About 30 years ago, scientists discovered a unique class of anticancer molecules in the bryozoan family, a phylum of marine invertebrates found in tropical waters.

The chemical structures of these molecules, which consist of oxidized rings and dense, highly complex knots of nitrogen atoms, have attracted the interest of organic chemists worldwide, who aim to recreate these structures from scratch in the laboratory. Had to make. However, despite the considerable effort, it has been an ambitious undertaking. So far, it is.

A team of Yale chemists, writing in the journal sciencehave succeeded for the first time in synthesizing eight compounds using an approach that combines innovative chemical strategies with state-of-the-art technology in small molecule structure determination.

“These molecules have been a tremendous challenge in the field of synthetic chemistry,” said Seth Herzon, a Milton-Harris Ph.D. 29. professor of chemistry in Yale’s Faculty of Arts and Sciences and corresponding author of the new study. “Several research groups have tried to recreate these molecules in the laboratory, but their structures are so densely, so intricately connected, that it hasn’t been possible. I’ve been talking about attempts to synthesize these compounds ever since. I’ve been studying since I was a graduate student in the early 2000s.”

In nature, the molecules are found in some species of bryozoa — tiny, aquatic animals that feed by filtering prey from the water through tiny tentacles. Researchers around the world consider bryozoans a potentially valuable source of new drugs, and several molecules isolated from bryozoans have been studied as novel anticancer agents. However, the complexity of the molecules often limits their further development.

Herzon’s team looked at a special type of bryozoa called Securiflustra securifrons.

“We worked on these molecules about a decade ago, and although we weren’t able to recreate them at the time, we gained insight into their structure and chemical reactions,” Herzon said. That informed our thinking.”

The new approach included three key strategic elements. First, Herzon and his team avoided making a reactive heterocyclic ring, called an indole, until the end of the process. A heterocyclic ring contains two or more elements — and this is known as specific ring reactivity and causes problems, Herzon said.

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

Finally, Herzon and his team used microcrystal electron diffraction (microED) analysis to help visualize the structure of the molecules. In this context, conventional methods for determining composition were inadequate, Herzon said.

The new approach resulted in eight new synthetic molecules with therapeutic potential — and the promise of more novel chemistry to come.

“These molecules fit right in with my love of complex synthetic challenges,” said Herzon, who is also a member of the Yale Cancer Center and holds a joint appointment in pharmacology and therapeutic radiology at the Yale School of Medicine. “On a molecular weight basis, they’re modest compared to other molecules we’ve studied in our lab. But from a chemical reactivity standpoint, they present some of the biggest challenges we’ve ever faced. “

Co-first authors of the new study are Yale chemistry graduate students Brandon Alexander and Noah Bartfeld. Co-authors are Vani Gupta, a Yale chemistry graduate student. Brandon Mercado, a Yale X-ray crystallographer and lecturer in the Department of Chemistry; and Mark Del Campo of Rigaku America Corporation.

The National Science Foundation helped fund the research.