Chemists at MIT have introduced an innovative method for synthesizing intricate molecules known as oligocyclotryptamines, which were initially sourced from plants and might serve as future antibiotics, pain relievers, or cancer-fighting medications.
Oligocyclotryptamines consist of several tricyclic structures termed cyclotryptamines, which are interconnected through carbon-carbon bonds. These compounds are typically found in limited amounts in nature, making laboratory synthesis a challenging task. The MIT researchers devised a technique to sequentially incorporate tryptamine-derived elements into a molecule, enabling precise assembly of the rings and allowing control over the spatial arrangement of both the individual pieces and the overall molecule.
“Many of these compounds haven’t been thoroughly examined due to the scarcity of material. I am optimistic that having a reliable source for these compounds will facilitate more comprehensive studies,” states Mohammad Movassaghi, an MIT chemistry professor and the study’s senior author.
This method not only enables scientists to reproduce the plant-derived oligocyclotryptamines but also paves the way for creating new variants that might possess improved medicinal properties or serve as molecular probes to better understand their action mechanisms.
Tony Scott, who earned his PhD in 2023, is the primary author of the paper published in the Journal of the American Chemical Society.
Fusing Rings
Oligocyclotryptamines fall under the category of alkaloids, which are organic compounds rich in nitrogen and primarily produced by plants. There are at least eight distinct oligocyclotryptamines isolated from the Psychotria plant genus, most of which are indigenous to tropical forests.
Since the 1950s, researchers have explored the structure and creation of dimeric cyclotryptamines, which consist of two cyclotryptamine units. Over the past two decades, significant advancements have been made in understanding and synthesizing these dimers and other smaller related compounds. Nevertheless, the largest oligocyclotryptamines, which are composed of six or seven fused rings, have remained unsynthesized until now.
A major obstacle in creating these molecules involves forming a bond between the carbon atoms of successive tryptamine-derived units. The oligocyclotryptamines have two types of linkages that include at least one carbon atom bonded to four other carbons, which complicates accessibility and makes controlling the stereochemistry—geometry of atoms around the carbon—quite challenging.
For years, Movassaghi’s group has worked on techniques to form carbon-carbon bonds among crowded carbon atoms. In 2011, they developed a method that transforms two carbon atoms into carbon radicals (atoms with an unpaired electron), facilitating their bonding. To create these radicals and ensure selective pairing, the researchers initially attach nitrogen atoms to the targeted carbon atoms to aid their binding.
When specific light wavelengths are directed onto the substrate with the linked fragments, it triggers the release of nitrogen gas, leaving behind two reactive carbon radicals that quickly bond. This bonding method also enables the researchers to control the stereochemistry of the resulting molecules.
Movassaghi has showcased this technique, termed diazene-directed assembly, by synthesizing various alkaloids, including communesins, which are found in fungi and consist of two joined ring-containing molecules. Then, Movassaghi and Scott turned their focus to the largest oligocyclotryptamine alkaloids, applying this method to link several monomers together.
The synthesis they crafted begins with a cyclotryptamine derivative, to which additional cyclotryptamine fragments with the correct stereochemistry and position are added one step at a time, utilizing the diazene-directed method previously established.
“We’re thrilled about this because this single method has allowed us to target multiple types of compounds,” notes Movassaghi. “This approach provides a pathway to various members of the natural product family, as extending the process by another cycle enables us to pursue new natural products.”
“A Tour de Force”
With this method, the researchers successfully synthesized molecules containing six or seven cyclotryptamine rings—an accomplishment previously unmatched.
“Researchers around the globe have sought methods for creating these molecules, and Movassaghi and Scott are the first to succeed,” remarks Seth Herzon, a chemistry professor at Yale University who did not participate in the study. He lauded the work as “a remarkable achievement in organic synthesis.”
Given that the researchers have managed to synthesize these naturally occurring oligocyclotryptamines, they are now poised to produce sufficient quantities for in-depth exploration of their potential therapeutic effects.
Moreover, they should be able to devise new compounds by incorporating slightly altered cyclotryptamine subunits. Movassaghi expresses, “We plan to continue using this precise method to add these cyclotryptamine units to build complex systems that have yet to be explored, including derivatives with possibly enhanced properties.”
This research received support from the U.S. National Institute of General Medical Sciences.
