Image 1: From left to right: Professor Seth Herzon, Brandon Alexander, Vaani Gupta, and Noah Bartfield. Photo by Emily Poag.
Modern chemistry has advanced our understanding of the fundamental makeup of much of our biological world, from our proteins to our genes. However, there are still many natural compounds whose complex chemistry scientists are only just beginning to unravel. Securamines and securines are two such families of compounds.
Since the 1990s, scientists have been interested in these compounds for their potential anti-cancer properties. Although teams of scientists have elucidated the structure of these compounds, including their characteristic nitrogen-containing rings known as heterocycles, recreating them has proved challenging due to their convoluted chemical composition—until now. A recent study published in Science by a team of Yale researchers has introduced a new method for creating securamines and securines entirely from scratch.
The Synthesis Problem
Securamines and securines are of biological interest because of their cytotoxicity—their ability to kill living cells. “They have been studied for years, and no one knows how they work,” said Brandon Alexander, the first author of the study and a chemistry graduate student in the Herzon lab at Yale. Through an unknown pathway, they are thought to hold therapeutic potential as anticancer agents. There also appears to be a curious correlation between the cytotoxicity, or toxicity to cells, of the compounds and their degree of halogenation, which refers to the number of chlorine or bromine ions attached to their central structure. This correlation suggests a potential link between the cytotoxicity of securamines and their interaction with certain nitrogen- or oxygen-containing structures, possibly pointing towards novel biological activity. However, to study the activity of securamines and securines, scientists need a reliable method for synthesizing them.
Securamines and securines are sourced from various species of tiny marine animals from the phylum Bryozoa, also known as moss animals. Bryozoa are simple organisms that live in diverse marine habitats, where they feed on phytoplankton and detritus, the leftover remains of plants and animals. These Bryozoans are commonly regarded as the primary reservoir of securamines and securines, since total synthesis of the compounds in the laboratory has proven difficult. Total synthesis refers to the process of creating complex molecules from simpler, commercially available starting compounds through a series of chemical reactions. By accomplishing the total synthesis of a complex molecule, chemists are then able to study and modulate its properties. Additionally, the way in which a molecule is synthesized in the laboratory may shine light on the mechanisms underlying its formation in nature. Finally, chemists hope that studying the synthesis of novel compounds will yield insights into emerging areas of chemistry, such as complex bond formation or innovative new applications of tools and methods within the field.
The problem of synthesizing securines and securamines is not new. “Back when I was a [graduate] student in 2006, people were publishing all of this work trying to make securamines […] and kept on reaffirming that these molecules are very challenging to synthesize,” said Seth Herzon, a professor of chemistry at Yale and senior author of the study. “Nobody has been able to actually find a fully human way to put them together.”
The challenge stems from the complex structure of these molecules, which includes many different chemical substructures, or functional groups. When these functional groups are isolated, they are predictable to work with. However, the complexity increases when many functional groups are combined within a single compound. Imagine a symphony orchestra where each musician represents a functional group. When a single musician performs, it’s easy to distinguish—or even replicate—their part. However, when multiple musicians play different melodies simultaneously, isolating each person’s contribution becomes challenging, resulting in a complex and sometimes unpredictable symphony that is more difficult to decipher. This is what has stumped chemists who have attempted the total artificial synthesis of securamines and securines.
Innovations in Total Synthesis
To solve this puzzle, Herzon’s team, led by Alexander, aimed to tackle two of the most challenging steps in the total synthesis process.
The first step involved recognizing that three of the major functional groups of securamines and securines bear a resemblance to the major functional groups of two amino acids, histidine and tryptophan. Among these, the most difficult group to work with was the indole, a functional group of the amino acid tryptophan that is composed of two fused rings: a benzene ring of six carbon atoms, and a pyrrole ring containing five carbon atoms and one nitrogen atom. Adding the indole group during synthesis posed a problem, because it tended to react with the other chemical reagents used in subsequent steps, and it even reacted with air. To overcome this obstacle, Herzon’s group devised a strategy to introduce the indole group late in the synthetic process, thereby minimizing its potential interference with other reaction steps. They achieved the synthesis of the indole ring by a photochemical transformation that involves the insertion of nitrogen into a carbon-hydrogen bond using light.
An additional challenge arose from the histidine residue in the molecules, which had undergone an unusual oxidation. In fact, the oxidized histidine substructure in securamines is unique and not found in any other known molecule. To solve this problem, Herzon’s group made use of work performed by Yale researcher Harry Wasserman roughly sixty years ago. Wasserman had developed a reaction of histidine-like rings with oxygen, known as an oxidative photocycloaddition, and Herzon’s team decided to use this chemistry. Part of their motivation was that histidine residues are known to be reactive with oxygen, so this strategy might parallel the way the molecules are made in nature.
“We were thinking, maybe this is what nature is actually doing, […] and we got very lucky! Our first reaction we tried actually worked beautifully for us,” Herzon said.
The second challenge was the process of adding chlorine substituents to the chemical structure. These components seem to play a role in the compounds’ cytotoxicity, but previous attempts to add chlorine to the central structure used two functional groups, a cysteine amide and an alkyl chloride in succession, which proved difficult and had poor yields. Herzon and his team recognized this as a challenging transformation that would require experimentation. They ultimately devised a novel approach to forging the key carbon-chlorine bond. As an added benefit, this method also created several other key functional groups in the securamine and securine structures, allowing the team to move very close to the desired chemical structure in a single step, and complete the synthesis.
Potential Impacts
Despite their general anticancer activity, Herzon doubts the practicality of using natural compounds like securamines or securines directly as anticancer therapeutics in the near future. “I think what’s more plausible is that we could find out what biological target they’re interacting with, and that target may potentially be valuable for treating disease,” Herzon said. Herzon plans to investigate this further by collaborating with a laboratory at the University of Illinois Urbana-Champaign, where he previously worked as a postdoctoral fellow.
By overcoming multiple decades-long challenges in replicating the complex structures of securamines and securines, the team’s findings pave the way for deeper exploration into their biological functions and therapeutic applications. Additionally, this research may provide a pathway for us to gain a better understanding of the molecular behavior of cytotoxic compounds. This achievement by the Herzon lab in total synthesis represents a major stride forward in the field of organic chemistry and another step toward unlocking the secrets of nature’s complex chemicals.