MIT Synthesizes 50-Year-Old Fungal Compound That Could Treat Pediatric Brain Cancer
- Gauri Khanna
- 1 day ago
- 4 min read
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MIT chemists have synthesized verticillin A for the first time since its discovery in 1970, overcoming molecular complexity that stymied researchers for decades
Modified versions of the fungal compound show promise against diffuse midline glioma, a rare pediatric brain tumour with few treatment options
The compound targets cancer cells with high levels of EZHIP protein, inducing cell death through DNA methylation: a mechanism that could inform future therapies
More than 50 years after scientists first isolated verticillin A from fungi, chemists at the Massachusetts Institute of Technology have successfully synthesized the compound as a breakthrough that immediately revealed therapeutic potential against a particularly challenging form of childhood brain cancer. The achievement, published in the Journal of the American Chemical Society, demonstrates how molecular complexity can delay scientific progress for decades, and why persistence in solving such puzzles occasionally yields unexpected rewards.
Fungi produce verticillin A as a defensive compound against pathogens in their environment. Researchers recognised its potential anticancer and antimicrobial properties early on, but its structural intricacy proved insurmountable with available chemical techniques. The molecule contains 10 rings and eight stereogenic centres which are carbon atoms with four different chemical groups attached in precise spatial arrangements. Even slight errors in assembling these components render the molecule inactive or unstable.
The Two-Oxygen Problem
Mohammad Movassaghi's laboratory at MIT had previously synthesized a related compound called Dideoxyverticillin A in 2009. That success made verticillin A's continued resistance more puzzling. The two molecules differ by merely two oxygen atoms; yet those atoms fundamentally altered the synthetic challenge.
The oxygen atoms make verticillin A extraordinarily fragile during chemical reactions. Standard procedures that worked for the related compound failed when applied to verticillin A, as the additional oxygen groups limited the types of chemical transformations the molecule could withstand without breaking down. Despite years of methodological advances in synthetic chemistry, the compound continued to resist laboratory recreation.
The breakthrough required rethinking the entire synthesis sequence. Both verticillin compounds consist of two identical fragments joined to form a dimer: essentially two mirror-image halves connected at the centre. For the deoxyverticillin variant, researchers had performed this joining reaction near the synthesis's end, then added four critical carbon-sulphur bonds. When applying this approach to verticillin A, however, the final product had incorrect stereochemistry with the molecular equivalent of having furniture assembled with legs facing the wrong direction.
The solution involved introducing carbon-sulphur bonds and a disulphide bridge much earlier in the synthesis to control stereochemistry from the outset. These sensitive sulphur-containing groups required protection through subsequent reactions (molecular masking that prevented their degradation) before being regenerated after joining the two molecular halves. The process ultimately requires 16 steps from the starting material, beta-hydroxytryptophan, to verticillin A.
Unexpected Anticancer Activity
With synthesis achieved, researchers could produce variants by slightly modifying the molecular structure. Collaborators at the Dana-Farber Cancer Institute tested these compounds against diffuse midline glioma (DMG), a rare brain tumour affecting children. DMG typically appears in the brainstem or thalamus and carries a grim prognosis, with median survival around nine months and few effective treatments available.
The testing revealed selective activity against DMG cell lines containing high levels of EZHIP protein. This protein influences DNA methylation: a process that controls which genes are active in cells. The verticillin derivatives appear to interact with EZHIP in ways that increase methylation, triggering programmed cell death in cancer cells whilst leaving normal cells relatively unaffected.
The most effective compounds were N-sulfonylated versions of both verticillin A and its deoxygenated relative. N-sulfonylation involves adding a functional group containing sulphur and oxygen, which increases molecular stability, making the compounds more suitable for potential therapeutic development. Interestingly, the natural fungal compound itself showed less potency than these modified variants, illustrating how synthetic chemistry can improve upon nature's designs.
From Laboratory Curiosity to Clinical Possibility
The Dana-Farber team has screened lead molecules against more than 800 cancer cell lines to understand their broader anticancer potential beyond DMG. Animal studies will follow to evaluate efficacy and safety before any human trials could proceed; a process that typically requires years of additional research.
The work exemplifies how fungal compounds continue to inform drug discovery decades after their initial isolation. Penicillin's discovery from fungal contamination revolutionised medicine nearly a century ago. Cyclosporine, derived from fungal sources, enabled modern organ transplantation. Statins, amongst the most prescribed medications globally, originated from fungal fermentation products.
Verticillin A's journey from laboratory curiosity to potential therapeutic agent consumed half a century which is a timeline that reflects both the compound's molecular complexity and the incremental nature of chemical synthesis advancement. Whether it ultimately succeeds as a cancer treatment remains uncertain. Clinical translation requires demonstrating efficacy in animals, then safety in humans, then therapeutic benefit in patient trials: hurdles where many promising compounds fail.
Yet the ability to synthesize verticillin A and generate derivatives enables investigations impossible when researchers could only work with tiny quantities isolated from fungi. This access transforms a scarce natural product into a renewable research tool, accelerating understanding of its biological mechanisms and potential applications. For children facing DMG diagnoses, that acceleration cannot come soon enough.
