Novel estrone mimetics with high 17beta-HSD1 inhibitory activity

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Pharmacology

Background:

• 17Beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) converts estrone to estradiol, the most potent human estrogen.
• Inhibiting 17beta-HSD1 offers a therapeutic strategy for estrogen-dependent diseases, including breast cancer and endometriosis.
• Targeting intracellular estradiol concentration is a key approach in managing these conditions.

Purpose of the Study:

• To design and identify novel inhibitors of 17beta-HSD1.
• To develop compounds that mimic the structure of estrone for effective enzyme inhibition.
• To explore new therapeutic leads for estrogen-dependent diseases.

Main Methods:

• Employed a combination of ligand- and structure-based drug design principles.
• Synthesized heterocyclic substituted biphenylols and their aza-analogs.
• Utilized molecular docking to investigate protein-ligand interactions.
• Assessed inhibitory activity and receptor affinity of synthesized compounds.

Main Results:

• Identified novel heterocyclic substituted biphenylols and aza-analogs as 17beta-HSD1 inhibitors.
• Compound 12 demonstrated high nanomolar inhibitory activity against 17beta-HSD1.
• Compound 12 exhibited very low affinity for estrogen receptors alpha and beta.
• Molecular docking provided insights into the binding mode of the inhibitors.

Conclusions:

• Compound 12 represents a novel and selective inhibitor of 17beta-HSD1.
• This compound can serve as a valuable tool for studying the pharmacological role of 17beta-HSD1.
• Compound 12 shows potential as a lead compound for developing new treatments for estrogen-dependent diseases.