2. Academic Validation
  3. Identifying Marine-Derived Tanzawaic Acid Derivatives as Novel Inhibitors against Osteoclastogenesis and Osteoporosis via Downregulation of NF-κB and NFATc1 Activation

Identifying Marine-Derived Tanzawaic Acid Derivatives as Novel Inhibitors against Osteoclastogenesis and Osteoporosis via Downregulation of NF-κB and NFATc1 Activation

  • J Med Chem. 2024 Feb 22;67(4):2602-2618. doi: 10.1021/acs.jmedchem.3c01748.
Chunmei Chen 1,  Lingxiang Xiao 2,  Xiaowei Luo 3,  Jian Cai 1,  Lishan Huang 4,  Huaming Tao 4,  Xuefeng Zhou 1,  Yanhui Tan 2,  Yonghong Liu 1 3
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
  • 2 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
  • 3 Guangxi Key Laboratory of Marine Drugs, Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China.
  • 4 Guangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
PMID: 38301128 DOI: 10.1021/acs.jmedchem.3c01748
Abstract

To discover novel osteoclast-targeting antiosteoporosis leads from Natural Products, we identified 40 tanzawaic acid derivatives, including 22 new ones (1-8, 14-19, 27-32, 37, and 38), from the South China Sea mangrove-derived fungus Penicillium steckii SCSIO 41025. Penicisteck acid F (2), one of the new derivatives showing the most potent NF-κB inhibitory activity, remarkably inhibited osteoclast generation in vitro. Mechanistically, 2 reduced RANKL-induced IκBα degradation, NF-κB p65 nuclear translocation, the activation and nuclear translocation of NFATc1, and the relevant mRNA expression. NF-κB p65 could be a potential molecular target for 2, which has been further determined by the cellular thermal shift assay, surface plasmon resonance, and the gene knock-down assay. Moreover, 2 could also alleviate osteoporosis in ovariectomized mice by reducing the quantities of osteoclasts. Our finding offered a novel potential inhibitor of osteoclastogenesis and osteoporosis for further development of potent antiosteoporosis agents.

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