1. Academic Validation
  2. Discovery of new inhibitors against both NF-κB and osteoclastogenesis from in-house library with α, β-unsaturated-enone fragment

Discovery of new inhibitors against both NF-κB and osteoclastogenesis from in-house library with α, β-unsaturated-enone fragment

  • Bioorg Chem. 2019 Jun;87:638-646. doi: 10.1016/j.bioorg.2019.03.066.
Chao Zhao 1 Dane Huang 2 Ruyue Li 3 Jiake Xu 4 Qiong Gu 5 Jun Xu 6
Affiliations

Affiliations

  • 1 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China.
  • 2 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China; Guangdong Province Engineering Technology Research Institute of T. C. M., Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou 510095, People's Republic of China.
  • 3 Guangdong Province Engineering Technology Research Institute of T. C. M., Guangdong Provincial Key Laboratory of Research and Development in Traditional Chinese Medicine, Guangzhou 510095, People's Republic of China; Guangzhou University of Chinese Medicine, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou 510095, People's Republic of China.
  • 4 Molecular Laboratory, School of Biomedical Science, University of Western Australia, Perth, Western Australia, Australia.
  • 5 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China. Electronic address: [email protected].
  • 6 Research Center for Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, People's Republic of China; School of Biotechnology and Health Sciences, Wuyi University, 99 Yingbin Road, Jiangmen 529020, People's Republic of China. Electronic address: [email protected].
Abstract

The α,β-unsaturated-enone contained Natural Products have been reported showing NF-κB inhibition effect. It is well known that NF-κB inhibitors can also be used to inhibit osteoclastogenesis. In a continual discovery new agents for anti-osteoclastogenesis, 8 different type compounds with α,β-unsaturated-enone fragments from our in-house library were evaluated for NF-κB inhibition and anti-osteoclastogenesis. Experimental results indicated five compounds exhibited inhibition of NF-κB signal pathway. Among them, one compound ((E)-2-(4-fluorobenzylidene)-3,4-dihydronaphthalen-1(2H)-one, 6a) simultaneously inhibits both osteoclastogenesis and NF-κB signal pathway. Furthermore, 12 compounds with similar scaffold with 6a were tested for anti-osteoclastogenesis. As a result, 9 compounds inhibited both NF-κB and osteoclastogenesis. Among them, compound 6b is the most potent inhibitor against NF-κB (IC50 = 2.09 μM) and osteoclast differentiation (IC50 = 0.86 μM). Further studies show that compound 6b blocks the phosphorylation of both p65 and IκBα, and suppresses NF-κB 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.

Keywords

NF-κB inhibitors; Osteoclastogenesis; RANKL; α,β–unsaturated enone.

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