At Northwestern University, Professor Karl A. Scheidt and his research team have resolved a structural problem that has remained unsettled for nearly three decades. The issue centered on two naturally occurring compounds found in rye pollen, secalosides A and B, which were first reported in the 1990s to slow tumor growth in animal models. Those early biological observations drew attention, but the underlying chemistry remained uncertain. Without definitive knowledge of the molecules’ three dimensional structures, further development stalled. The new work, published in the Journal of the American Chemical Society, establishes the precise stereochemical arrangement of these compounds and provides a firm foundation for renewed biological investigation.
Nam, Y., Tam, A. T., Reynolds, T. E., Rojas, D. N., Brekan, J. A., Sil, S., & Scheidt, K. A. (2026). Synthesis and Structural Confirmation of Secalosides A and B. Journal of the American Chemical Society, 148(1), 86–92. https://doi.org/10.1021/jacs.5c18864
The original studies on rye pollen extracts suggested that certain components might influence tumor progression through mechanisms that did not appear overtly toxic. While the results were preliminary and limited to animal systems, they were sufficiently intriguing to prompt isolation of the responsible molecules. Chemists identified two structurally complex natural products and named them secalosides A and B. Analytical methods available at the time, including advanced nuclear magnetic resonance spectroscopy, were able to determine the atoms present and how they were connected. What they could not fully resolve was the spatial orientation of key portions of the molecules. Two plausible three dimensional models emerged, differing only in the configuration at a central stereochemical position. That subtle distinction proved decisive, because in biological systems shape governs interaction. Even small differences in orientation can determine whether a compound binds to a receptor, fits into an enzyme pocket, or remains inactive.
Professor Karl A. Scheidt from Northwestern University stated,
“We’ve demonstrated we can make the core of this natural product. Now, we’re trying to find potential collaborators in immunology who could help us translate this to a possible clinical endpoint.”
The uncertainty persisted because conventional spectroscopic techniques could not discriminate conclusively between the mirror image possibilities. The competing structures were chemically identical in composition and connectivity, yet differed in the handedness of a critical region. Such stereochemical ambiguity is not uncommon in natural product chemistry, particularly when molecules contain densely functionalized ring systems. In this case, the secalosides possess an unusual and highly strained ten membered ring embedded within their core framework. The presence of that ring contributed both to the structural complexity and to the difficulty in determining the correct three dimensional arrangement.
To resolve the question, Scheidt’s group turned to total synthesis, the process of constructing a natural molecule from simpler building blocks in the laboratory. Total synthesis is often pursued not only to access scarce natural materials but also to confirm or revise proposed structures. If a chemist can build a candidate structure and demonstrate that it matches the naturally derived compound in every measurable respect, the structural assignment can be considered secure. In the case of the secalosides, the team designed synthetic routes to produce both of the proposed stereochemical variants. This approach required developing strategies to form the strained ten membered ring efficiently and with control over the configuration at the contested stereocenter.
Rather than attempting to assemble the strained ring directly, the researchers adopted an indirect method. They first constructed a larger, more flexible ring system that could be formed under milder conditions. Through a carefully designed transformation, that intermediate was then induced to contract into the smaller ring in a single step. This tactic allowed the team to overcome the inherent energetic barriers associated with forming compressed cyclic systems. Once both stereochemical candidates had been synthesized, each was compared in detail to authentic samples isolated from rye pollen. Spectroscopic data and physical properties were examined side by side. Only one synthetic version matched the natural compound precisely, thereby confirming the correct three dimensional structure of secalosides A and B.
The significance of the work lies less in immediate therapeutic implications and more in establishing structural certainty. In drug discovery and chemical biology, ambiguous molecular identity can undermine years of effort. Researchers investigating mechanism of action, designing analogs, or conducting computational modeling must know the exact arrangement of atoms in space. A single stereochemical error can lead to misleading biological conclusions. By settling the structural debate, the Northwestern team has removed a long standing obstacle and clarified the molecular template on which further studies can be based.
Natural products have historically served as starting points for major advances in medicine. Many clinically important drugs trace their origins to molecules first identified in plants, fungi, or microorganisms. In most cases, the naturally occurring compound itself is not administered in its original form. Instead, chemists modify the structure to improve stability, selectivity, solubility, or metabolic properties. That iterative process depends on an accurate understanding of the parent structure. The confirmed structures of secalosides A and B now enable systematic exploration of structure activity relationships. Researchers can begin to examine which portions of the molecule are essential for biological function and which may be altered to improve pharmacological characteristics.
It is important to note that the current findings do not establish a cancer treatment. The earlier reports of tumor suppression in animal models were preliminary and did not identify a defined molecular target. Questions remain regarding how these compounds interact with immune cells, whether they influence signaling pathways, and how they are processed in living systems. Future work will require collaboration between chemists, immunologists, pharmacologists, and oncologists. Detailed mechanistic studies will be necessary to determine whether the secalosides exert direct effects on tumor cells, modulate immune responses, or act through alternative pathways.
From an engineering and translational standpoint, the study demonstrates the continued relevance of synthetic chemistry in resolving biological uncertainty. Analytical instrumentation has advanced substantially over the past three decades, yet there remain cases in which synthesis provides the definitive answer. By recreating the molecules in the laboratory and systematically comparing alternatives, the researchers have provided a reliable structural blueprint. With that blueprint in hand, subsequent investigations can proceed without the ambiguity that has limited progress since the 1990s.
The work also underscores the interplay between fundamental chemistry and biomedical research. Structural elucidation may appear incremental compared to clinical breakthroughs, but it is foundational. Without precise molecular definition, efforts to optimize compounds or interpret biological data risk being built on unstable ground. In clarifying the architecture of secalosides A and B, Scheidt and his colleagues have addressed a long unresolved question and reopened a line of inquiry that had remained dormant due to structural uncertainty.
As research moves forward, attention will likely turn toward synthesizing derivatives, evaluating biological activity in controlled systems, and assessing pharmacokinetic behavior. Advances in synthetic methodology may allow for more efficient access to related structures, facilitating broader screening efforts. Whether rye pollen derived compounds ultimately contribute to therapeutic development remains to be determined. What is clear is that structural precision has now replaced speculation. In molecular science, that transition from uncertainty to defined architecture is often the step that enables meaningful progress.
Adrian graduated with a Masters Degree (1st Class Honours) in Chemical Engineering from Chester University along with Harris. His master’s research aimed to develop a standardadised clean water oxygenation transfer procedure to test bubble diffusers that are currently used in the wastewater industry commercial market. He has also undergone placments in both US and China primarely focused within the R&D department and is an associate member of the Institute of Chemical Engineers (IChemE).
