The novel ring distortion approach generates compounds that complement existing screening libraries that house many structurally simple compounds used to discover new drug therapies. By introducing dozens of complex small molecules developed from yohimbine, a drug which contains a complex ring system, and related natural products, researchers at the University of Florida College of Pharmacy will add to the arsenal of compounds available to drugmakers today.

“Despite all of the medical advances, there is a great need for better drugs,” said Rob Huigens, Ph.D., an assistant professor of medicinal chemistry and lead investigator of a study about ring distortion strategy published in Chemistry — A European Journal. “People are still suffering and dying of diseases that we have not been able to cure with current drug molecules. We need new organic molecules so that we can have a chance at creating more effective drugs.”

The makeup of screening libraries largely dictates the level of success for drugmakers in finding viable drugs to treat various diseases. Huigens said simple organic molecules fill the libraries today because they are easy to synthesize and produce in large numbers, but the absence of complex molecules has limited the discovery of new drug therapies.

Rob Huigens, Ph.D., an assistant professor of medicinal chemistry, left, and graduate student Nick Paciaroni, right, are among a team of UF Health researchers that have developed a novel ring distortion strategy to fight diseases.

“When you have an exciting new chemical library, generated by our ring distortion approach, that is being screened at our Center for Natural Products, Drug Discovery and Development, there is a very good chance of finding something important,” Huigens said. “Many drug discoverers trying to find solutions to cure a disease come back to organic screening libraries, and we are rapidly introducing structurally complex compounds that have never existed before.”

Huigens’ ring distortion strategy uses basic chemistry of the two rings found in yohimbine and other complex natural products, which enabled the rapid synthesis of 70 complex compounds by dramatically altering the complex ring system. UF researchers used chemical reactions to generate different molecular architectures, which are then screened for effectiveness in diverse disease areas such as cancer and inflammation. The screenings identified six biologically active compounds, including an anticancer compound that demonstrated an ability to suppress HIF transcription factors, a protein often linked to cancer growth.

“We discovered one compound that selectively targets cancer cells containing active transcription factor HIF, and it also exerts anti-inflammatory activity without killing noncancerous cells,” said Hendrik Luesch, Ph.D., a professor and chair of medicinal chemistry and the Debbie and Sylvia DeSantis Chair in Natural Products, Drug Discovery and Development. “Given that chronic inflammation can lead to cancer, and many cancers have activated HIF, this compound with its dual activity can be a starting point for medicinal chemistry campaigns geared to improve potency and drug-like properties.”

The six promising compounds identified are being developed to enhance the potency of the compounds and test for properties such as stability and toxicity. Successful preclinical trials with optimized compounds could pave the way for future clinical trials. In addition, this unique chemical library is being screened through collaboration with additional experts to drive discoveries in other disease areas.

Ring distortion strategy offers the potential for the discovery of many more biologically active small molecules that could address multiple disease areas. The new approach positions natural products as the starting point for the drug discovery process by teasing out novel molecular architectures that will then be screened. Huigens said the strategy challenges the traditional mindset of chemists who are reluctant to explore complex molecules because they are challenging to synthesize, since this strategy relies on rapid and diverse chemical syntheses pathways limited only by a chemist’s creativity.

“We want people to adopt a discovery mindset where they look at a complex natural product and say, ‘I want to be able to complement our simple compound library with complex structures,’” Huigens said.