A long-running rye pollen puzzle has finally been pinned down, and researchers say it could help revive interest in a natural compound once linked to tumor-fighting effects in animals.

Chemists at Northwestern University have confirmed the exact three-dimensional structures of secalosides A and B, two unusual molecules first found in rye pollen nearly 30 years ago. The work, published in the Journal of the American Chemical Society, gives researchers a clear molecular blueprint to study how the compounds interact with the immune system.

Nearly 30 years ago, researchers found the molecules appeared to slow tumor growth in animal studies. But the work stalled because scientists could not determine their exact structures.

“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 is also a member of the Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The researchers said a major obstacle had been a decades-long debate over two possible structural models. Both had the same atoms connected in the same way and the same overall shape, but one critical region was a mirror image in each model.

“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.”

To settle it, the team used total synthesis, building the molecules step by step in the lab. The process was especially difficult because secalosides A and B contain a rare, highly strained 10-membered ring at their core.

The researchers first made a larger, more flexible ring, then used a chemical reaction to convert it into the smaller strained ring in a single step. After making both proposed versions of the molecules, they compared them with samples extracted from rye pollen. Only one matched.

“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 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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