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.
Keywords: Aromatase inhibitors, AIS, breast cancer, estrogen, imidazole derivatives, triazole derivatives.
Anti-Cancer Agents in Medicinal Chemistry
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:
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad,Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad,Iran
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.
Export Options
About this article
Cite this article as:
Kalalinia Fatemeh, Jouya Mohammad , Komachali K. Alireza , Aboutourabzadeh M. Seyed , Karimi Gholamreza *, Behravan Javad , Abnous Khalil , Etemad Leila , Kamali Hossein and Hadizadeh Farzin *, Design, Synthesis, and Biological Evaluation of New Azole Derivatives as Potent Aromatase Inhibitors with Potential Effects against Breast Cancer, Anti-Cancer Agents in Medicinal Chemistry 2018; 18 (7) . https://dx.doi.org/10.2174/1871520618666180116105858
DOI https://dx.doi.org/10.2174/1871520618666180116105858 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
MicroRNAs in Renal Cell Carcinoma
MicroRNA Gynaecological Cancer Diagnostics: 99mTc-Cisplatin Complex as a Future Approach for Early, Prompt and Efficient Diagnosis of Gynaecological Cancer
Current Medical Imaging Dual Modulators of p53 and Cyclin D in ER Alpha Signaling by Albumin Nanovectors Bearing Zinc Chaperones for ER-positive Breast Cancer Therapy
Mini-Reviews in Medicinal Chemistry Pentoxifylline and Local Honey for Radiation-Induced Burn Following Breast Conservative Surgery
Current Clinical Pharmacology Impact of Cerebral Malaria on Brain Distribution of Mefloquine
Drug Metabolism Letters Leuckart Synthesis and Pharmacological Assessment of Novel Acetamide Derivatives
Anti-Cancer Agents in Medicinal Chemistry Stem Cell Transplantation for Hematological Malignancies: Prospects for Personalized Medicine and Co-therapy with Mesenchymal Stem Cells
Current Pharmacogenomics and Personalized Medicine New Therapeutic Strategies for Castration-Resistant Prostate Cancer
Recent Patents on Anti-Cancer Drug Discovery Nucleoside Transporter Proteins
Current Vascular Pharmacology Marine Peptides and Related Compounds in Clinical Trial+
Anti-Cancer Agents in Medicinal Chemistry Multiscale Imaging of Nanoparticle Drug Delivery
Current Drug Targets Chalcones as Promising Lead Compounds on Cancer Therapy
Current Medicinal Chemistry Biological and Chemical Diversity of Coral-Derived Microorganisms
Current Medicinal Chemistry Multifunctional Proteins in Tumorigenesis: Aminoacyl-tRNA Synthetases and Translational Components
Current Proteomics Azathioprine in Multiple Sclerosis
Mini-Reviews in Medicinal Chemistry CCL21 and IFNγ Recruit and Activate Tumor Specific T cells in 3D Scaffold Model of Breast Cancer
Anti-Cancer Agents in Medicinal Chemistry Chronic Complications of Diabetes Mellitus: A Mini Review
Current Diabetes Reviews Targeting Microtubules to Inhibit Angiogenesis and Disrupt Tumour Vasculature:Implications for Cancer Treatment
Current Cancer Drug Targets Molecular Mechanisms and Potential Treatment Targets for Ovarian Cancer by Analyzing Transcriptional Regulatory Network
Letters in Drug Design & Discovery Adipocytes Contribute to Resistance of Human Melanoma Cells to Chemotherapy and Targeted Therapy
Current Medicinal Chemistry