MIT Chemists Finally Synthesize Verticillin A, a Fungal Compound Showing Promise Against Pediatric Brain Cancer

Chemists at the Massachusetts Institute of Technology have achieved a milestone that has been more than half a century in the making. For the first time, researchers have successfully synthesized verticillin A, a rare and highly complex fungal compound that has long intrigued scientists for its anticancer potential. Beyond being a triumph of chemical synthesis, this breakthrough has opened the door to testing new drug-like variants of the compound, some of which are already showing strong activity against a deadly pediatric brain cancer.

Verticillin A was first isolated from fungi in 1970. In nature, fungi produce this compound as a defensive molecule to protect themselves from pathogens. Over the decades, scientists discovered that verticillin A and related molecules also have antimicrobial and anticancer properties, making them attractive candidates for drug discovery. However, the compound’s extraordinarily complex structure made it nearly impossible to synthesize in the laboratory—until now.

The new work was led by Mohammad Movassaghi, professor of chemistry at MIT, along with Jun Qi, associate professor of medicine at the Dana-Farber Cancer Institute, Boston Children’s Cancer and Blood Disorders Center, and Harvard Medical School. The study was published in the Journal of the American Chemical Society, with Walker Knauss, PhD ’24, as the lead author. Other contributors include Xiuqi Wang, a medicinal chemist and chemical biologist at Dana-Farber, and Mariella Filbin, research director in the Pediatric Neurology-Oncology Program at Dana-Farber and Boston Children’s.

Why Verticillin A Has Been So Hard to Make

Verticillin A is structurally daunting. The molecule contains 10 interconnected rings and eight stereogenic centers, meaning eight carbon atoms where the spatial arrangement of chemical groups must be perfectly controlled. Even a small mistake in orientation can lead to a completely different compound with different biological properties.

Movassaghi’s lab is no stranger to difficult molecules. Back in 2009, the team reported the synthesis of a closely related compound called (+)-11,11′-dideoxyverticillin A. That achievement was itself a major success. Yet verticillin A remained elusive, despite differing from the earlier compound by only two oxygen atoms.

Those two oxygen atoms turned out to be a big problem. Their presence made verticillin A far more fragile and chemically sensitive, severely limiting when and how certain reactions could be performed during synthesis. Reactions that worked for the earlier compound simply failed when applied to verticillin A.

Rethinking the Entire Synthetic Strategy

One of the most important insights from this work was that timing is everything in complex synthesis. In earlier approaches, the researchers joined two identical molecular halves—called a dimerization reaction—late in the process and then formed critical carbon–sulfur bonds afterward. That strategy worked for related molecules but failed to produce the correct stereochemistry for verticillin A.

To solve this, the team completely reordered the sequence of bond-forming steps. Instead of waiting until the end, they introduced a functional group containing two carbon–sulfur bonds and a disulfide bond much earlier in the synthesis. These sulfur-containing groups helped control the molecule’s three-dimensional shape, but they were also extremely delicate.

To protect them, the researchers temporarily “masked” the disulfide as a pair of sulfides, preventing breakdown during later chemical reactions. After the two molecular halves were successfully joined, the disulfide bond was carefully regenerated.

The synthesis begins with beta-hydroxytryptophan, an amino acid derivative, and proceeds through a carefully choreographed series of steps that introduce alcohols, ketones, amides, and other functional groups. Each step had to preserve the correct stereochemistry while avoiding damage to sensitive parts of the molecule.

In total, the synthesis requires 16 steps from the starting material to the final verticillin A molecule. One particularly striking achievement was the dimerization step itself, which involved combining two extremely complex fragments, each packed with functional groups and stereochemical features.

Turning a Chemical Feat Into a Cancer Research Tool

Successfully making verticillin A was only part of the story. Once the synthetic route was established, the team could begin doing something that had never been possible before: designing and producing modified versions of the compound.

These derivatives were sent to collaborators at Dana-Farber, where they were tested against diffuse midline glioma (DMG). DMG is a rare and devastating pediatric brain cancer with very few effective treatment options and a grim prognosis.

The results were encouraging. Several verticillin A derivatives showed strong activity against DMG cell lines, particularly those with high levels of a protein called EZHIP. EZHIP is known to interfere with normal DNA methylation patterns and has already been identified as a potential drug target in this cancer.

The researchers found that verticillin derivatives appear to interact with EZHIP in a way that increases DNA methylation, pushing cancer cells toward programmed cell death. Among the most effective compounds were N-sulfonylated (+)-11,11′-dideoxyverticillin A and N-sulfonylated verticillin A. N-sulfonylation, which adds a sulfur-and-oxygen-containing group, made the molecules more stable and more potent than the natural product itself.

Interestingly, the researchers emphasize that verticillin A in its natural form is not necessarily the strongest cancer-killing agent. Instead, its true value lies in the fact that being able to synthesize it enables the creation of better-designed derivatives with improved properties.

What Happens Next

These findings are still at an early, preclinical stage. More work is needed to confirm the exact molecular mechanisms involved and to evaluate safety and effectiveness in animal models of pediatric brain cancer. The Dana-Farber team is already working on these next steps.

Beyond DMG, the researchers have profiled their lead compounds against more than 800 different cancer cell lines. This broad screening effort could reveal whether verticillin-based molecules might be useful against other forms of cancer as well.

Why Natural Products Still Matter in Drug Discovery

Verticillin A is a reminder of why natural products continue to play such an important role in medicine. Many of today’s drugs—from antibiotics to cancer therapies—trace their origins to compounds made by plants, bacteria, or fungi. These molecules have been refined by evolution to interact with biological systems in powerful ways.

The challenge has always been access. When a compound is rare, fragile, or incredibly complex, studying it becomes nearly impossible. Advances in synthetic chemistry, like the work demonstrated here, change that equation by giving scientists control and flexibility.

By uniting expertise in chemistry, chemical biology, cancer biology, and clinical research, this project highlights how interdisciplinary collaboration can transform a long-standing chemical puzzle into a promising avenue for new cancer therapies.

Research paper: https://doi.org/10.1021/jacs.5c16112