A Florida State University researcher will investigate efficient strategies to chemically synthesize some of nature’s most complex molecular structures thanks to a grant from the National Institutes of Health.

Joel M. Smith, an assistant professor of Chemistry and Biochemistry, received the Maximizing Investigators’ Research Award, or MIRA, from the National Institute of General Medical Sciences to study the potential that synthesizing small, complex molecules could have on the biomedical and pharmaceutical industries. He will use the five-year, $1.8 million grant to investigate two primary areas — small, psychedelic molecules’ potential as treatment for various neurological diseases and complex, organic marine matter’s potential to provide key insights for fundamental pharmaceutical discovery.

“Earning this grant means that the scientific community still values the power of complex molecule synthesis and its role in making biomedical advancements,” Smith said. “Many critics claim that natural product synthesis is directionless and far too arduous. We embrace that criticism as a challenge to improve our craft.”

Psychedelic molecules have undergone a renaissance recently, as researchers have reinvigorated investigations into their effectiveness in treating various neurological disorders, some of which include migraines, severe depression, PTSD and Parkinson’s disease. Much of Smith’s research centers on chemical derivatives of psychedelics, novel molecules that resemble the parent psychedelic but contain small differences that hone their biological specificity and efficacy.

Derivatives of structurally simple psychedelics like N,N-dimethyltryptamine (also known as DMT and the psychoactive chemical in ayahuasca) and psilocin (the psychoactive chemical in “magic mushrooms”) have seen rapid medical advancement in recent years, but the development of derivatives of lysergic acid diethylamide, also known as LSD, has lagged due to its structural complexity.

Smith and his lab members aim to synthesize LSD derivatives to interrogate how a variety of slightly altered structural modification affect the substance’s psychedelic activity, metabolic stability, and efficacy as leads for neuropsychiatric treatment.

“It is anticipated that new LSD derivatives will pave a new direction in psychedelic science and will lay the groundwork for the discovery of psychedelic derivatives that have an unparalleled neurotherapeutic index, or range of doses at which a medication is effective without unacceptable adverse effects,” Smith said.

The chemical synthesis necessary to create these new molecules is made possible by a unique synthetic platform developed by the Smith Lab, which allows for the rapid generation of derivatives never previously synthesized.

“Dr. Smith earning this NIH MIRA grant strengthens the department’s confidence and determination for the further development of areas at the intersection of chemistry and health,” said Wei Yang, chair of the Department of Chemistry and Biochemistry. “It is synergic with the university’s vision for the significant enhancement of its biomedical and translational research portfolio.”

Smith’s second aim for the study is to create chemical derivatives of marine natural products that have been notoriously tricky to construct. Specifically, he is investigating manzamine alkaloids, which are structurally complex chemical metabolites that boast antimicrobial, antiviral and anti-inflammatory activity. A notable example of a manzamine alkaloid is manzamine A, a structurally daunting dimeric natural product with a uniquely intriguing structure.

“The advancement of molecules with marine origin is typically stifled by their limited access,” Smith said. “Nonetheless, some natural marine products have made it into the clinic due to heroic efforts by synthetic chemists.”

Smith’s strategy for both research areas hinges on using feedstock heterocyclic starting materials called pyridines, a type of raw material that often serves as the initial basis for chemical manufacturing of value-added substances. These are unnatural compounds that typically require a chemical reaction to be accessed. A versatile set of chemical reactions improves the variety of molecules that can be accessed from simple, cheap and abundant feedstocks like pyridine.

The precise chemical manipulation of these materials is a benchmark area of research in Smith’s lab, and he anticipates that wider accessibility to these unique marine alkaloid structures will open doors to a greater understanding of their biological activity and properties, benefitting scientists, physicians and patients alike.

“My lab is centrally focused on the advancement of biomedical research while also remaining committed to training the next generation of synthetic chemists,” Smith said.These developing minds are destined to discover fundamental advances in chemistry while concurrently finding translational solutions to unsolved pharmaceutical conundrums.”

After earning a doctorate in organic chemistry as a National Science Foundation Graduate Research Fellow from the University of California, Los Angeles in 2015, Smith was selected as an Arnold O. Beckman Postdoctoral Fellow at the Scripps Research Institute in La Jolla, California. Smith joined FSU’s faculty in 2018 upon the completion of his postdoctoral research, and he teaches both graduate and undergraduate organic chemistry courses in addition to his research endeavors.

For more information on Smith’s research and the Department of Chemistry and Biochemistry, visit smithlab.org and chem.fsu.edu.