These drugs currently rely on a chemical bond, which has been notoriously difficult, slow and expensive to manufacture. But a study, co-led by scientists at Scripps Research in the US and the University of Bristol in the UK and published in the journal Nature, has shown an ingeniously simple method to build that same bond in a much more economical and direct way.
Study co-lead author Professor Varinder Aggarwal, Alfred Capper Pass Chair of Chemistry at the University of Bristol, said: "This discovery could be a total game changer for manufacturing key medicines faster and more cost-effectively. 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."
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 $20 billion 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 in the same way Baran's lab had previously shown for simpler organic molecules.
Co-lead author Professor Phil Baran, Dr. Richard A. Lerner Endowed Chair at Scripps Research, in San Diego, California, said: "The point of this is to show that anyone in a garage can make an SGLT2 inhibitor with reagents that are widely available. We have not patented this method, so we welcome any generic drug company – or anyone else – who wants to use it to help bring costs down for patients."
A sugar molecule is covered in reactive sites called hydroxyl groups, and conventional methods for making a C-glycoside require temporarily shielding nearly all of the hydroxyls before the key bond is formed, and then removing those shields afterwards. It involves many steps and requires hazardous, highly reactive reagents.
The Scripps lab pioneered sulfonyl hydrazide reactions, which can forge new carbon-carbon bonds. In one of these sulfonyl hydrazide reactions, a small nitrogen-containing chemical group is attached to a molecule at a specific site. When the hydrazide is heated in the presence of a particular type of metal, it breaks apart and releases nitrogen gas, generating a reactive fragment called a radical at that exact spot. Because it is so reactive, that radical immediately seeks out and bonds with a second molecule, forming a new carbon-carbon bond without requiring any other added chemicals.
"This removes the engineering barrier to activating the radical precursor," Prof Baran explained.
"You don't need more complicated techniques like photochemistry, electrochemistry or stoichiometric metal salts – none of which are as easy to scale up."
To demonstrate how far this could be pushed, the Scripps team showed that the chemistry works at a much larger scale using dextrose powder bought cheaply from a public pharmacy, dissolved in ordinary household vinegar. The process was captured in a video and posted on YouTube.
Using this approach, they made all of the currently approved SGLT2 inhibitors, including several related compounds still in clinical trials, and complex natural products that previously required up to 20 separate synthetic steps to produce. They also showed the same chemistry could attach new chemical groups to other positions on a sugar molecule, not just the one site relevant to these particular diabetes drugs – a capability the team says could be useful for building entirely different classes of sugar-based compounds.
Prof Baran concluded: "A boring reaction is a useful one. It's simple to run and can be performed in labs across the world."
Paper
'C-glycoside synthesis via radical cross-coupling of glycohydrazides' by Yinliang Guo et al. in Nature
