects the expression of various inflammatory genes, such as IL-6 and TNF-α. 41 Our results revealed that LPS activated the NF-κB signaling pathway, thereby increasing IκB and p65 phosphorylation and IκB degradation. Previous studies have shown that LPS triggers inflammatory diseases by regulating the NF-κB signaling pathway.…”

“…LPS activated the mRNA expression of IL‐6, IL‐8 and TNF‐α at all the indicated time points. NF‐κB is a vital transcription factor that affects the expression of various inflammatory genes, such as IL‐6 and TNF‐α 41 . Our results revealed that LPS activated the NF‐κB signaling pathway, thereby increasing IκB and p65 phosphorylation and IκB degradation.…”

Discovering the Active Ingredients of Medicine and Food Homologous Substances for Inhibiting the Cyclooxygenase-2 Metabolic Pathway by Machine Learning Algorithms

“…Several typical binding modes of non-steroidal anti-inflammatory drugs (NSAIDs) interacting with COX-2 have been reported. These modes include the hydrophobic region of NSAIDs interacting with Tyr385, Trp387, and neighboring residues; the polar region of NSAIDs interacting with residues located above Tyr355; NSAIDs with negative charges interacting with Arg120 [47].…”