Title:Design, Synthesis, and Biological Evaluation of New Azole Derivatives as Potent Aromatase Inhibitors with Potential Effects against Breast Cancer
VOLUME: 18 ISSUE: 7
Author(s):Fatemeh Kalalinia, Mohammad Jouya, Alireza K. Komachali, Seyed M. Aboutourabzadeh, Gholamreza Karimi*, Javad Behravan, Khalil Abnous, Leila Etemad, Hossein Kamali and Farzin Hadizadeh*
Affiliation:Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad
Keywords:Aromatase inhibitors, AIS, breast cancer, estrogen, imidazole derivatives, triazole derivatives.
Abstract: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.
