Examination of ‘mirror molecules’ could lead to new drugs

A University of Texas at Dallas chemist and 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 use potential against cancer, infections. , depression, inflammation and a host of other conditions.

The results are important because even though the left and right versions (enantiomers) of the 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 essential to medicinal chemistry.

In a study published in 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, as opposed to 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 a single step of the synthesis process.

“Adding a prenyl group is nature’s way of putting these molecules together, but it has been difficult for scientists to replicate this successfully,” said Dr. Filippo Romiti, assistant professor of chemistry and biochemistry at the UT Dallas School of Natural Sciences and 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,” he said. said Romiti, who is also a Cancer Prevention & Research Institute of Texas (CPRIT) Fellow.

Natural compounds are an important source of potential new drugs, but because they are often present in only trace amounts, scientists and pharmaceutical companies must develop methods to synthesize larger quantities for laboratory testing or processing into medicines. .

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 considerably substances 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 was to create the synthesis process.

The researchers developed their method as part of an effort to synthesize polycyclic polyprenylated acylphloroglucinols (PPAPs), a class of more than 400 natural products with a broad spectrum of bioactivity, including in the fight against cancer, HIV, Alzheimer’s disease, depression, epilepsy and obesity. .

Romiti and his colleagues demonstrated proof of concept by synthesizing enantiomers of eight PPAPs, including nemorosonol, a chemical derived from a Brazilian tree that other researchers have demonstrated has antibiotic activity.

“For 20 years, we have known that nemorosonol is antimicrobial, but which enantiomer is responsible? Is it one or both?” » said Romiti. “It could be that one version has this property, but the other does not.”

Romiti and 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 some pretty interesting 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 to test.”

Romiti said further 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 scalable and more effective drug manufacturing processes, the results will allow researchers to more efficiently manufacture natural product analogues, which are optimized versions of the natural product that are more potent or more selective in their action in the body.

“We developed this process to be as respectful as possible to the pharmaceutical sector,” Romiti said. “This is a new tool allowing chemists and biologists to study 400 new drug leads that we can make, as well as their analogues, and test their biological activity. We now have access to powerful natural products which 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.