A breakthrough in the synthesis of mirror molecules opens the door to drug discovery

A University of Texas at Dallas chemist and his colleagues have developed a novel chemical reaction that will allow scientists to selectively synthesize left-handed or right-handed versions of naturally occurring “mirror molecules” and evaluate them for potential exploit in the fight against cancer and infections, depression, inflammation and much more. other diseases.

The results are critical because although the left- and right-handed versions, or enantiomers, of the chemical compounds have identical chemical properties, they differ in the way they react in the human body. Developing cost-effective ways to synthesize only versions with the desired biological effects is crucial in medicinal chemistry.

In a study published in the October 11 issue of the journal Scienceresearchers describe how their chemical synthesis method allows them to quickly, efficiently and in a scalable way produce a sample that is only one enantiomer of a pair of mirror-image molecules, rather than a mixture of the two. The novel method involves the addition of prenyl groups -; molecules made of five carbon atoms -; to enones using a newly developed catalyst in one step of the synthesis process.

Adding a prenyl group is how nature assembles these molecules, but successfully replicating this has been a challenge for scientists.”

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; she was way ahead of us. This research represents a paradigm shift in the way we can now synthesize gigantic quantities of biologically vigorous molecules and test them for therapeutic effects,” said Romiti, who is also a fellow at the Cancer Prevention and Research Institute of Texas (CPRIT).

Naturally occurring compounds are a significant source of potential novel drugs, but because they often exist only in tiny amounts, scientists and pharmaceutical companies must develop methods to synthesize larger quantities for testing in the laboratory or processing into drugs.

In their study, the researchers showed how incorporating a novel chemical reaction led to the synthesis process being completed in about 15 minutes at room temperature, which is more energy proficient than having to significantly heat or cold the substance during the reaction.

Romiti worked with scientists from Boston College, the University of Pittsburgh and the University of Strasbourg in France to develop the novel chemical reaction. Romiti’s role was to create the synthesis process.

The researchers developed their method to synthesize polycyclic polyprenylated acylphloroglucinols (PPAP), which are a class of over 400 natural products with a broad spectrum of bioactivities, including those fighting 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 from a Brazilian tree that other researchers have shown to have antibiotic effects.

“We have known for 20 years that nemorosonol has antimicrobial activity, but which enantiomer is responsible for it? One or both?” – Romiti said. “It’s possible that one version has this property but the other doesn’t.”

Romiti and his colleagues tested the 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 pretty decent activity against cancer cell lines,” Romiti said. “It was very engaging and could only have been discovered if we had access to gigantic amounts of pure enantiomeric sample to test.”

Romiti said further research would be needed to confirm whether one enantiomer of nemorosonol had specific antimicrobial activity and the other had anticancer activity.

The study’s results could impact drug discovery and translational medicine in several ways. In addition to information about scalable and more proficient drug production processes, the discoveries will enable scientists to produce more proficient natural product analogues, i.e. optimized versions of a natural product that have a stronger or selective effect on the body.

“We have designed this process to be as user-friendly as possible for pharmacists,” Romiti said. “This is a novel tool for chemists and biologists to study 400 novel potential drugs that we can produce, as well as their analogues, and test their biological activity. We now have access to powerful natural products that we could not previously synthesize in the laboratory.”

Romiti said the next step would be to exploit the novel reaction to synthesize other classes of natural products in addition to PPAP. 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), for his continued work in this field.

In addition to CPRIT, the research was supported by funding from the National Science Foundation and NIH (2R35GM130395, 2R35GM128779) to contributing authors and professors of chemistry, Dr. Peng Liu of the University of Pittsburgh and Dr. Amir Hoveyda of Boston College.