Syntheses of (14β,17α)-14-Hydroxy- and (14β,17α)-2,14-Dihydroxyestradiols and Their Activities

Area of Science:

• Biochemistry
• Pharmacology
• Organic Chemistry

Background:

• The Inagami-Tamura endogenous digitalis-like factor (EDLF) is a biologically active substance with potential cardiovascular effects.
• Understanding the structure of EDLF is crucial for elucidating its mechanism of action and therapeutic potential.

Purpose of the Study:

• To propose a structural model (Structure 1) for the Inagami-Tamura EDLF.
• To synthesize model compounds, specifically (14β,17α)-14-hydroxyestradiol (2) and (14β,17α)-2,14-dihydroxyestradiol (3), for structure-activity relationship studies.
• To evaluate the biological activity of the synthesized compounds in vitro.

Main Methods:

• Proposed a novel structure for EDLF based on existing data and chemical principles.
• Employed multi-step organic synthesis to prepare the target estradiol derivatives.
• Utilized isolated organ bath techniques to assess the contractile effects of the synthesized compounds on rat aorta and guinea pig left atrium.

Main Results:

• A proposed structure (Structure 1) for the Inagami-Tamura EDLF was presented.
• The synthesized compounds (14β,17α)-14-hydroxyestradiol and (14β,17α)-2,14-dihydroxyestradiol were successfully obtained.
• (14β,17α)-2,14-dihydroxyestradiol exhibited significant potency in inducing contractile responses in both isolated rat aorta and guinea pig left atrium.

Conclusions:

• The proposed structure provides a framework for further investigation of EDLF.
• The synthesized estradiol derivatives serve as valuable tools for studying EDLF's biological activity.
• The potent cardiovascular effects of (14β,17α)-2,14-dihydroxyestradiol highlight the potential of modified estrogens as modulators of cardiac and vascular function.