Unveiling a Potential Brain Cancer Treatment: A Fungal Compound's Journey
In a groundbreaking development, MIT chemists have successfully synthesized a fungal compound, verticillin A, which has shown promising signs as an anticancer agent. This achievement is particularly remarkable given the compound's complex structure, which posed a significant challenge for synthesis.
The Complexity of Verticillin A
Despite its similarity to other fungal compounds, verticillin A's structure, with just a couple of atoms' difference, made it incredibly difficult to synthesize. Professor Mohammad Movassaghi highlights the significance of this achievement, emphasizing the technological advancements that have enabled them to not only synthesize this compound but also create variants for further study.
A Promising Lead for Pediatric Brain Cancer
In tests on human cancer cells, a derivative of verticillin A demonstrated exceptional potential against a type of pediatric brain cancer known as diffuse midline glioma. While more tests are needed to evaluate its clinical potential, the initial results are encouraging. The study, led by Movassaghi and Jun Qi, offers a glimmer of hope in the fight against this rare and challenging cancer.
The Synthesis Challenge
Verticillin A's synthesis was a complex process. Researchers first isolated this compound from fungi in 1970, and its potential anticancer and antimicrobial properties have been of interest ever since. However, its intricate structure has made it a formidable challenge to synthesize.
In 2009, Movassaghi's lab synthesized a similar compound, (+)-11,11'-dideoxyverticillin A, which has a similar structure but differs by just two oxygen atoms. This compound has 10 rings and eight stereogenic centers, requiring precise attachment of chemical groups to ensure the correct stereochemistry.
Overcoming Synthesis Hurdles
The synthesis of verticillin A presented unique challenges. The presence of two oxygen atoms made the compound fragile and sensitive, even with years of methodological advancements. The researchers had to rethink their approach and create a new synthetic sequence to achieve the correct stereochemistry.
The synthesis begins with an amino acid derivative, beta-hydroxytryptophan, and involves the addition of various chemical functional groups, such as alcohols, ketones, and amides, to ensure the correct stereochemistry. A critical step involved introducing a functional group with two carbon-sulfur bonds and a disulfide bond early on to control the stereochemistry, but these sensitive disulfides had to be protected to prevent breakdown during subsequent reactions.
A Complex Dimerization Reaction
The verticillin A compounds consist of two identical fragments that must be joined to form a dimer. The researchers found that the timing of the dimerization reaction and the addition of critical carbon-sulfur bonds was crucial. They had to significantly change the order of these bond-forming events to achieve the desired stereochemistry.
Killing Cancer Cells: The Mechanism
Once the synthesis was successful, the researchers generated derivatives of verticillin A. These derivatives were tested against several types of diffuse midline glioma (DMG), a rare brain tumor. The most susceptible DMG cell lines were those with high levels of the protein EZHIP, which plays a role in DNA methylation.
The verticillin derivatives appear to interact with EZHIP, increasing DNA methylation and inducing programmed cell death in cancer cells. The most successful compounds were N-sulfonylated (+)-11,11'-dideoxyverticillin A and N-sulfonylated verticillin A, which are more stable due to the addition of a functional group containing sulfur and oxygen.
The Way Forward
The Dana-Farber team is now working to validate the mechanism of action of the verticillin derivatives and plans to test them in animal models of pediatric brain cancers. Jun Qi emphasizes the value of natural compounds in drug discovery and the team's commitment to evaluating the therapeutic potential of these molecules through their expertise in various fields, including chemistry, chemical biology, cancer biology, and patient care.
This research, funded by several organizations, offers a promising lead in the development of novel therapies for brain cancer, particularly for pediatric patients.
