Florida State University chemists have developed a method to quickly assemble highly complex natural molecules with potential biomedical applications, opening the door to new drug therapies based on the molecules’ structure.

James Frederick, associate professor of chemistry and biochemistry at Warner Hertz, and his team have made the first complete synthesis of fusicocadiene, a precursor to a new treatment in cancer chemotherapy. Their works have recently Journal of the American Chemical Society.

“The Frederich Institute specializes in the synthesis of structurally complex natural products, which are considered to have special translational potential, especially in medicine, but are currently not accessible in a practical way,” said Professor Frederich. “We build complex structures from scratch by extending existing chemical methods and developing entirely new methods.”

The function of biomolecules—the critical role that proteins, lipids, and other molecules play in driving the cellular processes that sustain life—is directly determined by their structure. By studying structurally complex substances in nature, such as Fusicoccum amygdala, the fungus that produces fusicocadiene, scientists can modify molecules and transform their chemical structures into starting points for drug discovery.

what is it

Fusicoccadienes are hydrocarbon precursor molecules of fusicoccans, a family of natural molecules derived from fungi that have great potential in biomedical applications. Some fusicoccans, including fusicoccin A and cotylenin A, can induce cell death in cancer cells by sensitizing them to their own cell death mechanisms.

The structure of fusicocadiene (5-8-5 ring system) is important for new drug therapy applications, but it is also very complex and difficult to synthesize in the laboratory. This system consists of two five-membered rings fused to a central eight-membered ring that forms the core of the molecule.

“The synthetic blueprint for preparing fusicocadiene has been extremely difficult to realize,” Frederich said. “This synthesis is the culmination of several doctoral thesis projects over almost a decade. Chemical synthesis requires great determination and requires special creativity from both students and principal investigators.”

How to make

The synthetic technique used to prepare fusicocadiene at the Frederich Institute involves converting one compound of the polyene precursor into another using light to accelerate the chemical process. After a molecule is generated, researchers perform modifications to change the molecular structure at precise site-specific locations to produce the desired compound and specific spatial arrangement, resulting in different functions and applications.

“Rather than designing molecules for target-specific endpoints, we envisioned an assembly scheme that could capture new non-natural compositions for iterations of molecules that could be used in future medicine,” Frederich said. “Our approach focuses on the direct construction of the 5-8-5 core during the early stages of molecule formation. We then exploit a variety of specific reactions to decorate the surrounding structure with different functionalities.”

why is it important

The process of taking freshly synthesized molecules from the lab and turning them into patient-ready treatments can take years, but labs like Frederich’s are taking important first steps by testing different structures, activating specific functions, and otherwise modifying natural molecules to form the basis of future effective medicines.

“Dr. Frederich’s research will foster the continuation of our department’s traditions and strengths in the fields of natural products and synthetic organic chemistry, bridge our department’s rich history with exciting new molecular biodesign initiatives, and lead to a vibrant and long-needed modern platform for FSU drug discovery,” said Wei Yang, chair of the Department of Chemistry and Biochemistry.

This research was supported by funding from the National Institute of General Medicine, part of the National Institutes of Health, and the Warner Hertz Foundation.

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For more information about work and research in Frederich’s Department of Chemistry and Biochemistry, please visit: chem.fsu.edu.