Chemists enhance boron's utility in drug design

Boron, a metalloid element that contains one fewer electron than carbon, has been the subject of many past researches for its potential as a drug component. However, there are currently only five FDA-approved boron-containing drugs because such molecules are highly unstable in the presence of molecular oxygen.

Recently, MIT chemists have designed a novel boron-containing chemical group called benzoxaboralone that could provide strategies to incorporate boron into drugs and potentially improve their binding ability to their targets. The chemical group is said to be 10,000 times more stable than its predecessors.

Previous works

Bortezomib is an effective boron-containing anti-cancer medication used to treat myeloma and mantle cell lymphoma. However, the hunger of boron for electrons leads it to interact with O2 or another reactive form of O, which further destroys the compound.

In 2018, the same researchers for benzoxaboralone tried attaching boron compounds to benzene to create a modified version of a drug called darunavir, an antiretroviral medication used to treat HIV/AIDS by blocking proteases. They found that this appended a benzene molecule bound to HIV protease much more tightly than the initial darunavir. However, it was soon found out that the molecule became eventually unstable under physiological conditions.

Increased Stability

In the new paper, the researchers decided to use a carboxylate group to further anchor boron within a molecule by forming strong covalent bonds with the carboxylate oxygen atoms, which “pacifies the boron so it can no longer react with an oxygen molecule in the way that boron in other contexts can, and it still retains its desirable properties,” says Ron Raines, the Firmenich Professor of Chemistry at MIT and the senior author of the new study.

One desirable property of benzoxaboralone is the ability to maintain a tight fit with the right target of the drug through hydrogen bonds, while also being able to reversibly unlock itself when covalently bound onto incorrect targets, Raines says.

Raines and his colleagues then used it to create a molecule that can bind to transthyretin (TTR), a transport protein that can cause amyloid diseases when it misfolds and aggregates. The team found that adding benzoxaboralone to an existing TTR drug helped stabilize transthyretin and prevent it from clumping.

Future applications

The MIT chemists have already been working on modifying darunavir to include benzoxaboralone. Now, they are in the process of measuring its binding strength to the HIV protease.

“Benzoxaboralone may offer medicinal chemists a useful tool that they can explore in many different types of drugs that bind to proteins or sugar molecules,” Raines says. “We are working hard on this because we think that this scaffold will provide much greater stability and utility than any other presentation of boron in a biological context.”

MIT graduate student Brian Graham and former graduate student Ian Windsor are the lead author of the study. Former MIT postdoc Brian Gold is also an author of the paper. MIT has filed for a patent on the use of benzoxaboralone in medicinal chemistry and other areas.

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Reference:

Trafton, A. (2021, March 2). Chemists boost boron’s utility. MIT News | Massachusetts Institute of Technology. https://news.mit.edu/2021/chemists-boost-borons-utility-0302

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