MIT chemists finally crack 50-year puzzle, opening new hope against deadly childhood brain cancer.
MIT chemists have achieved the first total synthesis of verticillin A, a complex fungal natural product discovered in 1970 and long recognized for its anticancer potential. The molecule’s dense architecture-featuring multiple rings, stereocenters, and sensitive sulfur-containing groups-has thwarted synthetic efforts for more than 50 years. By reordering key bond-forming steps and introducing fragile disulfide-containing groups early in a protected form, the team led by Mohammad Movassaghi developed a 16-step route starting from beta-hydroxytryptophan. This strategy allowed them to precisely control stereochemistry and overcome the extreme fragility imposed by just two extra oxygen atoms that distinguish verticillin A from a related, previously synthesized compound.
With synthetic access finally secured, the researchers were able to generate and test a series of verticillin A derivatives. Collaborators at Dana-Farber Cancer Institute found that certain N-sulfonylated derivatives showed strong activity against diffuse midline glioma, a rare and aggressive pediatric brain cancer with few treatment options. These compounds appear to interact with EZHIP, a protein involved in DNA methylation, increasing methylation and triggering programmed cell death in susceptible cancer cells. While further studies in animal models and broader cancer cell line panels are underway, the work illustrates how total synthesis of a challenging natural product can unlock a new platform for anticancer drug discovery.
References (APA style)
Knauss, W., Wang, X., Filbin, M. G., Qi, J., & Movassaghi, M. (2025). Total synthesis and anticancer study of (+)-verticillin A.
Journal of the American Chemical Society.
Trafton, A. (2025, December 9). After 50 years, MIT chemists finally synthesize elusive anti-cancer compound.
SciTechDaily.