A chemist from the University of Texas at Dallas and his colleagues have developed a new chemical reaction that allows researchers to selectively synthesize the left-handed or right-handed versions of “mirror molecules” found in nature and evaluate them for potential use against cancer and infections. , depression, inflammation and many other conditions.
The results are important because although the left- and right-handed versions, or enantiomers, of chemical compounds have identical chemical properties, they differ in the way 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.
In a study published in the Oct. 11 issue of the journal Sciencethe researchers describe how their chemical synthesis method can quickly, efficiently, and in a scalable manner produce a sample that is purely one enantiomer of a mirror-image pair of molecules, as opposed to a mixture of the two. The new method involves adding prenyl groups -; molecules made of five carbon atoms -; to enones through a newly developed catalyst in one step in 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.”
Dr. Filippo Romiti, assistant professor of chemistry and biochemistry, School of Natural Sciences and Mathematics at UT Dallas and corresponding author of the study
“Nature is the best synthetic chemist of all; it is way ahead of us. This research represents a paradigm shift in how we can now synthesize large quantities of biologically active molecules and test them for therapeutic activity,” says Romiti, who is also a researcher. Scientist from the Cancer Prevention & Research Institute of Texas (CPRIT).
Naturally occurring compounds are an important source of potential new drugs, but because they often occur only in very small quantities, scientists and pharmaceutical companies must develop methods to synthesize larger quantities for testing in the laboratory or to make drugs.
In their study, the researchers showed how integrating 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 significantly heat or cool substances during a reaction.
Romiti worked 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 was to create the synthesis process.
The researchers developed their method as part of an effort to synthesize polycyclic polyprenylated acyl phloroglucinols (PPAPs), a class of more than 400 natural products with a broad spectrum of bioactivity, including fighting 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.
“We’ve known for 20 years that nemorosonol is antimicrobial, but which enantiomer is responsible? Is it one or both?” Romiti said. “It may be that one version has this feature, 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 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 amounts of pure entantiomeric sample for testing.”
Romiti said more research will be needed to confirm whether one nemorosonol enantiomer is specifically antimicrobial and the other is anticancer.
The research results can impact drug discovery and translational medicine in several ways. In addition to informing scalable and more efficient drug manufacturing processes, the findings will allow researchers to create more efficient natural product analogs, which are optimized versions of the natural product that are more potent or selective in the way they work in the body.
“We have developed this process as pharmaceutically friendly as possible,” says Romiti. “This is a new tool for chemists and biologists to study 400 new drug leads that we can create, plus their analogues, and test their biological activity. We now have access to powerful natural products that we previously could not synthesize in the laboratory. “
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 Investigators’ Research Award for Early Stage Investigators from the National Institute of General Medical Sciences, part of the National Institutes of Health (NIH), to continue his work in this area to make.
In addition to CPRIT, the research was supported by funding from the National Science Foundation and from the NIH (2R35GM130395, 2R35GM128779) to co-corresponding authors and chemistry professors Dr. Peng Liu at the University of Pittsburgh and Dr. Amir Hoveyda at Boston College.
Source:
Magazine reference:
Ng, S., et al. (2024) Catalytic prenyl conjugate additions for the synthesis of enantiomerically enriched PPAPs. Science. doi.org/10.1126/science.adr8612.