Nearly three decades ago, researchers identified a distinct group of anticancer compounds in bryophytes, a category of marine invertebrates that live in tropical waters. The chemical structures of these molecules, which consist of a dense, highly complex knot of oxidized rings and nitrogen atoms, have attracted the attention of organic chemists around the world who are trying to recreate these structures from scratch in the laboratory. However, despite great efforts, it remained an unsolved task. So far it is.

A team of chemists from Yale University published in the journal Science succeeded in synthesizing eight compounds for the first time using an approach that combines an innovative chemical strategy with state-of-the-art technology in determining small molecule structure.

Milton Harris ’29 Ph.D. “These molecules have been an extraordinary challenge in the field of synthetic chemistry,” said Seth Herzon. Professor of Chemistry at Yale University School of Arts and Sciences and corresponding author of the new study. “Several research groups have tried to reproduce these molecules in the laboratory, but their structures are so dense, so intricately connected, that this has been impossible. I read about attempts to synthesize these compounds when I was a graduate student in the early 2000s.”

In nature, the molecules are found in some species of bryozoans, which are small aquatic animals that feed by straining prey from the water using tiny tentacles. Researchers around the world view bryophytes as a potentially valuable source of new drugs, and many molecules isolated from bryophytes are being studied as novel anticancer agents. But the complexity of molecules often limits their further development.

Gerzon’s team studied a specific type of bryophyte called Securiflustra securifrons .

“We studied these molecules about a decade ago, and although we could not reproduce them at the time, we gained an understanding of their structure and chemical reactivity that has shaped our thinking,” Herzon said.

Innovative chemical strategies

The new approach included three key strategic elements. First, Herzon and his team avoided creating the reactive heterocyclic ring known as indole until the end of the process. A heterocyclic ring contains two or more elements, and this particular ring is known to be reactive and cause problems, Herzon said.

Second, the researchers used techniques known as oxidative photocyclization to create some of the important bonds in the molecules. One of these photocyclizations involved the reaction of a heterocycle with molecular oxygen, first studied by Harry Wasserman of Yale University in the 1960s.

Finally, Herzon and his team applied microcrystal electron diffraction (MicroED) analysis to help visualize the structure of the molecules. Traditional methods for determining structure are inadequate in this context, Gerzon said.

The new approach resulted in eight new synthetic molecules and the promise of many new chemicals with therapeutic potential.

“These molecules tapped into my love of complex synthetic problems,” said Herzon, who is also a member of the Yale Cancer Center and holds a joint appointment in pharmacology and therapeutic radiology at Yale School of Medicine. “They are modest in molecular weight compared to other molecules we have studied in my laboratory. But from a chemical reactivity perspective, they represent some of the biggest challenges we have ever undertaken.”