Journal
BIOORGANIC CHEMISTRY
Volume 87, Issue -, Pages 638-646Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2019.03.066
Keywords
NF-kappa B inhibitors; alpha,beta-unsaturated enone; Osteoclastogenesis; RANKL
Funding
- Natural Science Foundation of China [81573310, 81473138, 81803361]
- GD-NSF [2018A030310143]
- Western Australia Medical & Health Research Infrastructure Fund
- Arthritis Australia foundation
- University of Western Australia (UWA) Research Collaboration Awards
- Australian Health and Medical Research Council (NHMRC) [1107828, 1127156]
- National Health and Medical Research Council of Australia [1127156] Funding Source: NHMRC
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The alpha,beta-unsaturated-enone contained natural products have been reported showing NF-kappa B inhibition effect. It is well known that NF-kappa B inhibitors can also be used to inhibit osteoclastogenesis. In a continual discovery new agents for anti-osteoclastogenesis, 8 different type compounds with alpha,beta-unsaturated-enone fragments from our in-house library were evaluated for NF-kappa B inhibition and anti-osteoclastogenesis. Experimental results indicated five compounds exhibited inhibition of NF-kappa B signal pathway. Among them, one compound ((E)-2-(4-fluorobenzylidene)-3,4-dihydronaphthalen-1(2H)-one, 6a) simultaneously inhibits both osteoclastogenesis and NF-kappa B signal pathway. Furthermore, 12 compounds with similar scaffold with 6a were tested for anti-osteoclastogenesis. As a result, 9 compounds inhibited both NF-kappa B and osteoclastogenesis. Among them, compound 6b is the most potent inhibitor against NF-kappa B (IC50 = 2.09 mu M) and osteoclast differentiation (IC50 = 0.86 mu M). Further studies show that compound 6b blocks the phosphorylation of both p65 and I kappa B alpha, and suppresses NF-kappa B targeted gene expression without interfering MAPKs and PI3K/Akt signal transduction pathways. This study demonstrates that we can identify promising synthesized compounds with new scaffolds as therapeutic solutions against osteoclastogenesis inspired by the privileged fragment derived from natural leads.
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