Nearly 30 years after rye pollen molecules were shown to slow tumor growth in animals, scientists have finally determined their exact three-dimensional structures.
Nearly 30 years ago, researchers noticed something surprising in rye pollen: two naturally occurring molecules seemed to slow tumor growth in animal studies. The finding drew interest, but the science hit a wall because no one could pin down a crucial detail that determines how a compound behaves in the body: its exact three dimensional shape.
Chemists at Northwestern University now report that they have solved that long running structural puzzle. By assembling the molecules step by step in the lab, the team confirmed the true 3D structures of secalosides A and B, giving researchers a reliable starting point for the next phase of work.
That “blueprint” matters because biology is shape driven. Once scientists know how a molecule is arranged in space, they can begin testing how it might interact with immune cells and other biological targets, and they can design close variants to see which features are important. In this case, it could help clarify whether specific components of rye pollen, a staple cereal crop grown for its grain, might eventually inspire new ideas for cancer treatment.
The study was recently published in the Journal of the American Chemical Society.
“In preliminary studies, other researchers found that rye pollen could help different animal models clear tumors through some unknown, non-toxic mechanism,” said Northwestern’s Karl A. Scheidt, who led the study. “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. This is an exciting starting point to make better versions of these molecules that could possibly inform approaches to cancer therapy.”
Scheidt is a professor of chemistry at Northwestern’s Weinberg College of Arts and Sciences and a professor of pharmacology (by courtesy) at Northwestern University Feinberg School of Medicine. He also is a member of the Chemistry of Life Processes Institute and of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Nature as inspiration for medicine
Nature has repeatedly provided starting points for major medical advances, even when the raw materials were not ready to be used as drugs in their original form. Many familiar medicines trace back to compounds first found in plants and microbes, which scientists later refined to make them safer, more effective, or easier for the body to use.
Morphine, a long used treatment for severe pain, comes from the opium poppy. Taxol, a key cancer therapy, was first obtained from the Pacific yew tree. Statins, widely taken to lower cholesterol and reduce heart disease risk, were developed from molecules discovered in fungi.
“Natural products aren’t necessarily effective drugs on their own, but they are great leads,” Scheidt said. “We can find inspiration in natural products and use chemistry to make better versions that are orally available, survive the metabolism and hit the right targets.”
Eventually, rye pollen potentially could join these ranks. Many consumers around the world already ingest rye pollen extract in supplement form to protect prostate health. But scientists haven’t yet optimized it for use as a pharmaceutical drug. Understanding how it works required knowing the molecules’ precise three-dimensional shape — information that proved elusive.
A molecular mystery
Using traditional techniques, such as advanced nuclear magnetic resonance spectroscopy, scientists could not fully reveal the orientation of the molecules’ key parts. As a result, two competing structural models persisted for decades.
Those two proposed structures had the same atoms, same connections and same overall shape. But a central part of the molecules are mirror images of each other. That subtle distinction can change how the molecule fits into a biological target and determine whether a molecule is biologically active or inert.
“It’s like your hands,” Scheidt said. “They are mirror images of each other, but you need a different glove for each. If you had two left-handed gloves, it wouldn’t work because your hands can’t be superimposed on top of one another.”
Building from scratch
To settle the question once and for all, the Northwestern team turned to total synthesis, or the step-by-step process of constructing a natural molecule in the laboratory. The approach was incredibly complicated and challenging. At their cores, secalosides A and B contain an extremely rare and highly strained feature: a tightly compressed, 10-membered ring that is notoriously difficult to build.
Scheidt and his team devised a clever workaround. They first built a larger, more flexible ring and then triggered a reaction that snapped it into a smaller, strained shape in a single step. After synthesizing both competing structural versions of the secalosides, the scientists compared them to samples isolated from rye pollen. Only one version matched perfectly, finally revealing the true molecular structure.
“We’ve demonstrated we can make the core of this natural product,” Scheidt said. “Now, we’re trying to find potential collaborators in immunology who could help us translate this to a possible clinical endpoint.”
Reference: “Synthesis and Structural Confirmation of Secalosides A and B” by Yunchan Nam, Anthony T. Tam, Troy E. Reynolds, Diego N. Rojas, Jonathan A. Brekan, Sneha Sil and Karl A. Scheidt, 23 December 2025, Journal of the American Chemical Society.
DOI: 10.1021/jacs.5c18864
The study was supported by the National Institute of General Medical Science, the Chemistry of Life Processes Institute Lambert Fellowship and the National Science Foundation.
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