After 50 Years, MIT Chemists Finally Synthesize Elusive Anti-Cancer Compound
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After 50 Years, MIT Chemists Finally Synthesize Elusive Anti-Cancer Compound
MIT chemists have, for the first time, successfully created in the laboratory a fungal molecule called verticillin A. This compound was first discovered more than 50 years ago and has been recognized for its potential as an anticancer agent.
Although verticillin A differs from some related molecules by only a small number of atoms, its complex structure made it much more challenging to synthesize than those similar compounds.
"We have a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge," says Mohammad Movassaghi, an MIT professor of chemistry. "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."
In experiments with human cancer cells, one modified form of verticillin A showed strong activity against a rare pediatric brain tumor known as diffuse midline glioma. The researchers caution that additional testing will be necessary before its suitability for clinical use can be determined.
Researchers first reported the isolation of verticillin A from fungi, which use it for protection against pathogens, in 1970. Verticillin A and related fungal compounds have drawn interest for their potential anticancer and antimicrobial activity, but their complexity has made them difficult to synthesize.
In 2009, Movassaghi's lab reported the synthesis of (+)-11,11'-dideoxyverticillin A, a fungal compound similar to verticillin A. That molecule has 10 rings and eight stereogenic centers, or carbon atoms that have four different chemical groups attached to them. These groups have to be attached in a way that ensures they have the correct orientation, or stereochemistry, with respect to the rest of the molecule.
Once that synthesis was achieved, however, synthesis of verticillin A remained challenging, even though the only difference between verticillin A and (+)-11,11'-dideoxyverticillin A is the presence of two oxygen atoms.
"Those two oxygens greatly limit the window of opportunity that you have in terms of doing chemical transformations," Movassaghi says. "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."
Both of the verticillin A compounds consist of two identical fragments that must be joined together to form a molecule called a dimer. To create (+)-11,11'-dideoxyverticillin A, the researchers had performed the dimerization reaction near the end of the synthesis, then added four critical carbon-sulfur bonds.
Yet when trying to synthesize verticillin A, the researchers found that waiting to add those carbon-sulfur bonds at the end did not result in the correct stereochemistry. As a result, the researchers had to rethink their approach and ended up creating a very different synthetic sequence.
"What we learned was the timing of the events is absolutely critical. We had to significantly change the order of the bond-forming events," Movassaghi says.
The verticillin A synthesis begins with an amino acid derivative known as beta-hydroxytryptophan, and then step-by-step, the researchers add a variety of chemical functional groups, including alcohols, ketones, and amides, in a way that ensures the correct stereochemistry.
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