A Comprehensive Guide to Ursodeoxycholic Acid from Synthesis to Applications

What Is Ursodeoxycholic Acid?

Ursodeoxycholic acid (UDCA) is a naturally occurring bile acid that has gained substantial attention in recent years due to its diverse range of therapeutic applications. Ursodeoxycholic acid is a secondary bile acid formed in the liver by the partial oxidation of primary bile acids. It is commonly derived from bovine and bear bile, although it can also be synthesized through chemical processes. In this article, Alfa Chemistry introduces in detail the synthesis method, characteristics, and related application and research progress of UDCA.

Synthesis Methods of Ursodeoxycholic Acid

Chemical routing of UDCA

UDCA can be obtained from cholic acid (CA), which itself first needs to be prepared from taurine and glycosylated derivatives in bile. For the chemical synthesis of UDCA, multiple protection and deprotection steps requiring toxic and hazardous reagents must be performed. The current chemical route to obtain UDCA has an end product yield of approximately 30%.

Microbial transformation or chemical enzymatic methods

To reduce the complexity of multi-step synthesis, the synthesis of UDCA starting from CA or chenodeoxycholic acid (CDCA) is a promising alternative route. One promising approach is the utilization of non-pathogenic, easy-to-manage microorganisms and their enzymes for biotransformation. An overview of reported enzymes and chemoenzyme cascades is shown below, where oxidation, reduction, and dehydroxylation reactions are highlighted with red, blue, and green arrows, respectively.

The chemoenzymatic process for the production of UDCA. [1]

Properties of Ursodeoxycholic Acid

While the exact mechanism of action of UDCA is not fully understood, there is ongoing research to elucidate its effects on improving bile acid composition, reducing hepatocyte apoptosis, modulating immune responses, and enhancing mitochondrial function, etc.

• Cholestatic effects
  By stimulating bile flow and decreasing biliary content, UDCA helps improve liver function and prevents further liver damage.
• Cytoprotective properties
  UDCA exerts important cytoprotective effects by reducing apoptosis, inhibiting inflammation, and stabilizing cell membranes.
• Anti-inflammatory and immunomodulatory effects
  UDCA exhibits potent anti-inflammatory activity by inhibiting pro-inflammatory cytokines and modulating immune responses.
• Antioxidant properties
  UDCA has direct and significant antioxidant properties and has been shown to inhibit the extent of hepatic lipid peroxidation in experimental cholestatic liver disease.

Applications of Ursodeoxycholic Acid

Ursodeoxycholic acid for liver disease

UDCA is commonly used for treating various liver diseases, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and non-alcoholic fatty liver disease (NAFLD).

Ursodeoxycholic acid and COVID-19

Studies have shown that ursodeoxycholic acid (UDCA) can reduce the expression of ACE2 by inhibiting the farnesoid X receptor (FXR), thereby preventing SARS-CoV-2 from entering cells. A large amount of initial work has been carried out to prevent COVID-19 based on ACE2 targeting. However, most studies are supported by limited clinical data. This means that more clinical trials using UDCA to treat or prevent COVID-19 need to be conducted to further evaluate its efficacy in preventing SARS-CoV-2 infection, reinfection, and breakthrough infection.

UDCA used for reducing the expression of ACE2 in SARS-CoV-2. [2]

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References

1. Tonin F, et al. Beilstein journal of organic chemistry, 2018, 14(1), 470-483.
2. Shida Pan, et al. Medicine (Baltimore). 2023, 3(3), 114–119.

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