Chemists at Northwestern University have built two molecules from rye pollen from scratch, and in doing so settled an argument that ran for nearly 30 years.
The molecules are secalosides A and B. Researchers found them in rye pollen decades ago and saw that they seemed to slow tumor growth in animals. Then the work stalled. Nobody could pin down their exact three-dimensional structures.
The new work appeared in the Journal of the American Chemical Society. Karl A. Scheidt, a professor of chemistry at Northwestern who led the study, put the old finding plainly. “In preliminary studies, other researchers found that rye pollen could help different animal models clear tumors through some unknown, non-toxic mechanism,” he said.
Two shapes, one right answer
Scientists spent decades debating two possible structures. Both had the same atoms, connected the same way, in the same overall shape. In one critical region, though, each was the mirror image of the other. Advanced nuclear magnetic resonance spectroscopy could not settle it.
Think of it like gloves. “They are mirror images of each other, but you need a different glove for each,” Scheidt said of human hands. A molecule that fits one biological target in one form may not fit it in the other, and that can decide whether it does anything at all.
The team used total synthesis, building the natural molecule step by step in the lab. It was hard going. Both secalosides contain a rare, highly strained ring of 10 members at their core, and rings that tight are notoriously difficult to assemble. The chemists got around that by making a larger, more flexible ring first, then triggering one reaction that collapsed it into the strained one.
They made both proposed versions and compared each with samples extracted from rye pollen. Only one matched perfectly.
What comes next
Nothing here is a treatment. Rye pollen extract is sold as a dietary supplement that many people take for prostate health, but scientists have not developed it into a drug. Scheidt said natural products are rarely effective drugs on their own. “They are great leads,” he said, and chemistry can then make versions that can be taken by mouth, survive metabolism and hit the right targets.
With the structure confirmed, the next job is finding which part of the molecule does the work. “This is an exciting starting point to make better versions of these molecules that could possibly inform approaches to cancer therapy,” Scheidt said. His group is now looking for immunology collaborators who could help move the work toward 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.
Sources
- Scientists solve a 30-year rye pollen mystery that could transform cancer research
- Scientists solve a 30-year rye pollen mystery that could transform cancer research
