2. Academic Validation
  3. Synthesis and Biological Evaluation of Heterocyclic Ring-Fused 20( S)-Protopanaxadiol Derivatives as Potent Antiosteoporosis Agents

Synthesis and Biological Evaluation of Heterocyclic Ring-Fused 20( S)-Protopanaxadiol Derivatives as Potent Antiosteoporosis Agents

  • J Med Chem. 2023 Sep 14;66(17):11965-11984. doi: 10.1021/acs.jmedchem.3c00601.
Shuan-Jing Wang 1,  Jiahui Zhang 2,  Jing-Zan Zhang 1,  Ruo-Nan Ning 2,  Chen-Chen Li 1,  Xing Xu 2,  Min Jiang 2,  Wen-Wei Qiu 1
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China.
  • 2 Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, 200025 Shanghai, China.
PMID: 37597216 DOI: 10.1021/acs.jmedchem.3c00601
Abstract

A series of heterocyclic ring-fused derivatives of 20(S)-protopanaxadiol (PPD) were synthesized and evaluated for their inhibitory effects on RANKL-induced osteoclastogenesis. Among these compounds, 33 (SH491, IC50 = 11.8 nM) showed the highest potency with 100% inhibition at 0.1 μM and 44.4% inhibition at an even lower concentration of 0.01 μM, which was much more potent than the lead compound PPD (IC50 = 10.3 μM). Cytotoxicity tests indicated that the inhibitory effect of these compounds on RANKL-induced osteoclast differentiation was not due to their cytotoxicity. Interestingly, SH491 also exhibited a notable impact on the osteoblastogenesis of MC3T3-E1 preosteoblasts. Mechanistic studies revealed that SH491 inhibits the expression of osteoclastogenesis-related marker genes and proteins, including TRAP, CTSK, MMP-9, and ATPase v0d2. In vivo, SH491 could dramatically decrease the ovariectomy-induced osteoclast activity and relieve osteoporosis obviously. Thus, these PPD derivatives could be served as promising leads for the development of novel antiosteoporosis agents.

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