Synthesis of Aminoalkoxy Substituted 4,5-Diphenylisoxazole Derivatives as Potential Anti-osteoporotic Agents

Author(s): Yeh-Long Chen, Chih-Hua Tseng, You-Chih Lo, Ru-Wei Lin, Chain-Fu Chen, Gwo-Jaw Wang, Mei-Ling Ho, Cherng-Chyi Tzeng.

Journal Name: Medicinal Chemistry

Volume 9 , Issue 5 , 2013

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Abstract:

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.

Keywords: 4, 5-Diphenylisoxazole, Cytotoxicity, Anti-osteoporotic Agents.

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Article Details

VOLUME: 9
ISSUE: 5
Year: 2013
Page: [748 - 755]
Pages: 8
DOI: 10.2174/1573406411309050015
Price: $58

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