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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Identification of Non-steroidal Aromatase Inhibitors via In silico and In vitro Studies

Author(s): Humaira Zafar*, Rabbia Anis, Sana Hafeez, Atia-tul-Wahab, Maria Aqeel Khan, Fatima Zehra Basha, Innokentiy Maslennikov and Muhammad Iqbal Choudhary*

Volume 19, Issue 10, 2023

Published on: 05 June, 2023

Page: [986 - 1001] Pages: 16

DOI: 10.2174/1573406419666230330082426

Price: $65

Abstract

Introduction: Breast cancer is the most common cancer affecting women worldwide, including Pakistan. More than half of breast cancer patients have hormone-dependent breast cancer, which is developed due to the over-production of estrogen (the main hormone in breast cancer).

Methods: The biosynthesis of estrogen is catalyzed by the aromatase enzyme, which thus serves as a target for the treatment of breast cancer. During the current study, biochemical, computational, and STD-NMR methods were employed to identify new aromatase inhibitors. A series of phenyl-3- butene-2-one derivatives 1-9 were synthesized and evaluated for human placental aromatase inhibitory activity. Among them, four compounds 2, 3, 4, and 8 showed a moderate to weak inhibitory activity (IC50 = 22.6 - 47.9 μM), as compared to standard aromatase inhibitory drugs, letrozole (IC50 = 0.0147 ± 1.45 μM), anastrozole (IC50 = 0.0094 ± 0.91 μM), and exemestane (IC50 = 0.2 ± 0.032 μM). Kinetic studies on two moderate inhibitors, 4 and 8, revealed a competitive- and mixed-type of inhibition, respectively.

Results: Docking studies on all active compounds indicated their binding adjacent to the heme group and interaction with Met374, a critical residue of aromatase. STD-NMR further highlighted the interactions of these ligands with the aromatase enzyme.

Conclusion: STD-NMR-based epitope mapping indicated close proximity of the alkyl chain followed by an aromatic ring with the receptor (aromatase). These compounds were also found to be non-cytotoxic against human fibroblast cells (BJ cells). Thus, the current study has identified new aromatase inhibitors (compounds 4, and 8) for further pre-clinical and clinical research.

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