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

Eur J Med Chem. 2022 Jan 5:227:113869. doi: 10.1016/j.ejmech.2021.113869. Epub 2021 Sep 29.


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.

Keywords: Breast cancer; Coumarin-based ERα antagonists; In vitro antiproliferative evaluation; In vivo anticancer evaluation; Synthesis.

MeSH terms

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


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