A groundbreaking method for creating stable, customizable sugar-based molecules is opening new doors for medicine and biological research.
Published on October 15, 2023
Walk into any kitchen, and you'll find sugars—those simple carbohydrates that sweeten our coffee and bake our cookies. But in the laboratory, sugars tell a far more complex story. In living organisms, chains of sugar molecules called glycans play crucial roles in nearly every biological process, from how cells recognize each other to how pathogens invade our immune systems.
For decades, scientists have sought to harness these natural sugar compounds for medicine, but they've faced a persistent problem: the very bonds that hold sugar molecules together are notoriously fragile inside the human body.
Enter C-glycosides—a special class of synthetic sugar molecules that mimic their natural counterparts but with one crucial difference: they're built to last. Recently, a team of researchers unveiled a revolutionary method to create these stable sugar-like compounds with unprecedented precision.
Novel "formal functional group deletion" approach enables precise molecular engineering
Potential for developing more stable and effective sugar-based therapeutics
To understand the significance of this breakthrough, we first need to distinguish between natural sugars and their synthetic counterparts. In nature, sugar molecules often connect to other molecules through what chemists call an anomeric position—specifically, through oxygen atoms (creating O-glycosidic bonds). While these O-glycosides are biologically ubiquitous, they possess a critical weakness: they're susceptible to hydrolysis, meaning they break down easily in acidic environments or when exposed to enzymes in the body 1 .
C-glycosides replace the fragile oxygen bond with a robust carbon-carbon bond
This fragility presents a major obstacle for drug development. Imagine designing a sugar-based medication to target cancer cells, only to have it dismantled by the body's digestive enzymes before it can reach its destination. This is where C-glycosides come in. By replacing the oxygen atom at the anomeric position with a carbon atom, scientists create compounds that maintain the shape and function of natural sugars but are far more chemically and metabolically stable 1 3 .
Creating effective C-glycosides isn't just about making stable molecules—it's also about controlling their three-dimensional shape. Sugar molecules can exist in two different configurations at their anomeric position, labeled α (alpha) and β (beta). These seemingly small differences dramatically affect how the molecule interacts with biological systems.
"The stereochemical outcomes of traditional methodologies to access C-glycosides rely heavily on substrate control" 1
The innovative approach developed by Xiaoshen Ma and Stephen J. Sujansky tackles the stereochemistry problem head-on. Their method, called formal functional group deletion, might sound complex, but the underlying principle is elegant in its simplicity. Instead of building up the C-glycoside from scratch, they start with a different type of sugar molecule (S-glycosides) that are easier to control stereochemically, then strategically "delete" the sulfur atom in a way that preserves the desired configuration 5 .
What makes this approach particularly powerful is its switchability. For the first time, chemists can reliably produce either the alpha or beta form of C-glycosides at will, both for furanoses (five-membered sugar rings) and pyranoses (six-membered sugar rings) 1 3 .
As Ma explained in a social media post, "By employing the ligand-coupling method of hypervalent sulfur species, we successfully translated the anomeric stereochemical information of S-glycosides to the corresponding C-glycoside products" .
In their groundbreaking study, Ma and Sujansky designed a series of experiments to demonstrate the versatility and reliability of their new C-glycosylation strategy. The experimental process can be broken down into several key stages 1 5 :
Prepare sulfur-containing sugars with defined stereochemistry
Form molecular scaffolds to maintain stereochemical information
Introduce carbon-based groups to the sulfur center
Remove sulfur atom while preserving original stereochemistry
The experimental results convincingly demonstrated that this new strategy represents a significant advancement in C-glycoside synthesis. The researchers successfully obtained both α- and β-anomers of various furanoses and pyranoses as single stereoisomers—a level of precision that traditional methods struggle to achieve 1 3 .
| Sugar Type | Ring Form | Anomeric Configurations |
|---|---|---|
| Hexoses | Pyranose | α and β |
| Pentoses | Pyranose | α and β |
| Furanoses | Five-membered | α and β |
| Heterocycle Type | Examples |
|---|---|
| Nitrogen-based | Pyridine, Imidazole, Pyrazole |
| Oxygen-based | Furan, Pyran |
| Sulfur-based | Thiophene, Thiazole |
| Parameter | Traditional Methods | New Strategy |
|---|---|---|
| Stereochemical Control | Relies on substrate control | Switchable and predictable |
| Anomeric Selectivity | Often mixed | Single stereoisomer |
| Scope of Sugars | Limited | Broad (furanoses and pyranoses) |
| Scope of Carbon Groups | Moderate | Extensive (various heterocycles) |
The groundbreaking results achieved by Ma and Sujansky depended on several crucial reagents and materials that facilitated the novel formal functional group deletion process.
Sulfur-containing sugar molecules with well-defined stereochemistry at the anomeric position
Reagents capable of forming hypervalent sulfur intermediates to maintain stereochemical information 5
Carbon-based nucleophiles, particularly heterocyclic aromatic compounds 1
Specialized chemical agents to initiate formation of hypervalent sulfur species
Both α- and β-anomers of various furanoses and pyranoses 3
Provides medicinal chemists with a powerful new tool for creating stable sugar-based therapeutics. Many current drugs—including certain antibiotics, anticancer agents, and antiviral medications—incorporate sugar components that could potentially be improved through C-glycoside analogs with enhanced metabolic stability 1 .
These robust C-glycosides will enable researchers to probe biological processes involving carbohydrates with greater precision. Scientists can use these compounds to study glycosylation—the process by which sugars attach to proteins and lipids—without worrying about enzymatic degradation interfering with their experiments.
The researchers have specifically highlighted the "potential for empowering future application in both chemical biology research and drug discovery" 1 . The broad scope of heterocyclic C-glycosides accessible through this method is particularly promising, as heterocycles are common structural elements in pharmaceuticals.
More stable and targeted therapeutics
Tools for studying cellular processes
Inspiration for other challenging syntheses
The development of a switchable and stereospecific C-glycosylation strategy via formal functional group deletion represents a significant milestone in synthetic chemistry. By solving the long-standing challenge of stereochemical control in C-glycoside synthesis, Xiaoshen Ma and Stephen J. Sujansky have opened new avenues for creating stable, functional sugar mimics with precise three-dimensional structures.
This breakthrough demonstrates how creative solutions to fundamental chemical problems can have far-reaching consequences. What begins as an exercise in molecular architecture in the laboratory may well lead to better medicines, improved diagnostic tools, and deeper understanding of biological processes in the years to come.