Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship

  • J Med Chem. 2019 Jul 11;62(13):6063-6082. doi: 10.1021/acs.jmedchem.9b00270.
Triveni Pativada  1 ,  Myung Hwan Kim  1 ,  Jung-Hun Lee  2 ,  Seong Su Hong  2 ,  Chun Whan Choi  2 ,  Yun-Hyeok Choi  2 ,  Woo Jung Kim  2 ,  Da-Woon Song  2 ,  Serk In Park  1 ,  Eun Jung Lee  1 ,  Bo-Yeon Seo  1 ,  Hankyeom Kim  3 ,  Hong Kyu Kim  4 ,  Kee Ho Lee  5 ,  Sung K Ahn  6 ,  Jin-Mo Ku  2 ,  Gil Hong Park  1
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, College of Medicine, Korea Molecular Medicine and Nutrition Research Institute , Korea University , Seoul 02841 , Korea.
  • 2. Bio-Center , Gyeonggido Business & Science Accelerator , Suwon 16229 , Korea.
  • 3. Department of Pathology , Korea University Guro Hospital , Seoul 08308 , Korea.
  • 4. Department of Surgery , Seoul National University Hospital , Seoul 03080 , Korea.
  • 5. Division of Radiation Cancer Research , Korea Institute of Radiological and Biomedical Sciences , Seoul 01812 , Korea.
  • 6. Statistics, Department of Finance and Management Science, College of Business , Washington State University , Pullman , Washington 99164-4746 , United States.
PMID: 31257875 DOI: 10.1021/acs.jmedchem.9b00270
Abstract

(E)-3,4-Dihydroxybenzylideneacetone (compound 1) inhibited receptor activator of NF-κB ligand-induced osteoclastogenesis of C57BL/6 bone marrow monocyte/macrophages with IC50 of 7.8 μM (IC50 of alendronate, 3.7 μM) while stimulating the differentiation of MC3T3-E1 osteoblastic cells, accompanied by the induction of Runt-related transcription factor 2, Alkaline Phosphatase, and osteocalcin. (E)-4-(3-Hydroxy-4-methoxyphenyl)-3-buten-2-one (compound 2c) showed a dramatically increased osteoclast-inhibitory potency with IC50 of 0.11 μM while sustaining osteoblast-stimulatory activity. (E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one (compound 2g) stimulated Alkaline Phosphatase production 2-fold at 50 μM without changing osteoclast-inhibitory activity, compared with compound 1. Oral administration of compounds 1, 2c, and 2g prevented ovariectomy-induced osteoporosis in ddY mice to a degree proportional to their osteoclastogenesis-inhibitory potencies. The administration of 1 (mg/kg)/d compound 2c ameliorated histomorphometry of osteoporotic bone to a degree comparable with 10 (mg/kg)/d alendronate. Conclusively, the in vitro capacity of a few benzylideneacetone derivatives to inhibit osteoclastogenesis supported by independent osteoblastogenesis activation was convincingly reflected in in vivo management of osteoporosis, suggesting a potential novel therapeutics for osteopenic diseases.