Scientists at MIT and Harvard Medical School report the first laboratory synthesis of verticillin A, a fungal natural product identified more than 55 years ago with reported anti-cancer activity. Their 16-step route protects fragile bonds and alters the sequence of bond-forming events to produce the precise dimeric 3D structure. Synthetic verticillin A and designed analogues killed cultured diffuse midline glioma (DMG) cells and engaged target proteins in biochemical tests. The synthesis opens the door to scaled production, analogue design, and further preclinical evaluation.
Long-Elusive Anti-Cancer Fungus Compound Verticillin A Synthesized in Lab After 55 Years
Potential Anti-Cancer Fungal Compound Finally Synthesized After 55 Years
Researchers at the Massachusetts Institute of Technology and Harvard Medical School have for the first time produced the fungal natural product verticillin A by total chemical synthesis — more than 55 years after the compound was first isolated. The advance removes a major supply bottleneck: in nature verticillin A is present only in minute quantities inside a microscopic fungus, making extraction impractical for detailed study.
The team developed a 16-step synthetic route that addresses verticillin A's complex three-dimensional architecture and the fragility of several key bonds. Central to the success was reworking a strategy previously developed by MIT chemist Mohammad Movassaghi for related molecules and changing the timing and sequence of bond-forming steps. The chemists protected vulnerable functional groups during intermediate steps and "unmasked" them after the two halves of the dimeric molecule were joined, enabling precise control of the final geometry.
The end goal, verticillin A, with its two identical halves. (Knauss et al.,J. Am. Chem. Soc., 2025)
“We have a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge,” said Mohammad Movassaghi. “What we learned was the timing of the events is absolutely critical.”
Structurally, verticillin A is a dimer composed of two mirror-image halves. Although that description is simple, assembling the molecule so it adopts the exact three-dimensional arrangement required for activity proved difficult until now.
After completing the synthesis, the researchers tested the laboratory-made verticillin A and several designed analogues on cultured cells from diffuse midline glioma (DMG), an aggressive pediatric brain cancer. The synthetic compounds showed activity consistent with previous reports for members of the verticillin family, reducing viability of DMG cells in cell-based assays. Biochemical experiments also indicated the synthetic molecules engage their intended protein targets inside cells, supporting the proposed mechanism of action.
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With an efficient synthetic route in hand, scientists can now produce gram-scale quantities, create systematic analogues for structure–activity studies, and probe pharmacology in more detail. These capabilities accelerate the next stages of preclinical research — including optimization, toxicity testing, and eventual in vivo studies — but translating a promising natural product into a safe, effective drug will require extensive further work.
“Natural compounds have been valuable resources for drug discovery, and we will fully evaluate the therapeutic potential of these molecules by integrating our expertise in chemistry, chemical biology, cancer biology, and patient care,” said Jun Qi, chemical biologist at Harvard Medical School.
The full study is published in the Journal of the American Chemical Society. The new synthetic route not only provides access to verticillin A itself but also enables the design and testing of many variants that could inform future cancer therapeutics.
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