Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• 4-Aryl-4H-chromene derivatives possess anti-proliferative, apoptotic, and anti-angiogenic properties in various tumor models.
• These compounds typically function by inhibiting tubulin polymerization, leading to caspase activation.
• Previous virtual screening identified a 4-aryl-4H-chromene scaffold that binds estrogen receptors (ERα and ERβ) with low nanomolar affinity.

Purpose of the Study:

• To synthesize novel 4-aryl-4H-chromene derivatives based on a previously identified scaffold.
• To evaluate the synthesized compounds as estrogen receptor antagonists, focusing on selectivity for ERα versus ERβ.
• To assess the anti-proliferative activity of these compounds in the MCF-7 cell line.

Main Methods:

• Synthesis of a series of 4-aryl-4H-chromene compounds with variations in C-4 arylether substituents and C-3 ester modifications.
• In vitro evaluation of estrogen receptor binding affinity and selectivity for ERα and ERβ.
• Assessment of anti-proliferative activity in the estrogen receptor-positive MCF-7 breast cancer cell line.

Main Results:

• The synthesized 4-aryl-4H-chromene derivatives demonstrated potent estrogen receptor antagonist activity.
• Compound 35 exhibited high selectivity for ERα (350-fold), while compound 42 showed high selectivity for ERβ (170-fold).
• These compounds displayed low micromolar anti-proliferative activity in the MCF-7 cell line.

Conclusions:

• The 4-aryl-4H-chromene scaffold can be modified to yield potent and selective ERα or ERβ antagonists.
• These selective ER antagonists hold promise for targeted therapeutic strategies in hormone-dependent cancers.
• Further investigation into the anti-cancer potential of these selective ER modulators is warranted.