Oligocyclotryptamine is a type of alkaloid that contains organic nitrogen compounds produced by plants. Until now, scientists have isolated at least eight types of these molecules from Psychotria plants- generally found in tropical forests.
In the last twenty years, great progress has been made in studying and making smaller oligocyclotryptamines and dimers. However, no one has been able to create the largest ones, which have six or seven fused rings. One limitation is that synthesization requires bond formation between a carbon atom of one tryptamine-derived subunit and a carbon atom of the next subunit.
MIT chemists have created a new method to synthesize complex plant-derived molecules. They devised a technique to add tryptamine-based components one by one so that scientists could precisely assemble the rings and control the 3D orientation of each component and the final product.
The compounds of oligocyclotryptamines are made of multiple tricyclic substructures called cyclotryptamine. These compounds are fused by carbon-carbon bonds. However, only a limited amount of these compounds are available naturally, and synthesizing them in the lab is quite difficult.
This new approach to synthesizing oligocyclotryptamines- found in plants- in the lab holds promising use in antibiotics, analgesics, or cancer drugs. It could also generate new variants that may have even better medicinal properties or molecular probes that can help reveal their mechanism of action.
Scientists have been trying to create carbon-carbon bonds between crowded carbon atoms for many years. In 2011, they developed a technique to transform two carbon atoms into carbon radicals and direct their union. To create these radicals and guide the paired union to be completely selective, scientists attached each of the targeted carbon atoms to a nitrogen atom; these two nitrogen atoms bind to each other.
Scientists then shone specific wavelengths of light on the substrate with two fragments linked by nitrogen atoms. This caused nitrogen atoms to break away as nitrogen gas, leaving two highly reactive carbon radicals close together, quickly bonding. This method also allowed scientists to control the stereochemistry of the molecules.
Scientists called this approach a diazene-directed assembly. It is demonstrated by synthesizing other types of alkaloids, including the communities- fungi compound with two ring-containing molecules, or monomers, joined together. This approach was later used to fuse more significant numbers of monomers, and scientists turned their attention to the largest oligocyclotryptamine alkaloids.
The new synthesis method starts with a single cyclotryptamine derivative. Additional cyclotryptamine fragments are then added individually, ensuring correct stereochemistry and positioning. This step-by-step addition is made possible by the diazene-directed process developed earlier by Movassaghi’s lab.
Mohammad Movassaghi, an MIT professor of chemistry and the senior author of the new study, said, “We’re excited about this because this single solution allowed us to go after multiple targets. That same route provides us a solution to multiple members of the natural product family because by extending the iteration one more cycle, your solution is now applied to a new natural product.”
Scientists used this approach to create molecules with six or seven cyclo tryptamine rings, which has never been done before. Now, they are looking forward to generating enough of the compounds so that their potential therapeutic activity can be more thoroughly investigated.
They should also be able to create novel compounds by switching in slightly different cyclotryptamine subunits, Movassaghi says.
Journal Reference:
- Tony Z. Scott, Mohammad Movassaghi. Unified, Biosynthesis-Inspired, Completely Stereocontrolled Total Synthesis of All Highest-Order [n + 1] Oligocyclotryptamine Alkaloids. Journal of the American Chemical Society. DOI: 10.1021/jacs.4c07705