After 50 Years, MIT Chemists Synthesize Elusive Cancer-Fighting Molecule

For over half a century, a molecule with promising anticancer properties has remained tantalizingly out of reach for scientists. First isolated from fungi in 1970, verticillin A presented a chemical architecture so delicate and complex that it defied all attempts at laboratory synthesis. Now, researchers at the Massachusetts Institute of Technology have cracked the code, achieving the first-ever total synthesis of this elusive compound. This breakthrough, detailed in a recent study, not only represents a monumental feat in organic chemistry but also opens a direct pathway to developing new treatments for a devastating childhood brain cancer.

The 50-Year Chemical Puzzle

Verticillin A belongs to a class of fungal compounds known for their potential antimicrobial and anticancer activity. For decades, its intricate structure—featuring 10 rings and eight stereogenic centers that must be oriented with perfect precision—posed an insurmountable synthetic challenge. The difficulty was particularly striking because verticillin A differs from a closely related molecule, (+)-11,11'-dideoxyverticillin A (synthesized by the same MIT lab in 2009), by only two oxygen atoms. Yet, as Professor Mohammad Movassaghi explains, those two atoms "greatly limit the window of opportunity... It makes the compound so much more fragile, so much more sensitive." This subtle difference forced a complete rethinking of the synthetic strategy that had worked before.

A Redesigned 16-Step Synthesis

The successful route to verticillin A required abandoning the previous synthesis sequence. The team, led by Professor Movassaghi and lead author Walker Knauss, started from a derivative of the amino acid beta-hydroxytryptophan. The critical innovation was introducing a group containing carbon-sulfur and disulfide bonds early in the process. Because disulfides are highly sensitive, they had to be chemically "masked" to prevent breakdown during subsequent reactions. After carefully building the structure and controlling stereochemistry at each step, the researchers performed a complex dimerization—joining two identical halves of the molecule—before finally restoring the disulfide groups. This 16-step process, a testament to precise chemical engineering, finally yielded verticillin A.

Promise Against Pediatric Brain Cancer

With the natural compound finally accessible, the researchers could create new derivatives by modifying its structure. Collaborators at Dana-Farber Cancer Institute, including Associate Professor Jun Qi, tested these variants against diffuse midline glioma (DMG), a rare pediatric brain tumor with very limited treatment options. The results were promising. The most effective molecules, N-sulfonylated versions of both verticillin A and its related compound, showed strong activity, particularly in DMG cell lines that produce high levels of a protein called EZHIP. This protein influences DNA methylation and is a known potential drug target for this cancer. The verticillin derivatives appear to increase DNA methylation in these cells, pushing them toward programmed cell death.

Unlocking a New Class of Therapeutics

This achievement transcends the synthesis of a single molecule. As Professor Movassaghi notes, "The natural product itself is not the most potent, but it's the natural product synthesis that brought us to a point where we can make these derivatives and study them." The developed synthetic platform now allows chemists to create countless designed variants of verticillin A, enabling detailed studies of structure-activity relationships. This could unlock an entire class of fungal-inspired molecules that were previously chemically inaccessible, providing a new library of compounds to screen against various cancers.

The research team plans to continue this work by further elucidating the exact mechanism of action of the verticillin derivatives and testing them in animal models of pediatric brain cancers. As Professor Qi states, the goal is to "fully evaluate the therapeutic potential of these molecules by integrating our expertise in chemistry, chemical biology, cancer biology, and patient care." The 50-year journey to synthesize verticillin A has not only solved a historic chemical puzzle but has potentially laid the foundation for a new frontier in the fight against some of medicine's most challenging diseases.