Synthesis and characterization of targeted 17β-hydroxysteroid dehydrogenase type 7 inhibitors

Area of Science:

• Medicinal Chemistry
• Enzyme Inhibition
• Hormone-Dependent Cancers

Background:

• Sex steroid hormones like estradiol (E2) and dihydrotestosterone (DHT) are implicated in hormone-dependent cancers.
• 17β-hydroxysteroid dehydrogenase type 7 (17β-HSD7) is a key enzyme regulating E2 and DHT levels.
• Targeting 17β-HSD7 offers a dual approach to decrease E2 and increase DHT, making it a potential therapeutic target for breast cancer.

Purpose of the Study:

• To synthesize and characterize novel carbamate derivatives as potential 17β-HSD7 inhibitors.
• To evaluate the in vitro inhibitory activity of these novel compounds against 17β-HSD7.
• To compare the efficacy of different structural modifications on 17β-HSD7 inhibition.

Main Methods:

• Chemical synthesis of novel carbamate derivatives (compounds 3 and 4) based on a 4-aza-5α-androstane nucleus.
• Molecular characterization of the synthesized compounds.
• In vitro enzymatic assays to determine the inhibitory activity (IC50 values) against 17β-HSD7-mediated transformation of estrone (E1) to estradiol (E2).

Main Results:

• Both novel carbamate derivatives (3 and 4) inhibited 17β-HSD7 in vitro.
• Compound 4, featuring a (17R)-spirocarbamate, exhibited significantly higher inhibitory potency (IC50 = 63 nM) compared to compound 3 (IC50 = 900 nM).
• Compound 4 was 14 times more potent than compound 3 and comparable in activity to the reference inhibitor 1 (IC50 = 111 nM), with a modified hydrophobic side chain presentation.

Conclusions:

• The introduction of a (17R)-spirocarbamate moiety is a more effective strategy for enhancing 17β-HSD7 inhibition than replacing the C-2 methylene with oxygen.
• Novel carbamate derivatives, particularly compound 4, show promising potential as 17β-HSD7 inhibitors for breast cancer therapy.
• Structural modifications, including the C17-spiranic E-ring, can optimize inhibitory activity without compromising efficacy.