Synthetic analogs of daidzein, having more potent osteoblast stimulating effect

• Published in: Bioorganic & medicinal chemistry letters 2011-01, Vol.21 (2), p.677-681
• Main Authors: Yadav, Dinesh K., Gautam, Abnish K., Kureel, Jyoti, Srivastava, Kamini, Sahai, Mahendra, Singh, Divya, Chattopadhyay, Naibedya, Maurya, Rakesh
• Format: Article
• Language: English
• Subjects: Animals; bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; bone mineralization; Bone Morphogenetic Protein 2 - genetics; Calcification, Physiologic - drug effects; Cell Differentiation - drug effects; Cells, Cultured; Daidzein; Deoxybenzoin; Formylation; Gene Expression Regulation - drug effects; genes; Isoflavones - chemical synthesis; Isoflavones - chemistry; Isoflavones - pharmacology; messenger RNA; Mineralization; Osteoblast proliferation; osteoblasts; Osteoblasts - cytology; Osteoblasts - drug effects; Osteoblasts - metabolism; osteocalcin; Osteocalcin - genetics; Osteogenic; Phytoestrogen; Phytoestrogens - chemical synthesis; Phytoestrogens - chemistry; Phytoestrogens - pharmacology; Rats; RNA, Messenger - genetics; Skull - cytology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.008

Series of daidzein derivatives were designed, synthesized, and assessed for stimulation of osteoblast function using primary culture of rat calvarial osteoblasts in vitro. Compounds 1c, 3a and 3c, each of 10.0 nM concentrations, were several folds more potent than daidzein of 1.0 μM concentration, in stimulating differentiation and mineralization of osteoblasts. At 10 mg kg −1 day −1 dose for three consecutive days showed anti-estrogenic effect of the same molecules. A series of didzein derivatives were synthesized and assessed for stimulation of osteoblast differentiation using primary cultures of rat calvarial osteoblasts. Data suggested that three synthetic analogs, 1c, 3a and 3c were several folds more potent than daidzein in stimulating differentiation and mineralization of osteoblasts. Further, these three compounds did not show any estrogen agonistic activity, however had mild estrogen antagonistic effect. Out of the three compounds, 3c was found to maximally increase the mineralization of bone marrow osteoprogenitor cells. Compound 3c also robustly increased the mRNA levels of osteogenic genes including bone morphogenetic protein-2 and osteocalcin in osteoblasts. Unlike daidzein, 3c did not inhibit osteoclastogenesis. Collectively, we demonstrate osteogenic activity of daidzein analogs at significantly lower concentrations than daidzein.