Development of target oriented chemotherapeutics for treatment of chronic diseases have been considered as an important approach in drug development. Following this approach, in our efforts for exploration of new osteogenic leads, substituted 3-aryl-2H-benzopyran and 3-aryl-3H-benzopyran derivatives (19, 20a-e, 21, 22a-e, 26, 27, 28a-e, 29, 31a-b, 32 and 33) have been characterized as estrogen receptor-β selective osteogenic (bone forming) agents. The synthesized compounds were evaluated for osteogenic activity using mouse calvarial osteoblast cells. Four compounds viz20b, 22a, 27and 32 showed significant osteogenic activity at EC50 values 1.35, 34.5, 407 and 29.5pM respectively. Out of these, 20b and 32 were analyzed for their bone mineralization efficacy and osteogenic gene expression by qPCR. The results showed that 20b and 32 significantly increased mineral nodule formation and the transcript levels of BMP-2, RUNX-2 and osteocalcin at 100pM concentrations respectively. Further mechanistic studies of 20b and 32 using transiently knocked down expression of ER-α and β in mouse osteoblast (MOBs) showed that 20b and 32 exerts osteogenic efficacy via activation of estrogen receptor-β preferentially. Additionally, compounds showed significant anticancer activity in a panel of cancer cell lines within the range of (IC50) 6.54-27.79μM. The most active molecule, 22b inhibited proliferation of cells by inducing apoptosis and arresting cell cycle at sub-G0 phase with concomitant decrease in cells at S phase.
Keywords: Anticancer; Antiestrogen; Antiosteoporotic; Estrogen; Isoflavone; SERMs.
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