Lathyrane Diterpenoids as Novel hPXR Agonists: Isolation, Structural Modification, and Structure-Activity...

Area of Science:

• Pharmacology
• Natural Product Chemistry
• Medicinal Chemistry

Background:

• Cholestasis is a condition where bile flow is reduced or blocked.
• The Pregnane X receptor (PXR) plays a key role in regulating the metabolism of xenobiotics and endobiotics.
• PXR is a promising therapeutic target for cholestasis treatment.

Purpose of the Study:

• To isolate and identify novel human PXR (hPXR) agonists from Euphorbia lathyris.
• To synthesize and evaluate a library of lathyrane diterpenoids for hPXR agonistic activity.
• To explore the structure-activity relationships (SARs) of these compounds for anticholestasis drug development.

Main Methods:

• Bioassay-guided isolation of compounds from Euphorbia lathyris.
• Synthesis of a lathyrane diterpenoid library (compounds 1-34).
• In vitro screening of the library for hPXR agonistic activity.
• Molecular modeling to understand SARs.

Main Results:

• Identification of potent hPXR agonists from the lathyrane diterpenoid library.
• Compound 8 demonstrated significant dose-dependent hPXR activation at micromolar concentrations.
• Upregulation of PXR downstream genes (CYP3A4, CYP2B6, MDR1) by compound 8.
• SAR analysis indicated the importance of C-7 acyloxy and C-14 carbonyl groups for activity.

Conclusions:

• Lathyrane diterpenoids represent a novel class of hPXR agonists.
• These compounds exhibit superior efficacy compared to the reference agonist rifampicin.
• Lathyrane diterpenoids hold potential for the development of new anticholestasis therapeutics.