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:Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
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.
