Novel Synthesis Technique Produces Boronic Acid-Based Drugs

A team of chemists from the Scripps Research Institute (TSRI) developed a simple technique for creating a class of molecules that could yield valuable disease treatments.

The researchers were able to transform abundant, inexpensive, structurally diverse carboxylic acids into boronic acids and related compounds with similar structures through a method called decarboxylative borylation.

Essentially, this process entails harnessing a single reaction and cheap nickel catalysts to replace a key carbon atom with a boron atom on a carboxylic acid, according to the announcement.

“Carboxylic acids are the ideal starting material for synthesizing boronic acids, but until now there hasn’t been any method for getting from one to the other,” said the principal investigator and professor of chemistry at TSRI Phil S. Baran, Ph.D., in a statement.

Two experiments were performed to verify decarboxylative borylation’s efficacy.

First, Baran and his team harnessed this technique to produce boronic acid versions of several commonly used drugs like vancomycin and atorvastatin (Lipitor).

Next, the TSRI group worked with researchers from the California Institute for Biomedical Research (CIBR) to develop boronic-acid based compounds engineered to inhibit an enzyme known as neutrophil elastate. Immune cells release this enzyme in the lungs during infections involving lung inflammation, like chronic obstructive pulmonary disease and cystic fibrosis.

Results from lab-dish tests indicated the boronic acid-based compounds had stronger elastase inhibitor capabilities compared to the other compounds, by binding very tightly to target molecules in a manner that allowed eventual detachment.

This factor potentially limited the impact of off-target interactions that cause unwanted side-effects.

“The next step is to see how well these compounds perform in animal models,” said study co-author and CIBR’s director of medicinal chemistry Arnab Chatterjee, in a statement. “In general, this new method allows us in a practical way to get into this largely unexplored but promising chemical space of borylated compounds, and thus enables us to revisit old targets, such as elastase, that have largely resisted prior drug development efforts.”

Borylated versions of drug compounds should display superior properties compared to their carboxylic acid counterparts, but previous efforts to prepare these compounds were difficult, greatly limiting their use in the pharmaceutical industry.

However, Baran notes that chemists can now efficiently install boron at any stage compared to devoting 95 percent of their time trying to introduce a single boron atom.

These findings were published in the journal Science.