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

Triveni Pativada, Myung Hwan Kim, Jung Hun Lee, Seong Su Hong, Chun Whan Choi, Yun Hyeok Choi, Woo Jung Kim, Da Woon Song, Serkin Park, Eun Jung Lee, Bo Yeon Seo, Hankyeom Kim, Hong Kyu Kim, Kee Ho Lee, Sung K. Ahn, Jin Mo Ku, Gil Hong Park

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)6063-6082
Number of pages20
JournalJournal of Medicinal Chemistry
Volume62
Issue number13
DOIs
Publication statusPublished - 2019 Jun 19

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Structure-Activity Relationship
Osteogenesis
Inhibitory Concentration 50
Alendronate
Osteoclasts
Osteoporosis
Alkaline Phosphatase
Osteocalcin
Ovariectomy
Osteoblasts
Oral Administration
Monocytes
Transcription Factors
Bone Marrow
Macrophages
Ligands
Bone and Bones
benzylideneacetone
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship. / Pativada, Triveni; Kim, Myung Hwan; Lee, Jung Hun; Hong, Seong Su; Choi, Chun Whan; Choi, Yun Hyeok; Kim, Woo Jung; Song, Da Woon; Park, Serkin; Lee, Eun Jung; Seo, Bo Yeon; Kim, Hankyeom; Kim, Hong Kyu; Lee, Kee Ho; Ahn, Sung K.; Ku, Jin Mo; Park, Gil Hong.

In: Journal of Medicinal Chemistry, Vol. 62, No. 13, 19.06.2019, p. 6063-6082.

Research output: Contribution to journalArticle

Pativada, T, Kim, MH, Lee, JH, Hong, SS, Choi, CW, Choi, YH, Kim, WJ, Song, DW, Park, S, Lee, EJ, Seo, BY, Kim, H, Kim, HK, Lee, KH, Ahn, SK, Ku, JM & Park, GH 2019, 'Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship', Journal of Medicinal Chemistry, vol. 62, no. 13, pp. 6063-6082. https://doi.org/10.1021/acs.jmedchem.9b00270
Pativada, Triveni ; Kim, Myung Hwan ; Lee, Jung Hun ; Hong, Seong Su ; Choi, Chun Whan ; Choi, Yun Hyeok ; Kim, Woo Jung ; Song, Da Woon ; Park, Serkin ; Lee, Eun Jung ; Seo, Bo Yeon ; Kim, Hankyeom ; Kim, Hong Kyu ; Lee, Kee Ho ; Ahn, Sung K. ; Ku, Jin Mo ; Park, Gil Hong. / Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 13. pp. 6063-6082.
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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.",
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AU - Pativada, Triveni

AU - Kim, Myung Hwan

AU - Lee, Jung Hun

AU - Hong, Seong Su

AU - Choi, Chun Whan

AU - Choi, Yun Hyeok

AU - Kim, Woo Jung

AU - Song, Da Woon

AU - Park, Serkin

AU - Lee, Eun Jung

AU - Seo, Bo Yeon

AU - Kim, Hankyeom

AU - Kim, Hong Kyu

AU - Lee, Kee Ho

AU - Ahn, Sung K.

AU - Ku, Jin Mo

AU - Park, Gil Hong

PY - 2019/6/19

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N2 - (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.

AB - (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.

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