MIT Chemists Synthesize Anticancer Compound Verticillin A After 50 Years
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A team of researchers at MIT has, for the first time, successfully synthesized verticillin A, a complex fungal compound discovered over half a century ago and showing promising potential as an anticancer agent. The breakthrough, published today in the Journal of the American Chemical Society, unlocks new avenues for studying and developing treatments for aggressive cancers, particularly a rare and devastating pediatric brain tumor.
The synthesis of verticillin A presented a significant challenge due to its intricate molecular structure. Despite being only subtly different from related compounds, the seemingly minor variations dramatically increased the difficulty of its creation. “We have a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge,” explained a senior researcher involved in the project. “Now we have the technology where we can not only access them for the first time, more than 50 years after they were isolated, but also we can make many designed variants, which can enable further detailed studies.”
A Long-Sought Synthesis
Scientists first isolated verticillin A from fungi in 1970, noting its potential antimicrobial and anticancer properties. However, its complexity hindered efforts to produce it synthetically. In 2009, the same MIT lab achieved the synthesis of a similar compound, (+)-11,11′-dideoxyverticillin A, which contains 10 rings and eight stereogenic centers – carbon atoms with specific spatial arrangements of attached chemical groups. Achieving the correct stereochemistry, or orientation of these groups, was crucial.
Despite this prior success, synthesizing verticillin A itself remained elusive. The difference between the two compounds lies in just two oxygen atoms, but these seemingly small additions proved remarkably disruptive. “Those two oxygens greatly limit the window of opportunity that you have in terms of doing chemical transformations,” a lead chemist stated. “It makes the compound so much more fragile, so much more sensitive, so that even though we had had years of methodological advances, the compound continued to pose a challenge for us.”
The researchers discovered that the timing of key chemical reactions was critical. Unlike their approach with (+)-11,11′-dideoxyverticillin A, where a dimerization reaction occurred near the end of the synthesis, they had to significantly alter the sequence for verticillin A. “What we learned was the timing of the events is absolutely critical. We had to significantly change the order of the bond-forming events,” the chemist added.
The synthesis begins with a derivative of the amino acid beta-hydroxytryptophan, with researchers meticulously adding functional groups – alcohols, ketones, and amides – to ensure the correct stereochemistry. A key step involved introducing carbon-sulfur bonds and a disulfide bond early in the process, which were then temporarily “masked” to prevent breakdown during subsequent reactions before being regenerated later. “This particular dimerization really stands out in terms of the complexity of the substrates that we’re bringing together, which have such a dense array of functional groups and stereochemistry,” noted a researcher. The entire process requires 16 steps.
Promising Results Against Pediatric Brain Cancer
With a successful synthesis in hand, the team generated derivatives of verticillin A and collaborated with researchers at Dana-Farber Cancer Institute/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School to test their efficacy against human cancer cells. The results were particularly encouraging against diffuse midline glioma (DMG), a rare and aggressive pediatric brain cancer with limited treatment options.
The compounds demonstrated the most significant impact on DMG cell lines with high levels of a protein called EZHIP, which plays a role in DNA methylation. Identifying EZHIP as a potential target is a crucial step toward developing more effective therapies. “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…to be more target specific for novel therapy development,” said Jun Qi, an associate professor of medicine and senior author of the study.
The verticillin derivatives appear to interact with EZHIP, increasing DNA methylation and triggering programmed cell death in cancer cells. N-sulfonylated (+)-11,11′-dideoxyverticillin A and N-sulfonylated verticillin A proved to be the most potent compounds. N-sulfonylation, the addition of a sulfur and oxygen-containing functional group, enhances the molecules’ stability. “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,” explained a senior researcher.
The Dana-Farber team is currently working to validate the mechanism of action and plans to test the compounds in animal models of pediatric brain cancers. “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,” Qi stated. “We have also profiled our lead molecules in more than 800 cancer cell lines, and will be able to understand their functions more broadly in other cancers.”
The research was supported by funding from the National Institute of General Medical Sciences, the Ependymoma Research Foundation, and the Curing Kids Cancer Foundation.
