2. Academic Validation
  3. Discovery of a novel homoisoflavonoid derivative 5g for anti-osteoclastic bone loss via targeting FGFR1

Discovery of a novel homoisoflavonoid derivative 5g for anti-osteoclastic bone loss via targeting FGFR1

  • Eur J Med Chem. 2024 Mar 27:270:116335. doi: 10.1016/j.ejmech.2024.116335.
Zhihao Chen 1,  Alessandra Marie Encarnacion 2,  Robin Prakash Sirvin Rajan 3,  Hongyuan Yao 2,  Sunwoo Lee 3,  Eunae Kim 4,  Tae-Hoon Lee 5
Affiliations

Affiliations

  • 1 Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • 2 Department of Interdisciplinary Program of Biomedical Engineering, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • 3 Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic of Korea.
  • 4 Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju, 61452, Republic of Korea; Host-directed Antiviral Research Center, College of Veterinary Medicine, Chonnam National University, Gwangju, 61186, Republic of Korea. Electronic address: eunaekim@chosun.ac.kr.
  • 5 Department of Oral Biochemistry, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, 61186, Republic of Korea. Electronic address: thlee83@jnu.ac.kr.
PMID: 38555854 DOI: 10.1016/j.ejmech.2024.116335
Abstract

Several Flavonoids have been shown to exert anti-osteoporosis activity. However, the structure-activity relationship and the mechanism of anti-osteoporosis activity of Flavonoids remain unknown. In this study, we prepared a series of novel homoisoflavonoid (HIF) derivatives to evaluate their inhibitory effects on osteoclastogenesis using TRAP-activity in vitro assay. Then, the preliminary structure-activity relationship was studied. Among the evaluated novel Flavonoids, derivative 5g exerted the most inhibitory bioactivity on primary osteoclast differentiation without interfering with osteogenesis. It was hence selected for further in vitro, in vivo and mechanism of action investigation. Results show that 5g likely directly binds to the Fibroblast Growth Factor receptor 1 (FGFR1), decreasing the activation of ERK1/2 and IκBα/NF-κB signaling pathways, which in turn blocks osteoclastogenesis in vitro and osteoclastic bone loss in vivo. Our study shows that homoisoflavonoid (HIF) derivatives 5g can serve as a potential novel candidate for treating osteoporosis via inhibition of FGFR1.

Keywords

FGFR1; Flavonoids; Osteoclastogenesis; Structure modification.

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