Fungal Compound With Anti-Cancer Properties Finally Synthesized After More Than 50 Years

In 1970, researchers first isolated verticillin A, a compound produced by fungi to defend themselves against pathogens and long noted for its potential to combat cancer. Its intricate structure and scarcity in nature made it extraordinarily difficult to reproduce in the laboratory. More than five decades later, a team from the Massachusetts Institute of Technology (MIT) and Harvard Medical School reported the first total synthesis of verticillin A — published December 2, 2025 in the Journal of the American Chemical Society — marking a pivotal advance in cancer research. (SciTechDaily)

What is verticillin A?

Verticillin A is a naturally occurring fungal compound whose molecule is built from two identical halves fused together, forming what chemists call a dimer. That dimeric configuration, combined with a precisely arranged three-dimensional shape, is central to both its biological activity and the difficulty of making it. The compound belongs to a family known as epidithiodiketopiperazines (ETPs) and has long shown cytotoxic, anti-cancer and antimicrobial properties, which is why it has drawn scientific interest for half a century.

Why has synthesizing verticillin A been so challenging?

The obstacles stem from verticillin A’s complex 3D structure and inherent instability. Its two halves must be aligned with exact stereochemistry, and its sulfur-containing functional groups are highly sensitive — vulnerable to carbon-centered radicals and even UV light. Remarkably, the molecule differs from related compounds chemists had previously made by only a couple of atoms, yet those subtle differences dramatically raised the synthetic challenge. As senior author Mohammad Movassaghi put it, the team gained “a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge.”

How did researchers overcome these challenges?

The team, led by MIT chemist Mohammad Movassaghi and Dana-Farber/Harvard Medical School’s Jun Qi, with Walker Knauss as lead author, reworked approaches previously used for similar molecules. Starting from an amino acid derivative called beta-hydroxytryptophan, they added functional groups step by step, masked the fragile disulfide as a pair of alkyl sulfides to survive an ambitious radical dimerization that fused the two halves, and then “unmasked” the sensitive groups at the end to reveal the correct structure. The result was a 16-step synthesis yielding verticillin A with the precise 3D geometry required. “What we learned was the timing of the events is absolutely critical,” Movassaghi said. “We had to significantly change the order of the bond-forming events.” (Journal of the American Chemical Society)

What did the compound do against cancer?

Crucially, the researchers did not stop at making the molecule — they tested it. They evaluated synthetic verticillin A and several designed variants on lab-grown cells of diffuse midline glioma (DMG), an aggressive and often fatal brain cancer that primarily affects children. Molecules related to verticillin A had previously shown promise against DMG, and the new synthetic versions again proved potent at killing the cancer cells. The study found that verticillin A and its N1-sulfonylated derivatives regulated histone H3K27 trimethylation (H3K27me3) levels inside cells and engaged a protein called EZHIP, driving the cancer cells toward apoptosis. That interaction with EZHIP suggests a path to treating pediatric cancers sensitive to H3K27me3 alteration. (Neuroscience News)

What are the implications of this synthesis?

Being able to produce verticillin A in the lab — for the first time, more than 50 years after it was isolated — unlocks what had been a largely unreachable class of molecules. Scientists can now study its mechanisms in depth, evaluate its efficacy across cancer types, and, just as importantly, design and build many structural variants. “Now we have the technology where we can not only access them for the first time… but also we can make many designed variants, which can enable further detailed studies,” Movassaghi said. Those analogs could become the starting points for new cancer therapies.

What are the next steps in this research?

The team plans to investigate verticillin A’s interactions with cancer cells more fully and to pursue its therapeutic potential, combining expertise in chemistry, chemical biology, and cancer biology. The work was supported by the National Institute of General Medical Sciences, the Ependymoma Research Foundation, and the Curing Kids Cancer Foundation — funding that reflects the strong interest in finding treatments for childhood brain cancers like DMG. After more than half a century of effort, the synthesis offers fresh hope for new medicines drawn from nature’s own chemistry. (PubMed)