These drugs currently rely on a chemical bond, which has been notoriously difficult, slow and expensive to manufacture. But the study, carried out alongside scientists at Scripps Research and published in Nature, has shown a disarmingly simple method to build that same bond in a much more economical and direct way.
Carbohydrates are some of the most common and important molecules in nature. They play key roles in how our bodies store energy, recognize other molecules, and send signals between cells. Scientists have long been interested in a special type of carbohydrate sugar-based molecules called C-glycosides.
These are sugars that are linked to other molecules in a way that makes them much more stable in the body. This is especially important for medicines, including widely prescribed drugs used to treat type 2 diabetes, heart failure and chronic kidney disease.
The researchers deployed popular type 2 diabetes medicines including dapagliflozin, canagliflozin, empagliflozin, collectively known as SGLT2 inhibitors, with a market value of more than $20bn a year.
To effectively treat diabetes, SGLT2 inhibitors must resemble glucose enough to bind to a protein in the kidneys that normally pulls glucose out of the blood, but not so closely that the body breaks them down for fuel. Creating the drugs requires modifying a section of a sugar molecule so it contains a C-glycoside, making the sugar resistant to breakdown.
However, swapping a sugar’s oxygen for a carbon has historically been hard to manufacture. The scientists demonstrated that a sugar molecule can be directly converted into a sulfonyl hydrazide by mixing it with a common reagent in mild acid (like acetic acid or vinegar) and letting the product crystallize. That single step installs the hydrazide group at the exact carbon where the sugar’s C-glycoside bond needs to form, setting up the sugar to react as a radical precursor.
“This discovery could be a total game changer for manufacturing key medicines faster and more cost-effectively," said Professor Varinder Aggarwal. "Due to its operational simplicity and ready availability of the starting materials, I have no doubt it will be the method of choice to make these important molecules in the future.
“After several unsuccessful attempts, we found that a particular coupling method – originally developed by Professor Phil Baran’s group at Scripps – worked exceptionally well with these sugars. The Baran group were already working on this methodology so we joined forces with that lab to further develop the process.”