Researchers at Simon Fraser University and a group of international collaborators say discovering antiviral and anticancer drugs may soon be faster and cheaper as they describe in their new paper “A short de novo synthesis of nucleoside analogs” in Science.
For the past 50 years, scientists have used man-made, synthetic, and nucleoside analogues to create drug therapies for diseases that involve the cellular division and/or the viral reproduction of infected cells. These diseases include hepatitis, herpes simplex, HIV, and cancer.
But, according to chemist Robert Britton, PhD, “That process has been intensive and challenging, limiting, and preventing the discovery of new drug therapies.”
Now, using the new technique, scientists can create new nucleoside analogues months earlier than with the previous method, paving the way for quicker drug discoveries, he adds.
“Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials,” write the investigators.
“Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of D- or L-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs.
“This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.”
“The reduction in time and cost of synthesis will vary, depending on the individual nucleoside analogue, but we have examples where we cut a 20-plus step synthesis, which takes several months to complete at the very least, down to three or four steps, which would only take a week or so,” says Britton. “This is clearly a critical factor when it comes to treating newly evolved viruses like SARS-CoV-2 (COVID-19).”
The team shortened the process by replacing naturally occurring carbohydrates typically used for synthesizing these types of drugs.
“This entirely new approach builds in opportunities to diversify these drug scaffolds and should inspire new and unusual nucleoside analogue drug discoveries,” continues Britton.
The team also replaced naturally derived chiral materials with achiral materials since they are generally cheaper and more versatile.
“One of our priorities is identifying problems limiting the speed of drug discovery and development, especially regarding synthesizing custom nucleoside analogues,” notes L.-C. Campeau, Merck’s head of process chemistry and discovery process chemistry. “We are very excited to collaborate with professor Britton in establishing new methods to access this therapeutically important class of molecules.”
Britton is also an investigator with GlycoNet, a Canada-wide network of researchers working to further our understanding of the biological roles of sugars. The three-year project was funded by GlycoNet and Merck, patent pending.
