After more than five decades of effort across the field, chemists at the Massachusetts Institute of Technology have successfully synthesized verticillin A, a complex fungal molecule long recognized for its anticancer potential but never before made in the laboratory. The achievement provides access to a class of compounds that were previously available only in trace amounts from natural sources and opens new paths for systematic drug development.
Knauss, W., Wang, X., Filbin, M. G., Qi, J., & Movassaghi, M. (2025). Total Synthesis and Anticancer Study of (+)-Verticillin A. Journal of the American Chemical Society, 147(50), 46430–46439. https://doi.org/10.1021/jacs.5c16112
The work was led by Mohammad Movassaghi, professor of chemistry at MIT, in collaboration with researchers at Dana-Farber Cancer Institute and Boston Children’s Hospital.
Verticillin A belongs to a family of fungal metabolites that show activity against cancer cells and pathogens. Despite its promise, the compound’s tightly packed structure has made it exceptionally difficult to construct using synthetic chemistry. Small differences in atomic arrangement, particularly the placement of oxygen atoms and sulfur-containing groups, create significant challenges in controlling chemical reactivity and molecular stability during synthesis.
Mohammad Movassaghi, professor of chemistry at MIT, stated,
“We have a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge. Now we have the technology where we can not only access them for the first time, more than 50 years after they were isolated, but also we can make many designed variants, which can enable further detailed studies.”
Earlier work from the Movassaghi laboratory succeeded in synthesizing a closely related compound that lacks two oxygen atoms found in verticillin A. While that molecule already required an intricate sequence of reactions, the added oxygen atoms in verticillin A reduced the number of viable synthetic pathways even further, forcing the researchers to rethink their overall strategy.
Rather than following conventional approaches in which sensitive bonds are introduced near the end of a synthesis, the team reversed the order of key steps. Sulfur-containing groups that play a central role in controlling molecular shape were installed earlier in the process and temporarily protected to prevent degradation. These decisions allowed the researchers to preserve the correct three-dimensional arrangement of atoms throughout the sequence.
The final synthesis begins with a modified amino acid and proceeds through sixteen carefully controlled steps. Two identical molecular fragments are ultimately joined in a demanding dimerization reaction that must preserve both structural symmetry and stereochemistry. According to the researchers, the timing of this step proved critical to achieving the correct final structure.
Beyond demonstrating a long-sought synthetic capability, the work has immediate implications for cancer research. Once the synthesis was established, the team used it as a platform to generate modified versions of verticillin A with improved stability. These derivatives were tested by collaborators at Dana-Farber against several cancer cell lines, including diffuse midline glioma, a rare and aggressive pediatric brain tumor with limited treatment options.
In cell-based studies, some verticillin derivatives showed selective activity against glioma cells that express high levels of the protein EZHIP, which is involved in DNA methylation. The compounds appear to alter methylation patterns in a way that triggers programmed cell death. While the results are preliminary and limited to laboratory experiments, they suggest a possible biological mechanism that can now be explored in greater detail.
Researchers emphasize that the natural compound itself is not necessarily optimized as a drug candidate. Instead, its value lies in serving as a chemical foundation from which more potent and selective molecules can be designed. Having a reliable synthetic route makes it possible to systematically vary the structure and study how those changes affect biological activity.
From an engineering and chemistry standpoint, the work highlights how advances in synthetic methodology can unlock previously inaccessible regions of chemical space. Complex natural products often resist straightforward synthesis, but once a route is established, they become powerful tools for probing biological systems.
The team is now extending the work to animal models and broader cancer screening efforts. While significant steps remain before any clinical application, the successful synthesis of verticillin A resolves a long-standing challenge in organic chemistry and provides a new starting point for research at the intersection of chemistry, biology, and medicine.
Rather than marking an endpoint, the achievement illustrates how persistence in method development can eventually transform a theoretical target into a practical research tool, with potential implications well beyond its original discovery.
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).
