MIT chemists have, for the first time, successfully created in the laboratory a fungal molecule called verticillin A, which was first discovered more than 50 years ago and has been recognized for its potential as an anticancer agent:
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.
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“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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Once the researchers had successfully completed the synthesis, they were also able to tweak it to generate derivates of verticillin A. Researchers at Dana-Farber then tested these compounds against several types of diffuse midline glioma (DMG), a rare brain tumor that has few treatment options.
The researchers found that the DMG cell lines most susceptible to these compounds were those that have high levels of a protein called EZHIP. This protein, which plays a role in the methylation of DNA, has been previously identified as a potential drug target for DMG.
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The verticillin derivatives appear to interact with EZHIP in a way that increases DNA methylation, which induces the cancer cells to under programmed cell death. The compounds that were most successful at killing these cells were N-sulfonylated (+)-11,11?-dideoxyverticillin A and N-sulfonylated verticillin A. N-sulfonylation — the addition of a functional group containing sulfur and oxygen — makes the molecules more stable.
A genuinely impressive triumph. Yet again Feynman’s observation and amazement that with their complex and extensive suite of subtle techniques that the organic synthetic chemists keep beating the physicists in being able to construct molecules from atoms in ways we are still far from being able to accomplish in a nano-mechanistic manner.
Handle, your observation is true in many domains: rather than the “science” preceding the engineering, the engineering ordinarily precedes the science. Merely the latest example is that of AI: no one has much of an idea how it works, and many deny that it works, and yet it does.
I’d go a step further.
I don’t even think, “science,” in the contemporary professional sense, even meaningfully exists outside of it’s social and financial functions. It’s just engineering and mathematics doing all of the heavy lifting behind the scenes while science gets to sweep in after the fact and get the credit publicly.
Most scientists are just glorified data accountants in lab coats, which is more of an insult to accountants than anything else – except accountants actually serve a valuable function.