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.
Medicinal Chemistry
Title:Synthesis of Aminoalkoxy Substituted 4,5-Diphenylisoxazole Derivatives as Potential Anti-osteoporotic Agents
Volume: 9 Issue: 5
Author(s): Yeh-Long Chen, Chih-Hua Tseng, You-Chih Lo, Ru-Wei Lin, Chain-Fu Chen, Gwo-Jaw Wang, Mei-Ling Ho and Cherng-Chyi Tzeng
Affiliation:
Keywords: 4, 5-Diphenylisoxazole, Cytotoxicity, Anti-osteoporotic Agents.
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.
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Chen Yeh-Long, Tseng Chih-Hua, Lo You-Chih, Lin Ru-Wei, Chen Chain-Fu, Wang Gwo-Jaw, Ho Mei-Ling and Tzeng Cherng-Chyi, Synthesis of Aminoalkoxy Substituted 4,5-Diphenylisoxazole Derivatives as Potential Anti-osteoporotic Agents, Medicinal Chemistry 2013; 9 (5) . https://dx.doi.org/10.2174/1573406411309050015
DOI https://dx.doi.org/10.2174/1573406411309050015 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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