Human estrogen receptor α antagonists, part 2: Synthesis driven by rational design, in vitro antiproliferative, and in vivo anticancer evaluation of innovative coumarin-related antiestrogens as breast cancer suppressants.

Abstract

New twelve in silico designed coumarin-based ERα antagonists, namely 3DQ-1a to 3DQ-1е, were synthesized and confirmed as selective ERα antagonists, showing potencies ranging from single-digit nanomolar to picomolar. The hits were confirmed as selective estrogen receptor modulators and validated as antiproliferative agents using MCF-7 breast cancer cell lines exerting from picomolar to low nanomolar potency, at the same time showing no agonistic activity within endometrial cell lines. Their mechanism of action was inspected and revealed to be through the inhibition of the Raf-1/MAPK/ERK signal transduction pathway, preventing hormone-mediated gene expression on either genomic direct or genomic indirect level, and stopping the MCF-7 cells proliferation at G0/G1 phase. In vivo experiments, by means of the per os administration to female Wistar rats with pre-induced breast cancer, distinguished six derivatives, 3DQ-4a, 3DQ-2a, 3DQ-1a, 3DQ-1b, 3DQ-2b, and 3DQ-3b, showing remarkable potency as tumor suppressors endowed with optimal pharmacokinetic profiles and no significant histopathological profiles. The presented data indicate the new compounds as potential candidates to be submitted in clinical trials for breast cancer therapy.

• Authors: Nezrina Kurtanović, Nevena Tomašević, Sanja Matić, Marina M Mitrović, Danijela A Kostić, Manuela Sabatino, Lorenzo Antonini, Rino Ragno, Milan Mladenović
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 227 Pg. 113869 (Jan 05 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 34710747 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Coumarins
• ESR1 protein, human
• Estrogen Receptor Antagonists
• Estrogen Receptor alpha
• coumarin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Coumarins (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Estrogen Receptor Antagonists (chemical synthesis, chemistry, pharmacology)
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Female
• Humans
• MCF-7 Cells
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Molecular Structure
• Rats
• Rats, Wistar
• Structure-Activity Relationship