Novel estrogen receptor (ER) modulators containing various hydrophobic bent-core structures

Area of Science:

• Medicinal Chemistry
• Endocrinology
• Molecular Pharmacology

Background:

• Estrogen receptor (ER) modulators are crucial for treating hormone-dependent diseases.
• Previous work identified compound 4, an m-carborane-containing ER modulator with weak activity.
• Developing novel ER partial agonists with improved profiles is an ongoing challenge.

Purpose of the Study:

• To design and synthesize novel ER partial agonists based on compound 4.
• To explore the impact of replacing the m-carborane moiety with various bent-core structures on ER modulation.
• To identify potent and selective ER modulators for potential therapeutic applications.

Main Methods:

• Synthesis of novel analogues of compound 4, incorporating pseudo cyclic, tetrahydropyrimidinone, m-benzene, adamantane, and 9,10-dimethyl-m-carborane moieties.
• Estrogen receptor (ER) binding assays using [6,7-(3)H]-17β-estradiol.
• Transactivation assays to assess ER agonistic and antagonistic activities.
• MCF-7 cell proliferation assays to evaluate partial agonist efficacy.

Main Results:

• Compound 9, featuring a 9,10-dimethyl-m-carborane moiety, exhibited significantly greater binding affinity to the ER compared to compound 4.
• Compound 9 demonstrated superior partial agonist activity in MCF-7 cell proliferation assays compared to compound 4.
• The synthesized analogues showed varied ER binding affinities and modulatory activities, with compound 9 being the most promising.

Conclusions:

• The replacement of the m-carborane moiety with specific bent-core structures, particularly the 9,10-dimethyl-m-carborane group, can enhance ER binding affinity and partial agonistic activity.
• Compound 9 represents a promising candidate for a selective ER modulator (SERM).
• Further investigation into compound 9 is warranted for its potential therapeutic development.