Synthesis of 12β-Methyl-18-nor-bile Acids.

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Farnesoid X nuclear receptor (FXR) and Takeda G-protein-coupled bile acid receptor 5 (TGR5) are critical targets for metabolic and neurodegenerative diseases.
• Developing selective bile acid therapeutics requires understanding receptor-specific signaling pathways.

Purpose of the Study:

• To synthesize novel 12β-methyl-18-nor-bile acids as potential therapeutic agents.
• To create chemical probes for investigating bile acid receptor functions.
• To establish scalable synthetic routes for new bile acid analogues.

Main Methods:

• Application of a Nametkin-type rearrangement on protected cholic acid derivatives.
• Catalytic hydrogenation and deprotection steps to yield target bile acids.
• Optimization of the synthetic sequence for multi-gram scale, chromatography-free production.

Main Results:

• Successful synthesis of 12β-methyl-18-nor-chenodeoxycholic acid and its 17-epi-epimer.
• Development of a chromatography-free synthetic route.
• Characterization of novel cis-C-D ring-junctured and 14(13 → 12)-abeo-bile acids.
• Mechanistic insights into anti-hydrogenation product formation via deuteration experiments.

Conclusions:

• The developed synthetic strategy provides access to valuable 12β-methyl-18-nor-bile acids.
• These novel compounds can serve as probes for drug discovery targeting FXR and TGR5.
• The study advances the development of bile acid-based therapeutics for complex diseases.