By Harshit
CAMBRIDGE, MASSACHUSETTS, DECEMBER 22, 2025
Chemists at the Massachusetts Institute of Technology have achieved a long-sought milestone in synthetic chemistry: the first successful laboratory synthesis of verticillin A, a complex fungal molecule first identified more than half a century ago. Beyond solving a major chemical challenge, the breakthrough is already yielding promising results against an aggressive pediatric brain cancer.
Verticillin A, originally isolated from fungi in 1970, has intrigued scientists for decades because of its potent biological activity. However, its extraordinarily delicate and intricate molecular structure made it one of the most difficult natural products to recreate in the lab—until now.
Why Verticillin A Defied Chemists for Decades
Verticillin A belongs to a family of fungal defense molecules that help protect fungi from pathogens. These compounds have long been investigated for potential anticancer and antimicrobial effects, but progress was limited by their chemical complexity.
Even closely related molecules proved far easier to synthesize. In 2009, the MIT team succeeded in making (+)-11,11′-dideoxyverticillin A, a near-twin of verticillin A that differs by only two oxygen atoms. Yet those seemingly minor differences fundamentally altered how the molecule behaved during synthesis.
“Those two oxygens greatly limit the window of opportunity for chemical transformations,” explained Mohammad Movassaghi, professor of chemistry at MIT. “They make the molecule far more fragile and sensitive, which is why verticillin A remained inaccessible for so long.”
Rethinking the Synthetic Strategy
Both verticillin A and its relatives are dimers—structures formed by joining two identical molecular halves. In earlier work, Movassaghi’s team connected the halves late in the process. That strategy failed for verticillin A, producing incorrect stereochemistry and unstable intermediates.
The breakthrough came when the team reversed their thinking.
“What we learned is that timing is absolutely critical,” Movassaghi said. “We had to significantly change the order of bond-forming events.”
Starting from a beta-hydroxytryptophan derivative, the researchers introduced sulfur-containing groups early, carefully protecting them so they could survive later steps. Only after assembling the two halves did they restore the sensitive disulfide bonds. The full synthesis required 16 precisely controlled steps.
The work was published in the Journal of the American Chemical Society, with Walker Knauss, PhD ’24, as lead author.
A New Weapon Against Diffuse Midline Glioma
With verticillin A finally accessible, the researchers could also create modified versions designed for biological testing. Collaborators at Dana-Farber Cancer Institute evaluated these compounds against Diffuse Midline Glioma, a rare and highly lethal childhood brain tumor.
Several derivatives showed strong activity, particularly in tumor cells that express high levels of EZHIP, a protein known to disrupt DNA methylation and drive tumor growth. The most effective compounds were chemically stabilized versions of verticillin A and its dideoxy counterpart.
“These compounds appear to restore DNA methylation in cancer cells, which pushes them toward programmed cell death,” said Jun Qi, associate professor of medicine at Harvard Medical School and co-senior author of the study.
Why Synthesis Matters More Than the Natural Product
Interestingly, the original fungal molecule itself was not the most potent. The true advance was gaining the ability to redesign it.
“The natural product synthesis brought us to a point where we can make derivatives and study them systematically,” Movassaghi said. “That’s what opens the door to real therapeutic development.”
The Dana-Farber team has already screened lead compounds across more than 800 cancer cell lines, and animal studies are planned to further evaluate safety and effectiveness.
A Broader Impact on Drug Discovery
Natural products have historically been a rich source of medicines, from antibiotics to cancer therapies. The verticillin A synthesis demonstrates how modern chemistry can unlock compounds that were once considered unreachable.
By combining advanced synthetic methods with cancer biology and medicinal chemistry, the researchers hope to translate this achievement into new treatment strategies—not only for pediatric brain tumors, but potentially for other cancers as well.