Commonwealth _ MIT chemists have developed an innovative method to synthesize complex molecules known as oligocyclotryptamines, which are naturally occurring compounds found in certain plants and hold potential as antibiotics, analgesics, and cancer treatments. These molecules consist of multiple tricyclic substructures, called cyclotryptamine, that are fused by carbon-carbon bonds. Due to the scarcity of these compounds in nature and the difficulty of synthesizing them in the lab, researchers have long sought a way to produce them more efficiently.
Oligocyclotryptamines are part of a larger class of molecules called alkaloids nitrogen-containing organic compounds produced mainly by plants. At least eight different types of oligocyclotryptamines have been identified, primarily in the Psychotria genus of flowering plants, which thrive in tropical forests. Although scientists have been able to study and synthesize smaller members of the oligocyclotryptamine family, such as dimeric cyclotryptamines, which consist of two fused cyclotryptamine subunits, the larger molecules, with six or seven fused rings, have eluded synthesis until now.
One of the major challenges in synthesizing these molecules is the formation of carbon-carbon bonds between two cyclotryptamine subunits. The oligocyclotryptamines feature two types of carbon linkages, which often involve carbon atoms that are already bonded to four other atoms, making them bulky and difficult to manipulate. Controlling the stereochemistry, the 3D spatial arrangement of atoms around the carbon centers adds another layer of complexity to the synthesis process.
The research team, led by MIT Professor Mohammad Movassaghi, overcame these challenges by building on their previous work in carbon-carbon bond formation. In 2011, Movassaghi’s lab developed a method for joining carbon atoms that are already crowded with other atoms. This approach involves converting the two carbon atoms into carbon radical atoms with one unpaired electron using a process known as diazene-directed assembly.
In this method, each of the targeted carbon atoms is first attached to a nitrogen atom, and the two nitrogen atoms then bind to each other. When the researchers expose the molecule to specific wavelengths of light, the nitrogen atoms break away as nitrogen gas, leaving behind the reactive carbon radicals. These radicals, now in close proximity, join together almost immediately, forming a carbon-carbon bond while allowing the researchers to control the stereochemistry.
Movassaghi’s team first demonstrated this technique by synthesizing other alkaloids, such as communesins, which are found in fungi and consist of two ring-containing molecules (monomers) fused. Encouraged by their success, the team extended their work to tackle the synthesis of larger oligocyclotryptamines, eventually developing a method to add cyclotryptamine fragments with precise stereochemistry and position selectivity, one at a time, to a cyclotryptamine derivative. This stepwise addition is made possible by the diazene-directed process.
This innovative approach enabled the team to synthesize oligocyclotryptamines with six or seven fused cyclotryptamine rings, a feat that had never been accomplished before. “Researchers worldwide have been trying to find a way to make these molecules, and Movassaghi and Scott are the first to pull it off,” remarked Seth Herzon, a chemistry professor at Yale University, who was not involved in the study. He described the work as “a tour de force in organic synthesis.”
The success of this synthesis represents a significant breakthrough in organic chemistry. With this method, the researchers can now produce larger quantities of naturally occurring oligocyclotryptamines, allowing for a more thorough investigation into their therapeutic potential. These compounds, which have shown promise as antibiotics, analgesics, and cancer drugs, can now be studied in greater detail to determine their effectiveness and safety.
