Design, Synthesis, and Biological Evaluation of New Azole Derivatives as Potent Aromatase Inhibitors with Potential Effects against Breast Cancer

Purpose: Some aromatase inhibitors are FDA-approved agents as first-line therapy in the treatment of endocrine-responsive breast cancer. In this study, we aimed to develop new azole derivatives with higher specificity and potency.

Methods: New aromatase inhibitors were designed by Molecular Operating Environment (MOE) software and synthesized in a one-step SN2 reaction. These compounds were characterized by melting point, 1H- and 13CNMR, elemental analysis and mass spectra. The in vitro and in vivo aromatase inhibition of these compounds was evaluated using the Estrone ELISA assay, and by measuring the inhibition of androstenedione-induced uterine hypertrophy. The selectivity of aromatase inhibition was investigated by the inhibition of ACTH stimulation on the plasma concentrations of aldosterone and cortisol.

Results: Docking simulations showed that four new azole derivatives could efficiently interact with enzyme active sites. The in vitro aromatase-inhibition assay showed that the compounds 1,3,5-tris(imidazol-1- ylmethyl)benzene (3b) and 1,3-Bis(imidazole-1- ylmethyl) benzene (3d) effectively inhibited aromatase, with IC50 values of 0.2 nM and 6.8 nM, respectively; these values were similar to known aromatase inhibitor letrozole (IC50 0.3 nM). The in vivo aromatase-inhibitory potency of compound 3b was similar to letrozole, although compound 3b acted more selectively.

Conclusion: This report introduced a new compound that can be considered as a new lead for further investigation to explore more-potent and more-selective aromatase inhibitors.

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