Nearly 30 years ago, scientists discovered a unique class of anti-cancer molecules in a family of bryozoans, a phylum of marine invertebrates found in tropical waters.
The chemical structures of these molecules, which consist of a dense and highly complex knot of oxidized rings and nitrogen atoms, have sparked the interest of organic chemists around the world, who set out to recreate these structures from scratch in the laboratory. However, despite considerable efforts, it remains an elusive task. Until now, that is.
A team of Yale chemists, writing in the journal Sciencehas managed to synthesize eight of the compounds for the first time using an approach that combines an inventive chemical strategy with the latest technology in small molecule structure determination.
“These molecules have posed an exceptional challenge to the field of synthetic chemistry,” said Seth Herzon, Ph.D. by Milton Harris '29. Professor of Chemistry in the Yale School of Arts and Sciences and corresponding author of the new study. “Several research groups have attempted to recreate these molecules in the laboratory, but their structures are so dense, so intricately connected, that it has not been possible. I have been reading about efforts to synthesize these compounds since I was a graduate student in the early of the 2000s.”
In nature, the molecules are found in some species of bryozoans, small aquatic animals that feed by filtering prey from the water through tiny tentacles. Researchers around the world consider bryozoans to be a potentially valuable source of new drugs, and many molecules isolated from bryozoans have been studied as new anticancer agents. However, the complexity of molecules often limits their further development.
Herzon's team examined a particular species of bryozoan called Securilustra securifrons.
“We worked on these molecules about a decade ago, and although we didn't manage to recreate them at the time, we gained information about their structure and chemical reactivity, which informed our thinking,” Herzon said.
The new approach included three key strategic elements. First, Herzon and his team avoided building a reactive heterocyclic ring, known as an indole, until the end of the process. A heterocyclic ring contains two or more elements, and this specific ring is known to be reactive and create problems, Herzon said.
Second, the researchers used methods known as oxidative photocyclizations to build some of the key bonds in the molecules. One of these photocyclizations involved the reaction of a heterocycle with molecular oxygen, which was first studied by Harry Wasserman of Yale in the 1960s.
Finally, Herzon and his team employed microcrystal electron diffraction (MicroED) analysis to help visualize the structure of the molecules. Herzon considers that in this context conventional methods for determining structures are not suitable.
The result of the new approach is eight new synthetic molecules with therapeutic potential and the promise of more new chemistry in the future.
“These molecules respond perfectly to my love of complex synthetic challenges,” said Herzon, who is also a member of the Yale Cancer Center and holds joint appointments in pharmacology and therapeutic radiology at Yale School of Medicine. “In terms of molecular weight, they are modest compared to other molecules we have studied in my laboratory. But from the point of view of chemical reactivity, they present some of the biggest challenges we have ever faced.”
Co-authors of the new study are Yale chemistry graduate students Brandon Alexander and Noah Bartfield. Co-authors are Vaani Gupta, a Yale chemistry graduate student; Brandon Mercado, Yale X-ray crystallographer and professor in the Department of Chemistry; and Mark Del Campo of Rigaku Americas Corporation.
The National Science Foundation helped fund the research.