Nearly three decades after scientists first identified a pair of molecules in rye pollen with the potential to slow tumor growth, a breakthrough has finally been achieved. Researchers at Northwestern University have determined the three-dimensional structures of these molecules, secalosides A and B, marking a significant advancement in cancer research. This discovery, published in the Journal of the American Chemical Society, opens new avenues for understanding how components of rye pollen interact with the immune system and could inspire innovative cancer therapies.
The announcement comes as a relief to the scientific community, which had been stalled due to the inability to visualize these molecules. “In preliminary studies, other researchers found that rye pollen could help different animal models clear tumors through some unknown, non-toxic mechanism,” said Karl A. Scheidt, the study’s lead author and a professor at Northwestern University. “Now that we confirmed the structure of these molecules, we can identify 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.”
Nature as Inspiration for Medicine
Throughout history, nature has been a rich source of inspiration for medical breakthroughs. Many of today’s most powerful drugs have origins in natural products. For instance, morphine, a critical pain reliever, is derived from the opium poppy, while Taxol, a key cancer treatment, was isolated from the Pacific yew tree. Statins, used to lower cholesterol, trace their roots back to fungi.
“Natural products aren’t necessarily effective drugs on their own, but they are great leads,” Scheidt explained. “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.”
Rye pollen, a staple cereal crop, could potentially join these ranks. While it is already consumed in supplement form for prostate health, its precise mechanism of action remained a mystery until now. Understanding the molecules’ three-dimensional shape was crucial to unlocking their potential as a pharmaceutical drug.
A Molecular Mystery
The challenge of determining the structure of secalosides A and B was compounded by the limitations of traditional techniques like advanced nuclear magnetic resonance spectroscopy. Two competing structural models had persisted for decades, with both sharing the same atoms and connections but differing in a crucial way: a central part of the molecules are mirror images of each other.
“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 resolve this molecular mystery, the Northwestern team employed total synthesis, a step-by-step process of constructing a natural molecule in the laboratory. This approach was both complex and challenging, as secalosides A and B contain a rare and highly strained feature: a tightly compressed, 10-membered ring.
Scheidt and his team devised an innovative strategy by first constructing a larger, more flexible ring and then triggering a reaction to snap it into the smaller, strained shape. After synthesizing both structural versions of the secalosides, they 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. This breakthrough not only sheds light on the potential of rye pollen in cancer treatment but also exemplifies the ongoing quest to harness nature’s bounty for medical innovation.
