Chemists at Northwestern University have successfully determined the precise three-dimensional structures of secalosides A and B, two molecules found in rye pollen that have shown potential in slowing tumor growth. By utilizing total synthesis to build these molecules from scratch in a laboratory, researchers have resolved a decades-long structural mystery, providing a foundation for future cancer therapy research.
Solving a Long-Standing Molecular Puzzle
Researchers first identified secalosides A and B in rye pollen nearly 30 years ago, noting their ability to inhibit tumor growth in preliminary animal models. However, the development of these compounds as potential therapeutic agents stalled because scientists could not determine their exact atomic arrangement.
Traditional analytical methods, including advanced nuclear magnetic resonance (NMR) spectroscopy, proved insufficient to distinguish between two potential structural models. While both models contained the same atoms, they differed in the orientation of a critical molecular region, which existed as a mirror image in each version. According to Karl A. Scheidt, a professor of chemistry at Northwestern’s Weinberg College of Arts and Sciences, this distinction is significant because small changes in molecular "handedness" can fundamentally alter how a compound interacts with biological targets.
How Chemists Built the Molecules
To confirm the structure, the Northwestern team employed total synthesis, a process of constructing complex natural molecules step-by-step. The project, published in the Journal of the American Chemical Society, presented a major hurdle: the molecules contain a rare, highly strained 10-membered ring.
To assemble this structure, the researchers first created a larger, more flexible ring. They then triggered a chemical reaction to compress it into the required strained state in a single step. By synthesizing both candidate versions of the molecules in the laboratory, the team compared them against natural samples extracted from rye pollen. Only one of the synthesized versions matched the natural product, allowing the researchers to definitively confirm the correct structure.
Future Implications for Cancer Research
The confirmation of these molecular blueprints allows scientists to move beyond basic observation. Rye pollen extract is currently marketed as a dietary supplement for prostate health, but it has not been developed into a pharmaceutical drug.
"Now that we confirmed the structure of these molecules, we can find the active ingredient—or what part of the molecule is doing the work," said Scheidt, who also serves as a professor of pharmacology (by courtesy) at Northwestern University Feinberg School of Medicine.
The research team aims to collaborate with immunologists to understand how these compounds interact with the immune system to clear tumors. By identifying the active components, chemists may eventually be able to design improved versions of these molecules that are more effective, orally available, and capable of surviving metabolism.
Historical Context of Natural Product Discovery
The pursuit of cancer therapies derived from nature has a long history in pharmacology. Many life-saving medications originated from natural sources:
- Morphine: Derived from the opium poppy.
- Taxol: Isolated from the Pacific yew tree and widely used in chemotherapy.
- Statins: Developed from compounds found in fungi to manage cholesterol.
The Northwestern study, which received support from the National Institute of General Medical Science, the Chemistry of Life Processes Institute Lambert Fellowship, and the National Science Foundation, marks a step toward determining if secalosides can join these established medical treatments.