Structure-guided design of icaritin-based scaffold modifications for enhanced osteoporotic therapy.

Icaritin, a flavonoid compound, has been shown to alleviate osteoporosis by promoting the differentiation of osteoblasts. However, research on the structural modification and optimization of icaritin has been limited. To enhance the anti-osteoporotic efficacy of icaritin, we structurally modified the compound by substituting the hydroxyl groups, resulting in the synthesis of 22 derivatives. The impact of these compounds was examined by evaluating Human embryonic palatal mesenchymal (HEPM) cells viability with the MTT assay, along with assessing osteogenic potential through measurement of alkaline phosphatase (ALP) activity. In vivo validation of anti-osteoporotic activity was conducted using a prednisolone induced zebrafish model. The results indicated that compound 8a exhibited significant osteogenic activity. Structure-activity relationship analysis revealed that 7-OH esterification substantially potentiated osteogenic activity without eliciting cytotoxic effects in HEPM cells. However, modifications at the 3-OH and 5-OH positions enhanced cytotoxicity while diminishing osteogenic activity. Collectively, our findings characterize icaritin derivatives exhibiting enhanced osteogenic efficacy through improved osteoblast differentiation and present a promising compound for development of anti-osteoporotic drug candidate.