論文 - 詳細
| RRC ID | 82651 |
|---|---|
| 著者 | Takashima S, Morishita K, Yamamoto M, Ando M, Kawai S, Otake K, Shoji Y, Hinoi E, Kitao T, Shirahase H. |
| タイトル | A Novel Series of Coumarin Derivatives That Exert Osteoblastogenic Effects in Mesenchymal Stem Cells and Osteogenic Effects in Ovariectomized Female Rats. |
| ジャーナル | Chem Pharm Bull (Tokyo) |
| Abstract |
Osteoporosis is treated with oral and parenteral resorption inhibitors and parenteral osteogenic drugs. However, orally active small-molecule osteogenic drugs are not clinically available. Natural coumarin derivatives, such as osthole, exert osteoblastogenic effects. In the present study, novel 4,6-substituted coumarin derivatives were synthesized, and their osteoblastogenic effects were assessed in a bone mesenchymal stem cell line (ST2 cell), and structure-activity relationships were discussed. Among the derivatives tested, the osteoblastogenic effects of 2-oxo-4-[4-(tetrahydro-2H-pyran-4-yloxymethyl)phenyl]-2H-chromene-6-carboxamide (11m) and 2-oxo-4-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-2H-chromene-6-carboxamide (29v) were potent: EC200 for increasing alkaline phosphatase (ALP) activity were 34 and 24 nM, respectively. The maximal plasma concentrations (Cmax) of 11m and 29v (10 mg/kg, per os (p.o.)) in female rats were 3637 and 975 nM, respectively, resulting in high Cmax/EC200 ratios of 105.9 and 40.8, respectively, indicating possible osteoblastogenic effects in vivo. Compound 11m (10 mg/kg, p.o., 8 weeks) was previously reported to increase plasma bone-type ALP activity as well as femoral metaphyseal and diaphyseal cortical bone volumes and mineral contents in micro-computed tomography analyses of ovariectomized female rats (OVX rats). Compound 29v at the same dose also exerted osteoblastogenic and osteogenic effects in OVX rats; however, these effects were weaker than those of 11m. Furthermore, 11m and 29v inhibited cyclin-dependent kinase 8 (CDK8) activity, suggesting that their osteoblastogenic effects involved the suppression of CDK8. In conclusion, a synthetic 4,6-substituted coumarin structure is a useful scaffold for osteoblastogenic and osteogenic compounds via the inhibition of CDK8, and 11m and 29v have potential as anti-osteoporotic drugs that exert osteogenic effects on cortical bone. |
| 巻・号 | 72(12) |
| ページ | 1084-1104 |
| 公開日 | 2024-1-1 |
| DOI | 10.1248/cpb.c24-00559 |
| PMID | 39721699 |
| MeSH | Alkaline Phosphatase / metabolism Animals Cell Line Coumarins* / chemical synthesis Coumarins* / chemistry Coumarins* / pharmacology Dose-Response Relationship, Drug Female Mesenchymal Stem Cells* / drug effects Molecular Structure Osteoblasts* / drug effects Osteogenesis* / drug effects Ovariectomy* Rats Rats, Sprague-Dawley Structure-Activity Relationship |
| IF | 1.416 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | ST2(RCB0224) |