Synthesis and activity of oleanolic acid derivatives, a novel class of inhibitors of osteoclast formation

doi:10.1016/j.bmcl.2005.01.061

Bioorganic & Medicinal Chemistry Letters

Volume 15, Issue 6, 15 March 2005, Pages 1629-1632

https://doi.org/10.1016/j.bmcl.2005.01.061 Get rights and content

Abstract

Two series of oleanolic acid derivatives were synthesized and their inhibitory activity on the formation of osteoclast-like multinucleated cells (OCLs) induced by 1α,25-dihydroxy vitamin D₃ was evaluated in a co-culture assay system. The structure–activity relationships, together with electronic structure based on the frontier molecular orbitals, for example, HOMO and LUMO, related to different amino acid substituents were studied. Derivatives with proline or phenylalanine showed a tendency to enhance the inhibitory activity.

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The experimental results on 23 releases of 10 projects show that COSTE greatly improves the diversity of the synthetic instances without compromising the ability of prediction models to find defects. In addition, COSTE outperforms the other oversampling techniques under the same testing effort. The statistical analysis indicates that COSTE’s ability to outperform the other oversampling techniques is significant under the statistical Wilcoxon rank sum test and Cliff’s effect size.
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Glycyrrhetinic acid (GA), the major bioactive pentacyclic triterpene aglycone of licorice root, was known to play a vital role in anti-ulcer, anti-depressant, anti-inflammatory, and anti-allergic. In this study, we semi-synthesized five GA derivatives by a series of chemical reactions. They were selected as substrates for the biotransformation and yielded thirteen metabolites by Bacillus subtilis ATCC 6633 and Bacillus megaterium CGMCC 1.1741. Their structures were identified on the basis of extensive spectroscopic methods and nine of them were found for the first time. Two main types of reactions, regio- and stereo-selective hydroxylation and glycosylation, especially in the unactivated C-H bonds including C-11, C-19 and C-27, were observed in the biotransformation process, which greatly expand the chemical diversities of GA derivatives. All compounds were tested for their inhibitory effects on nitric oxide (NO) generation in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Among them, olean-12-ene-3β,7β,15α,19α,30-pentol (16) and olean-12-ene-3β,7β,15α,27,30-pentol (17) showed significant inhibitory effect with IC₅₀ values of 0.64 and 0.07 μM, respectively.
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Citation Excerpt :
Bone resorption of osteoclast may play more important role in this equilibrium. Osteoclast has become a potential therapeutic target, and many natural plant-derived compounds can regulate the function of osteoclast including icariin and OA [26,27]. Many scholars reported that OA inhibited RANKL-induced osteoclastogenesis via RANKL signaling pathway in RAW264.7 cell [4].
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2019, Bioorganic Chemistry
Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer’s disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman’s assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of K_i = 4.29 μM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing K_i = 1.72 µM and K_i′ = 1.28 μM, respectively.

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Synthesis and activity of oleanolic acid derivatives, a novel class of inhibitors of osteoclast formation

Abstract

Graphical abstract

Eur. J. Pharmacol.

Can. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Biochem. Biophys. Res. Commun.

Environ. Toxicol. Pharmacol.

Postgrad. Med.