Click estradiol dimers with novel aromatic bridging units: synthesis and anticancer evaluation

J Enzyme Inhib Med Chem. 2024 Dec;39(1):2367139. doi: 10.1080/14756366.2024.2367139. Epub 2024 Jun 21.

Abstract

Estradiol dimers (EDs) possess significant anticancer activity by targeting tubulin dynamics. In this study, we synthesised 12 EDs variants via copper-catalysed azide-alkyne cycloaddition (CuAAC) reaction, focusing on structural modifications within the aromatic bridge connecting two estradiol moieties. In vitro testing of these EDs revealed a marked improvement in selectivity towards cancerous cells, particularly for ED1-8. The most active compounds, ED3 (IC50 = 0.38 μM in CCRF-CEM) and ED5 (IC50 = 0.71 μM in CCRF-CEM) demonstrated cytotoxic effects superior to 2-methoxyestradiol (IC50 = 1.61 μM in CCRF-CEM) and exhibited anti-angiogenic properties in an endothelial cell tube-formation model. Cell-based experiments and in vitro assays revealed that EDs interfere with mitotic spindle assembly. Additionally, we proposed an in silico model illustrating the probable binding modes of ED3 and ED5, suggesting that dimers with a simple linker and a single substituent on the aromatic central ring possess enhanced characteristics compared to more complex dimers.

Keywords: Estradiol; cancer cell; dimer; in silico; tubulin.

MeSH terms

  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Click Chemistry
  • Dimerization
  • Dose-Response Relationship, Drug*
  • Drug Screening Assays, Antitumor*
  • Estradiol* / chemical synthesis
  • Estradiol* / chemistry
  • Estradiol* / pharmacology
  • Humans
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Estradiol

Grants and funding

This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic through the e-INFRA CZ (ID: 90254). We also acknowledge the contributions from infrastructural projects CZ-OPENSCREEN (LM2023052) and EATRIS-CZ (LM2023053) and by the project National Institute for Cancer Research (Program EXCELES, ID Project No. LX22NPO5102), IGA_LF_2024_038 and UCT Prague Internal Grant No. A1_FPBT_2023_003.