Nearly 30 years ago, researchers discovered two unusual molecules in rye pollen that appeared to slow tumor growth in animal studies. Despite the promising findings, the research hit a dead end because scientists were unable to determine the exact three-dimensional structures of the molecules.
Now, chemists at Northwestern University have solved that long-standing mystery. By building the molecules from scratch in the lab, they confirmed for the first time the precise structures of secalosides A and B.
With a precise molecular model available, researchers can now investigate how these compounds from rye pollen, which comes from a cereal crop widely grown for its grain, interact with the immune system. That knowledge could eventually help guide the development of new approaches to cancer treatment.
The findings were published in the Journal of the American Chemical Society.
“In preliminary studies, other researchers found that rye pollen could help different animal models eliminate tumors through some unknown, non-toxic mechanism,” said Karl A. Scheidt of Northwestern, who led the study. “Now that we confirm the structure of these molecules, we can find the active ingredient, or which part of the molecule is doing the work. This is an exciting starting point for creating better versions of these molecules that could possibly inform cancer therapy approaches.”
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’s Feinberg School of Medicine. He is also a member of the Institute for Life Process Chemistry and the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.
The role of nature in drug discovery
Many important medicines have their roots in nature. Scientists have long studied plants, fungi and microbes in search of compounds that could inspire new treatments.
Morphine, a powerful pain reliever, comes from the opium poppy. Taxol, an important chemotherapy drug, was first isolated from the Pacific yew. Statins, which help lower cholesterol and reduce the risk of heart disease, originated from mushrooms.
“Natural products are not necessarily effective drugs on their own, but they are great clues,” Scheidt said. “We can find inspiration in natural products and use chemistry to create better versions that are orally available, survive metabolism and hit the right targets.”
Rye pollen could eventually join that list. Rye pollen extract is already sold as a dietary supplement that many people use to support prostate health. However, scientists have not yet turned it into a pharmaceutical treatment. A major obstacle was the lack of a clear picture of the three-dimensional structures of the molecules.
Solving a decades-long molecular puzzle
Traditional techniques, including advanced nuclear magnetic resonance spectroscopy, were unable to fully determine how key parts of the molecules were arranged. As a result, scientists spent decades debating between two possible structural models.
Both versions contained the same atoms connected in the same way and shared the same general shape. The difference was that a critical region existed as a mirror image in each model. Even that subtle variation can dramatically affect how a molecule interacts with biological targets and whether it produces a biological effect.
“It’s like your hands,” Scheidt said. “They’re mirror images of each other, but you need a different glove for each one. If you had two left-handed gloves, it wouldn’t work because your hands can’t overlap each other.”
Building molecules from scratch
To resolve the uncertainty, the Northwestern team relied on total synthesis, a process in which researchers build a natural molecule step by step in the lab.
The work proved exceptionally difficult because secalosides A and B contain in their core an extremely rare and highly strained 10-membered ring. Such a compressed structure is notoriously difficult to assemble.
The researchers overcame the problem by first creating a larger, more flexible ring. They then triggered a chemical reaction that turned it into the smallest strained ring in a single step.
After producing both proposed versions of the molecules, the team compared them to samples taken from rye pollen. Only one matched perfectly, allowing the researchers to definitively identify the correct structures.
“We have shown that we can make the core of this natural product,” Scheidt said. “We are now trying to find potential collaborators in immunology who can help us translate this into a potential clinical endpoint.”
The study, “Synthesis and structural confirmation of secalosides A and B,” was supported by the National Institute of General Medical Sciences, the Lambert Fellowship of the Institute for the Chemistry of Life Processes, and the National Science Foundation.