Breakthrough in mirror molecule synthesis opens doors for drug discovery
· News-MedicalA University of Texas at Dallas chemist and his colleagues have developed a new chemical reaction that will allow researchers to synthesize selectively the left-handed or right-handed versions of "mirror molecules" found in nature and assess them for potential use against cancer, infection, depression, inflammation and a host of other conditions.
The results are important because, while the left- and right-handed versions, or enantiomers, of chemical compounds have identical chemical properties, they differ in how they react in the human body. Developing cost-effective ways to synthesize only the version with a desired biological effect is critical to medicinal chemistry.
Naturally occurring compounds are a significant source of potential new medicines, but because they often occur only in minute quantities, scientists and pharmaceutical companies must develop methods to synthesize larger amounts to test in the lab or to manufacture into drugs.
In their study, the researchers demonstrated how incorporating their new chemical reaction resulted in a synthesis process that reached completion in about 15 minutes at room temperature, which is more energy-efficient than having to heat or cool substances significantly during a reaction.
Romiti collaborated with researchers at Boston College, the University of Pittsburgh and the University of Strasbourg in France to develop the new chemical reaction. Romiti's role involved creating the synthesis process.
The researchers developed their method as part of an effort to synthesize polycyclic polyprenylated acylphloroglucinols (PPAPs), which are a class of more than 400 natural products with a broad spectrum of bioactivity, including combatting cancer, HIV, Alzheimer's disease, depression, epilepsy and obesity.
Romiti and his colleagues demonstrated a proof of concept by synthesizing enantiomers of eight PPAPs, including nemorosonol, a chemical derived from a Brazilian tree that has been shown by other researchers to have antibiotic activity.
"For 20 years, we've known that nemorosonol is antimicrobial, but which enantiomer is responsible? Is it one or both?" Romiti said. "It could be that one version has this property, but the other does not."
"Our entantiomer of nemorosonol had pretty decent effects against cancer cell lines," Romiti said. "This was very interesting and could only have been discovered if we had access to large quantities of a pure entantiomeric sample to test."
Romiti said more research will be needed to confirm whether one nemorosonol enantiomer is specifically antimicrobial and the other anticancer.
The study results could impact drug discovery and translational medicine in several ways. In addition to informing scalable and more efficient drug-manufacturing processes, the findings will enable researchers to make more efficiently natural product analogs, which are optimized versions of the natural product that are more potent or selective in how they work in the body.
"We developed this process to be as pharma-friendly as possible," Romiti said. "This is a new tool for chemists and biologists to study 400 new drug leads that we can make, plus their analogs, and test their biological activity. We now have access to potent natural products that we previously could not synthesize in the lab."
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