Chemists have created a groundbreaking chemical reaction that enables researchers to selectively produce either the left-handed or right-handed varieties of ‘mirror molecules’ found in nature. This advancement could lead to important applications in treating cancer, infections, depression, inflammation, and various other health conditions.
Researchers at the University of Texas at Dallas have developed a novel chemical reaction, allowing them to selectively synthesize either left-handed or right-handed versions of “mirror molecules”. This could open doors for new treatments for cancer, infection, depression, inflammation, and many other disorders.
This discovery is crucial because the chemical compounds’ left- and right-handed versions, known as enantiomers, share the same chemical traits but behave differently in the human body. Finding cost-efficient methods to produce the version that exhibits a particular biological effect is vital for pharmaceutical chemistry.
In their study published on October 11 in the journal Science, the researchers explain how their synthesis technique can quickly and efficiently create a pure sample of one enantiomer, avoiding the common issue of obtaining a mixture of both. This new approach employs the addition of prenyl groups—composed of five carbon atoms—to enones through a one-step process using a newly designed catalyst.
“In nature, molecules are assembled using prenyl groups, but replicating this in the lab has posed significant challenges,” said Dr. Filippo Romiti, assistant professor of chemistry and biochemistry at UT Dallas and a lead author on the study.
“Nature is the ultimate synthetic chemist; she’s way ahead of us. This research signifies a major shift in our ability to synthesize large amounts of biologically active molecules for therapeutic testing,” added Romiti, who is also a Cancer Prevention & Research Institute of Texas (CPRIT) Scholar.
Naturally occurring substances present a wealth of potential new medicinal options. However, since they often exist in very limited quantities, scientists and pharmaceutical companies need to create synthetic methods to boost their available amounts for laboratory testing or drug manufacturing.
The researchers showed that their new reaction could complete the synthesis in approximately 15 minutes at room temperature, making it more energy-efficient than processes requiring significant heating or cooling.
Romiti worked alongside scientists from Boston College, the University of Pittsburgh, and the University of Strasbourg in France to develop this chemical reaction, focusing on creating the synthesis process.
Their study aimed to synthesize polycyclic polyprenylated acylphloroglucinols (PPAPs), a diverse class of over 400 natural compounds known for their extensive bioactivity, including fighting cancer, HIV, Alzheimer’s disease, depression, epilepsy, and obesity.
Romiti and the team provided proof of concept by synthesizing enantiomers of eight PPAPs, one being nemorosonol, a chemical derived from a Brazilian tree recognized for its antibiotic properties by other researchers.
“For two decades, we’ve known that nemorosonol exhibits antimicrobial effects, but we need to determine which enantiomer is responsible—one or both?” Romiti noted. “It’s possible that one form possesses this attribute, while the other does not.”
Romiti and his colleagues examined 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 showed promising effects on cancer cell lines,” Romiti mentioned. “This was a significant finding, made possible by having access to a pure enantiomeric sample for testing.”
Further research is necessary to determine whether one specific nemorosonol enantiomer has antimicrobial properties while the other is anticancer.
The findings of this study could revolutionize drug discovery and translational medicine in several important ways. In addition to enhancing scalable and efficient drug manufacturing, these insights will help researchers create improved versions of natural products that are more effective or selective in their actions within the body.
“We designed this process to be as approachable for pharmaceutical applications as possible,” Romiti stated. “Now, chemists and biologists have a new tool to explore 400 potential drug candidates and their analogs to examine their biological impacts. We can now synthesize potent natural products that were previously inaccessible in the laboratory.”
Looking ahead, Romiti plans to apply this new reaction to synthesize additional classes of natural products beyond PPAPs. In August, he was awarded a five-year, $1.95 million Maximizing Investigators’ Research Award for Early Stage Investigators from the National Institute of General Medical Sciences, a branch of the National Institutes of Health (NIH), to further his research in this domain.
Alongside CPRIT, this research received support from the National Science Foundation and the NIH (grants 2R35GM130395, 2R35GM128779), to co-corresponding authors and chemistry professors Dr. Peng Liu from the University of Pittsburgh and Dr. Amir Hoveyda from Boston College.
