Source : WAM
Researchers at the Massachusetts Institute of Technology (MIT) have, for the first time, successfully synthesised verticillin A, a complex fungal compound discovered over 50 years ago and long considered a potential anti-cancer agent.
Verticillin A’s highly intricate structure has made it far more difficult to synthesise than related compounds, even though it differs from them by only a few atoms.
“We have a much better appreciation for how those subtle structural changes can significantly increase the synthetic challenge,” said Mohammad Movassaghi, a Professor of Chemistry at MIT. “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 tests on human cancer cells, a derivative of verticillin A showed particular promise against diffuse midline glioma, a type of pediatric brain cancer.
Movassaghi and Jun Qi, Associate Professor of Medicine at Dana-Farber Cancer Institute/Boston Children’s Cancer and Blood Disorders Centre and Harvard Medical School, are the senior authors of the study, published in the Journal of the American Chemical Society.
Verticillin A consists of two identical halves that must be precisely fused into a dimer with the correct three-dimensional arrangement—a challenge that had prevented its synthesis for decades.
To construct verticillin A, the researchers used innovative techniques, including altering the order of molecule addition and protecting fragile bonds from breaking during synthesis.
Their 16-step process, which involved ‘unmasking’ some functional groups after combining the two halves, produced the precise 3D structure required.
“What we learned was the timing of the events is absolutely critical,” said Movassaghi. “We had to significantly change the order of the bond-forming events.”
With verticillin A now synthesised, researchers can advance studies on its interaction with cancer and explore its potential as a treatment.
“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,” Jun Qi said.
