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J Med Chem ; 62(13): 6063-6082, 2019 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-31257875

RESUMEN

(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.


Asunto(s)
Compuestos de Bencilideno/uso terapéutico , Butanonas/uso terapéutico , Osteogénesis/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Compuestos de Bencilideno/síntesis química , Compuestos de Bencilideno/farmacocinética , Butanonas/síntesis química , Butanonas/farmacocinética , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Femenino , Fémur/patología , Humanos , Ratones , Estructura Molecular , Subunidad p50 de NF-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Osteoblastos/metabolismo , Osteocalcina/metabolismo , Osteoclastos/metabolismo , Osteoporosis/tratamiento farmacológico , Células RAW 264.7 , Relación Estructura-Actividad , Tibia/patología
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