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.

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.