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Synthesis of aminoalkoxy substituted 4,5-diphenylisoxazole derivatives as potential anti-osteoporotic agents.
Chen, Yeh-Long; Tseng, Chih-Hua; Lo, You-Chih; Lin, Ru-Wei; Chen, Chain-Fu; Wang, Gwo-Jaw; Ho, Mei-Ling; Tzeng, Cherng-Chyi.
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  • Chen YL; Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
Med Chem ; 9(5): 748-55, 2013 Aug.
Article en En | MEDLINE | ID: mdl-23061562
Certain 4,5-diarylisoxazole derivatives have been found to possess broad biological effects, including antiinflammatory and anticancer activities. Recently, we have reported preparation of certain isoflavone derivatives and investigated for their anti-osteoporotic and antiproliferative activities in a detailed SAR study. The present report describes the conversion of isoflavones into novel 4,5-diphenylisoxazole derivatives by the treatment with NH2OH. Alkylation followed by amination of these 4,5-diphenylisoxazoles gave the desired aminoalkoxy substituted 4,5-diphenylisoxazole derivatives. These compounds were evaluated in vitro for the osteogenic differentiation and quantification of mineralization. Although 5-isopropoxy-2-[4-(4-methoxyphenyl)isoxazol-5-yl]phenol (3) exhibited approximately 2.8-fold more activity than the positive Ipriflavone in the promotion of osteoblast activity (277% mineralization), the low cell viability (6%) and high cytotoxicity (68%) prompted us to further pursue more suitable candidates. A series of aminoalkyl side chains were introduced with aims to decrease cytotoxicity. Among them, 5-{4-isopropoxy-2-[4-(pyrrolidin-1-yl)butoxy]phenyl}-4-(4- methoxyphenyl)isoxazole (7a) exhibited approximately 2-fold more activity than the positive Ipriflavone in the promotion of osteoblast activity (194% mineralization) with comparable cell viability (71% v.s. 77%). Compound 7a was non cytotoxic against hADSCs and therefore, was selected as a lead for further structural optimization.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteogénesis / Osteoporosis / Pirrolidinas / Conservadores de la Densidad Ósea / Isoxazoles Límite: Animals / Humans Idioma: En Revista: Med Chem Asunto de la revista: QUIMICA Año: 2013 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Países Bajos
Buscar en Google
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PubMed Links

Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Osteogénesis / Osteoporosis / Pirrolidinas / Conservadores de la Densidad Ósea / Isoxazoles Límite: Animals / Humans Idioma: En Revista: Med Chem Asunto de la revista: QUIMICA Año: 2013 Tipo del documento: Article País de afiliación: Taiwán Pais de publicación: Países Bajos