EuroWire, WASHINGTON: Scientists at the Massachusetts Institute of Technology have successfully synthesised verticillin A, a complex fungal compound first identified more than 50 years ago and long recognised for its anti-cancer properties. The achievement marks the first laboratory synthesis of the compound and resolves a longstanding challenge in organic chemistry that had limited scientific study of the molecule since its discovery.
Verticillin A was originally isolated from fungi in the early 1960s and drew attention due to its biological activity, including its ability to interfere with cancer cell growth. Despite this early promise, researchers were unable to reproduce the compound synthetically because of its highly intricate molecular architecture. The structure differs only slightly from related fungal compounds, yet those subtle differences created major obstacles to assembling the molecule with the precise three-dimensional arrangement required for its biological function.
The newly reported work demonstrates how those challenges were overcome using advances in synthetic chemistry. Mohammad Movassaghi, a professor of chemistry at MIT and one of the senior authors of the study, said the effort provided a clearer understanding of how small structural variations can dramatically increase synthetic complexity. The researchers developed methods that allowed them to control the order in which chemical bonds were formed, enabling construction of the compound after decades of unsuccessful attempts by the scientific community.
Laboratory testing of a verticillin A derivative showed activity in human cancer cells, including against diffuse midline glioma, a rare and aggressive pediatric brain cancer. Diffuse midline glioma is characterised by limited treatment options and poor outcomes, making it a focus of ongoing research. The findings were obtained using cultured human cancer cells and represent early-stage experimental results rather than clinical data.
The study was co-led by Movassaghi and Jun Qi, an associate professor of medicine affiliated with the Dana-Farber Cancer Institute, the Boston Children’s Cancer and Blood Disorders Center, and Harvard Medical School. Their findings were published in the Journal of the American Chemical Society, one of the leading peer-reviewed journals in the field of chemistry.
Decades-long challenge in fungal compound synthesis resolved
At the molecular level, verticillin A consists of two identical halves that must be fused together to form a dimer with an exact spatial configuration. Achieving this precise alignment was the central challenge that had prevented synthesis for decades. According to the researchers, even minor deviations in orientation during assembly can disrupt the compound’s biological properties, making strict control over the three-dimensional structure essential.
To address this, the team designed a 16-step synthetic process that carefully controlled when and how each chemical bond was formed. The researchers altered the traditional sequence of bond-forming reactions and temporarily protected fragile molecular regions from breaking during critical stages. Certain functional groups were deliberately left masked until after the two halves of the molecule had been successfully joined, ensuring the final compound adopted the required three-dimensional structure.
Timing of chemical reactions proved critical
Movassaghi said the work highlighted the importance of timing in chemical synthesis. By changing the order of key steps, the researchers were able to guide the molecule into its correct configuration, a result that had not been achieved previously. The approach also allows for the creation of related variants of verticillin A, which can be used to study how small chemical modifications influence biological activity.
With laboratory synthesis now established, verticillin A can be produced in quantities sufficient for broader scientific investigation. Qi said natural compounds have historically played a significant role in drug discovery, and access to synthetically produced verticillin A enables more detailed study of how the molecule interacts with cancer cells. Researchers plan to examine its properties using integrated approaches spanning chemistry, chemical biology, cancer biology, and patient-focused research, with the aim of expanding understanding of its potential role in cancer science.