Discovery of a novel anti-osteoporotic agent from marine fungus-derived structurally diverse sirenins

  • Eur J Med Chem. 2023 Dec 19:265:116068. doi: 10.1016/j.ejmech.2023.116068.
Jian Cai  1 ,  Li Gao  2 ,  Yue Wang  3 ,  Yuanteng Zheng  2 ,  Xiuling Lin  4 ,  Pingzheng Zhou  4 ,  Chunmei Chen  5 ,  Kechun Liu  2 ,  Lan Tang  4 ,  Yonghong Liu  1 ,  Yanhui Tan  6 ,  Meng Jin  7 ,  Xuefeng Zhou  8
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; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 2. Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Ji'nan, 250103, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Ji'nan, 250103, China.
  • 3. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541001, China.
  • 4. School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou, 510515, China.
  • 5. 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.
  • 6. State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541001, China. Electronic address: [email protected].
  • 7. Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Ji'nan, 250103, China; Engineering Research Center of Zebrafish Models for Human Diseases and Drug Screening of Shandong Province, Ji'nan, 250103, China. Electronic address: [email protected].
  • 8. 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; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: [email protected].
PMID: 38141284 DOI: 10.1016/j.ejmech.2023.116068
Abstract

Thirteen new sirenin derivatives named eupenicisirenins C-O (1-13), along with a biosynthetically related known one (14), were isolated from the mangrove sediment-derived fungus Penicillium sp. SCSIO 41410. The structures, which possessed a rare cyclopropane moiety, were confirmed by extensive analyses of the spectroscopic data, quantum chemical calculations, and X-ray diffraction. Among them, eupenicisirenin C (1) exhibited the strongest NF-κB inhibitory activities, as well as suppressing effects on cGAS-STING pathway. Moreover, 1 showed the significant inhibitory effect on RANKL-induced osteoclast differentiation in bone marrow macrophages cells, and also displayed the therapeutic potential on prednisolone-induced zebrafish osteoporosis. Transcriptome analysis and the following verification tests suggested that its anti-osteoporotic mechanism is related to the extracellular matrix receptor interaction-related pathways. This study provided a promising marine-derived anti-osteoporotic agent for the treatment of skeletal disease.

Keywords
Anti-osteoporosis; Eupenicisirenins; Marine fungus; Sirenins.
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