MIT chemists have successfully synthesized verticillin A, a complex fungal molecule discovered in 1970, for the first time in the lab. The breakthrough enables the creation of variants showing promise against diffuse midline glioma, a rare pediatric brain cancer. This long-elusive compound's structure had thwarted synthesis efforts despite its potential as an anticancer agent.
In a landmark achievement, researchers at the Massachusetts Institute of Technology (MIT) have produced verticillin A in the laboratory, more than five decades after its initial isolation from fungi in 1970. The molecule, which fungi use to defend against pathogens, has long intrigued scientists for its anticancer and antimicrobial properties, but its intricate architecture—featuring 10 rings and eight stereogenic centers—proved exceptionally challenging to replicate.
Verticillin A differs from a related compound, (+)-11,11'-dideoxyverticillin A, by just two oxygen atoms, yet these subtle changes rendered it far more fragile and sensitive during synthesis. Mohammad Movassaghi, an MIT professor of chemistry, noted, "We have a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge." His team, building on a 2009 synthesis of the related molecule, redesigned the process entirely. The new 16-step route begins with beta-hydroxytryptophan, carefully controlling stereochemistry and introducing protective groups for disulfide bonds to enable dimerization of two identical halves.
"What we learned was the timing of the events is absolutely critical. We had to significantly change the order of the bond-forming events," Movassaghi explained. This approach not only yielded verticillin A but also allowed the creation of derivatives, including N-sulfonylated versions that enhance stability.
Collaborating with experts at Dana-Farber Cancer Institute and Boston Children's Hospital, the team tested these variants on human cancer cells. One derivative excelled against diffuse midline glioma (DMG) cell lines with high levels of the EZHIP protein, which influences DNA methylation and triggers cell death in affected tumors. Jun Qi, an associate professor of medicine, stated, "Identifying the potential targets of these compounds will play a critical role in further understanding their mechanism of action, and more importantly, will help optimize the compounds... for novel therapy development."
The study, led by Walker Knauss with co-authors Xiuqi Wang and Mariella Filbin, appears in the Journal of the American Chemical Society. While promising, the researchers stress that further preclinical testing, including animal models, is essential before clinical evaluation. Funding came from the National Institute of General Medical Sciences, the Ependymoma Research Foundation, and the Curing Kids Cancer Foundation.
This synthesis unlocks access to an entire class of complex fungal molecules, potentially advancing treatments for pediatric brain cancers with few options.
