Nearly 30 years ago, researchers discovered two unusual molecules in rye pollen that appeared to slow tumor growth in animal studies. Despite the promising discovery, research stalled because scientists were unable to determine the exact three-dimensional structure of the molecule.
Now, chemists at Northwestern University have solved this long-standing mystery. By building the molecules from scratch in the lab, we confirmed for the first time the exact structures of secarosides A and B.
With a precise molecular blueprint now available, researchers are now able to investigate how compounds in rye pollen interact with the immune system. Rye pollen is derived from grains that are widely cultivated as grains. That knowledge could ultimately help develop new approaches to cancer treatment.
The survey results are Journal of the American Chemical Society.
“In preliminary studies, other researchers have found that rye pollen may help eliminate tumors in various animal models through an unknown non-toxic mechanism,” said Carl A. Scheidt of Northwestern University, who led the study. “Now that we have determined the structure of these molecules, we can find the active ingredient, or which part of the molecule, is at work. This is an interesting starting point for creating better versions of these molecules that could potentially inform approaches to cancer treatment.”
Mr. Scheidt is a professor of chemistry in the Northwestern University Weinberg College of Arts and Sciences and a courtesy professor of pharmacology in the Northwestern University Feinberg School of Medicine. He is also a member of the Life Process Chemistry Institute 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 microorganisms for compounds that could lead to new treatments.
Morphine, a powerful painkiller, is made from the opium poppy. Taxol, an important chemotherapy drug, was first isolated from the Pacific yew tree. Statins, which lower cholesterol and reduce the risk of heart disease, are derived from fungi.
“Natural products are not necessarily effective medicines in and of themselves, but they can provide great clues,” Scheidt said. “We can find inspiration in natural products and use chemistry to create better orally ingestible versions that sustain metabolism and hit the right targets.”
Rye pollen may 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 developed it as a medicine. A major obstacle was the inability to clearly understand the three-dimensional structure of the molecule.
Solving a decades-old molecular puzzle
Traditional techniques, including advanced nuclear magnetic resonance spectroscopy, have not been able to fully determine how the key parts of the molecule are 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 had the same overall shape. The difference is that each model has one critical region as a mirror image. Even subtle differences can have a dramatic impact on how a molecule interacts with its biological target and whether it produces a biological effect.
“It’s like your hand,” Scheidt said. “They’re mirror images of each other, but each requires a different glove. If you have two left-handed gloves, it won’t work because you can’t overlap your hands.”
Build molecules from scratch
To resolve the uncertainty, the Northwestern University team turned to total synthesis, a process in which researchers build natural molecules step-by-step in the laboratory.
This study proved extremely difficult because secarosides A and B contain an extremely rare and highly tense 10-membered ring at their core. This tightly compressed structure is notoriously difficult to assemble.
The researchers overcame this problem by first creating a larger, more flexible ring. They then triggered a chemical reaction that transformed them into tiny strained rings in one step.
After creating both proposed versions of the molecule, the team compared them to samples extracted from rye pollen. There was only one exact match, allowing the researchers to clearly identify the correct structure.
“We have shown that we can create a core of this natural product,” Scheidt said. “We are currently trying to find potential collaborators in immunology to help translate this into potential clinical endpoints.”
This study, “Synthesis and structural confirmation of secarosides A and B,” was supported by the National Institute of General Medical Sciences, the Institute of Bioprocess Chemistry Lambert Fellowship, and the National Science Foundation.
