Rye pollen’s cancer-fighting structure revealed for first time

• Link to: Northwestern Now Story

•      Rye pollen slows tumor growth in animal models of cancer
•      Chemists determined the 3D structure of the bioactive molecules in rye pollen
•      With new blueprint, researchers could develop strategies for cancer treatment

EVANSTON, Ill. --- Nearly three decades ago, scientists found that a pair of molecules in rye pollen exhibited an unusual ability to slow tumor growth in animal models of cancer. But progress stalled for one seemingly simple reason: No one knew exactly what the molecules looked like.

Now, Northwestern University chemists have finally cracked the case. In a new study, the team definitively determined the three-dimensional structures of both molecules — secalosides A and B — by building them from scratch.

With the correct blueprint now in hand, scientists can finally investigate how specific components of pollen from rye — a staple cereal crop grown for its grain — interact with the immune system and whether it could inspire new strategies for cancer treatment.

The study was published last week in the Jan. 14 issue of 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

Throughout history, researchers, biologists and healthcare workers have looked to nature as an inspiration for new treatments. Some of the most powerful drugs in modern medicine originated not in the lab but in tree bark, microbes and flowers. Morphine, the gold standard for relieving severe pain, is derived from the opium poppy. Taxol, a widely used and effective cancer treatment, was originally isolated from the Pacific yew tree. And statins, which lower cholesterol to prevent heart disease, can trace their origins back to 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.”

The study, “Synthesis and structural confirmation of secalosides A and B,” was supported by the National Institute of General Medical Science, the Chemistry of Life Processes Institute Lambert Fellowship and the National Science Foundation.