A Long-Standing Chemistry Challenge Solved as MIT Makes a Rare Anti-Cancer Molecule
Verticillin A was discovered 50 years ago. And recently, the scientists at MIT have succeeded in creating this stable and rare fungal molecule in the laboratory. This compound was considered a game-changer for many years due to its potential anti-cancer properties. But the biggest challenge was the synthesis part. Where scientists struggled to develop the exact structure that is active. But with the help of continuous research and years of hard work, researchers not only have access to verticillin A but can also create modified versions to study its medical potential in more detail.
Verticillin A was first discovered in 1970 in fungi, where it acts as a natural defense against harmful pathogens. Over the past few years, scientists have found that this molecule and similar fungal compounds could have anticancer and antimicrobial effects. This serves as the biggest lead for the scientific community. However, despite decades of effort, verticillin A remained out of reach because of its fragile and intricate chemical structure.
Mohammad Movassaghi is one of the Chemistry professors from MIT. He mentioned that they understood how difficult it can be to synthesize molecules when there are the slightest changes in their structures.
He further explained that advances in chemical methods finally allowed the team to build the compound and also design new variants for research.
In early laboratory tests, one modified version of verticillin A showed strong activity against diffuse midline glioma (DMG), a rare and aggressive pediatric brain tumor. The researchers emphasize that this finding is only an initial step and that much more testing is needed before considering clinical use.
The study was led by Mohammad Movassaghi and Jun Qi, associate professors of medicine at Dana-Farber Cancer Institute and Harvard Medical School. It was published on December 2 in the Journal of the American Chemical Society. Walker Knauss, PhD ’24, was the lead author, along with researchers from Dana-Farber and Boston Children’s Hospital.
Challenges during the Development of Verticillin A
Verticillin A belongs to a family of compounds with extremely complex structures. It contains multiple interconnected rings and several stereogenic centers, that is, the carbon atoms that must be arranged in a highly precise three-dimensional orientation. Even the slightest errors in this arrangement can make the final molecule ineffective or unstable.
In 2009, Movassaghi’s lab successfully synthesized a closely related compound called (+)-11,11′-dideoxyverticillin A. Although it was very similar in structure to Anti-Cancer Molecule verticillin A, there is a slight change present in this structure. The molecule verticillin A contains two additional oxygen atoms, and those small differences made the latter molecule far more fragile and difficult to handle during chemical reactions.
“These two oxygen atoms dramatically narrow the conditions under which reactions can occur,” Movassaghi explains. “Even with years of progress, verticillin A continued to challenge us.”
Both verticillin A molecules are dimers, meaning they are formed by joining two identical fragments. Earlier methods added certain carbon-sulfur bonds near the end of the synthesis, but this approach failed for verticillin A because it did not produce the correct three-dimensional structure. The team had to rethink the order in which bonds were formed completely.
Coming to the last part, beta-hydroxytryptophan acted like a building block. Scientists started adding the functional groups such as alcohols, ketones, and amides in a careful manner and with a thorough, step-by-step strategy. This was highly essential in maintaining the stereochemistry of the molecule.
Sensitive sulfur-containing groups were added early but temporarily protected to prevent damage during later steps. In total, the synthesis required 16 carefully planned steps.
Testing the Cancer-Fighting Potential
After completing the synthesis, the researchers produced several verticillin A derivatives. Scientists at Dana-Farber tested these compounds against different DMG cell lines. They found that cells with high levels of a protein called EZHIP were especially sensitive to the compounds.
EZHIP is known to influence DNA methylation, a process that controls gene activity. The verticillin derivatives appear to increase DNA methylation in these cancer cells, triggering programmed cell death. The most effective compounds were modified forms of verticillin A that were chemically stabilized through a process called N-sulfonylation.
“The natural molecule itself is not the strongest,” Movassaghi notes, “but making it allowed us to design and study better versions.”
The research team is now working to confirm how these compounds work and plans to test them in animal models of pediatric brain cancer. The study highlights how complex natural molecules can still play a critical role in future drug discovery when chemistry and biology work hand in hand.
