A chemist at the University of Texas at Dallas and his colleagues have developed a new chemical reaction that will allow researchers to selectively synthesize left- or right-handed versions of “mirror molecules” found in nature and evaluate them for potential use against cancer. and infections. , depression, inflammation and a host of other conditions.
The results are important because, while right- and left-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 for medicinal chemistry.
In a study published in the October 11 issue of the journal ScienceThe researchers describe how their chemical synthesis method can quickly, efficiently, and scalably produce a sample that is purely an enantiomer of a mirror-image pair of molecules, rather than a mixture of the two. The new method involves adding prenyl groups (molecules made up of five carbon atoms) to enones using a newly developed catalyst in one step of the synthesis process.
“Adding a prenyl group is nature’s way of assembling these molecules, but it has been a challenge for scientists to successfully replicate this,” said Dr. Filippo Romiti, assistant professor of chemistry and biochemistry in the Faculty of Natural Sciences and UT Dallas Mathematics and a corresponding author of the study.
“Nature is the best synthetic chemist of all; it is far ahead of us. This research represents a paradigm shift in the way we can now synthesize large quantities of biologically active molecules and test their therapeutic activity,” said Romiti, who He is also a Cancer Prevention and Research Institute of Texas (CPRIT) Fellow.
Natural compounds are an important source of potential new drugs, but because they often appear only in trace amounts, scientists and pharmaceutical companies must develop methods to synthesize larger quantities for testing in the laboratory or manufacturing them into drugs.
In their study, the researchers demonstrated how incorporating their new chemical reaction resulted in a synthesis process that was completed 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 from 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 fighting cancer, HIV, Alzheimer’s, depression, epilepsy and obesity. .
Romiti and colleagues demonstrated proof of concept by synthesizing enantiomers of eight PPAPs, including nemorosonol, a chemical derived from a Brazilian tree that other researchers have shown to have antibiotic activity.
“For 20 years, we have 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.”
Romiti and his colleagues tested their nemorosonol enantiomer against lung and breast cancer cell lines provided by Dr. John Minna, director of the Hamon Center for Therapeutic Oncology Research at UT Southwestern Medical Center.
“Our nemorosonol enantiomer had quite 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 enantiomeric sample for testing.”
Romiti said more research will be needed to confirm whether one enantiomer of nemorosonol is specifically antimicrobial and the other anticancer.
The study results could impact drug discovery and translational medicine in several ways. In addition to informing more efficient, scalable drug manufacturing processes, the findings will allow researchers to more efficiently manufacture natural product analogues, which are optimized versions of the natural product that are more potent or selective in how they function 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 drugs that we can make, in addition to their analogues, and test their biological activity. We now have access to powerful natural products that we could not synthesize in the laboratory before.”
Romiti said the next step will be to apply the new reaction to the synthesis of other classes of natural products, in addition to PPAPs. In August he received a five-year, $1.95 million Maximizing Early-Stage Investigator Research Award from the National Institute of General Medical Sciences, a component of the National Institutes of Health (NIH), to continue his work. in this area.
In addition to CPRIT, the research was supported by funding from the National Science Foundation and the NIH (2R35GM130395, 2R35GM128779) to co-authors and chemistry professors Dr. Peng Liu of the University of Pittsburgh and Dr. Amir Hoveyda of Boston College. .