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

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Cancer Research

Background:

• Estradiol dimers (EDs) are recognized for their anticancer properties, primarily through interference with tubulin dynamics.
• Targeting tubulin dynamics is a validated strategy in cancer therapy, with compounds like 2-methoxyestradiol showing efficacy.

Purpose of the Study:

• To synthesize and evaluate novel estradiol dimer variants with improved anticancer activity and selectivity.
• To investigate the structure-activity relationships of EDs based on modifications in the aromatic bridge.
• To elucidate the mechanism of action and binding modes of potent EDs.

Main Methods:

• Synthesis of 12 estradiol dimer variants using copper-catalysed azide-alkyne cycloaddition (CuAAC).
• In vitro anticancer activity screening, including cytotoxicity assays (IC50 determination) against cancer cell lines (e.g., CCRF-CEM).
• Assessment of anti-angiogenic properties using an endothelial cell tube-formation model.
• Cell-based assays and in vitro studies to investigate mitotic spindle assembly interference.
• In silico modeling to predict binding modes of active compounds.

Main Results:

• The synthesized EDs demonstrated improved selectivity towards cancerous cells.
• ED3 (IC50 = 0.38 μM) and ED5 (IC50 = 0.71 μM) exhibited superior cytotoxic effects compared to 2-methoxyestradiol (IC50 = 1.61 μM) in CCRF-CEM cells.
• ED3 and ED5 displayed significant anti-angiogenic properties.
• Mechanism studies confirmed that EDs interfere with mitotic spindle assembly.
• In silico models suggested that simpler linkers and single substituents on the aromatic core enhance ED activity.

Conclusions:

• Estradiol dimers, particularly ED3 and ED5, represent a promising class of anticancer agents with enhanced potency and selectivity.
• Structural modifications, specifically a simple linker and a single aromatic substituent, are key for optimizing ED activity.
• The observed anti-mitotic and anti-angiogenic effects highlight the therapeutic potential of these novel EDs in cancer treatment.