“Unlike most people, I find organic reaction mechanisms really fun,” she admits. “I was nervous about taking organic chemistry in college. All I knew about it was people said it was hard. But for some reason I just had a natural knack for it.”
At the back of her mind was the notion that a chemistry degree would one day enable her to become a doctor. Instead, she became intrigued by complex organic reactions and set out to discover the optimal catalysts to “steer” the formation of chiral molecules—that is, molecules with stereogenic centers—that can form as one of two mirror-image compounds.
Mattson came to WPI in 2016, bringing her groundbreaking work on catalysts to produce dimeric chomanones—a class of naturally occurring compounds that hold strong biomedical potential. These complex molecules have been shown to have activity against a wide range of diseases, including tuberculosis and malaria, and they also can be effective antibiotics. Within a year she had secured NIH funding to work on techniques to more efficiently produce the desired isomer of these complex molecules in the lab. Her “Tricks for Noncovalent Catalysis” (a 2017 piece in Science magazine) highlighted unique approaches to using catalysts that could lead to life-saving medical discoveries.
At WPI her “knack” for synthesizing bioactive natural products has become the foundation of an interdisciplinary research collaboration on the interface of synthetic chemistry, pharmacology, and cell biology. Researchers at WPI and UMass Medical School are working together to explore new approaches for developing drugs to treat cancer, especially when the cells have become resistant to first-line therapies.
Collaborating on Cancer
Cisplatin—the standard treatment for several cancers, including ovarian—is initially successful in causing apoptosis—or programmed cell death—in cancer cells. But in up to 75 percent of patients the tumors become drug-resistant, and the patient dies. “There is often no alternative treatment,” says Mattson. A promising avenue for developing new drugs is a dimeric chromanone called phomoxanthone A, which can be extracted from Phomopsis longicolla, a fungus that grows on teak trees in Northern Thailand. “Others have demonstrated its cytotoxicity,” Mattson explains, “but no one fully understands its mechanism of action, or what it targets in the cancer cell. Many of these natural products have good biological activity, whether it’s anti-cancer or anti-bacterial or anti-malarial. It’s what they call, in chemistry, a ‘privileged’ structure.”
Naturally occurring phomoxanthone A is costly and complicated to isolate. It’s also notoriously difficult to synthesize in the lab. That’s where Mattson’s bonding “tricks” come in. Her breakthrough work on catalysts has made it possible to create a reliable supply of the biologically active formation, making sustained, in-depth experimentation possible.
The phomoxanthone A molecules synthesized in Mattson’s lab are being developed for use as probes that will let researchers see inside cells to pinpoint and analyze the anticancer action of the molecule within different cell lines—including lymphoma, oral cancer, and ovarian cancer. The researchers will also compare the response of cells that are still cisplatin-sensitive, and those that have become resistant. The team expects that the data gathered will shed light on the phenomenon of drug resistance, and open up pathways for new drug discovery.
The inquiry is focused on proteins and lipids found in the inner membrane of the mitochondria, a structure within the cell. Of particular interest are BCL2, a protein that regulates cell function, and cardiolipin, a phospholipid that, in oversupply, can disrupt the normal properties of the membrane. The hypothesis is that a better understanding of these targets could inspire the creation of drugs that work by controlling the production of these, or other biomolecules—which might offer a new target for halting the reproduction of cancerous cells.
Two doors down from Mattson’s office is her friend and mentor Suzanne Scarlata, professor of chemistry and biochemistry. The Scarlata lab studies the localization and movement of proteins and small molecules in cells. “Because phomoxanthone A is fluorescent,” she notes, “its interactions with cells can be easily followed on a high-resolution fluorescence microscope.” Students in the Mattson/Scarlata lab have observed the drug being taken into cancer cells. “By tagging different cell organelles with different color fluorophores, we find that the drug anchors itself into the double lipid membrane of cell mitochondria. Because the mitochondria are critical in providing energy to cells, cells containing the drug become fatigued and die.” She adds that future studies will attach potential partners of phomoxanthone A with different color fluorescent tags to follow their associations in living cells.
At UMass Medical School, assays by the high-throughput screening facility led by Professor Paul Thompson, along with mass spectrometry studies led by Professor Scott Shaffer, will provide data to validate the targets and action mechanisms. “Once we identify the biomolecules of interest, and figure out where the active site is, we can begin to confirm how those molecules are coming together, on a molecular level,” Mattson explains. The intent is to transform phomoxanthone A from an interesting exotic natural product to a known actor that can play a leading role in future drug discovery.
Theory and Purpose Coalesce
Early in her career, Mattson says, “I became really interested in hydrogen bond donors—designing my own and seeing how they could be used to solve problems of complex molecular synthesis.” Her first breakthrough on exploiting noncovalent bond formation to favor the production of a desired isomer was in using silanediols—compounds containing silicon bonded to two OH groups.
One of the challenges in synthesizing chromanones is that conventional catalysts, which work by forming strong covalent bonds with their target molecules, are often not effective because it can be difficult to form covalent bonds with chromanones. What is needed are molecules that can form weaker hydrogen bonds with anions, or negatively charged regions of the target molecule.
Mattson’s group was the first to show that the ability of silanediols to recognize anions in other molecules and to act as so-called hydrogen-bond donors gives them great potential as enantioselective catalysts, capable of controlling the synthesis of chromanones so that the process produces only the desired stereoisomer. Working with students in her WPI lab led her to realize better outcomes by using copper bis(oxazoline) as a catalyst, in the presence of a ligand.
“With the silanols, we were hitting a wall, in terms of the effectiveness of stereocontrol,” she says. “We could control it [the stereochemistry] to 57 percent—but you want it to be 100!” The copper catalyst, with almost perfect results, is now her “go-to method”—the breakthrough that makes the work on phomoxanthone A possible. Mattson’s “tricks” make it possible to create a library of closely related analogs—that is, similar compounds that are more readily synthesized, but that still have the key bioactive properties.
While naturally occurring molecules such as the chromanones offer a good starting point to inspire drug discovery, structurally simplified bioactive derivatives can serve as more accessible scaffolds to study the relationship between structure and biological activity. The analogs that prove to be the most cytotoxic will be employed in photoaffinity labeling assays to determine exactly what is necessary to get the anti-cancer activity.
“I’ve been trying to get into drug discovery for a long time,” Mattson says. “I’ve had my eye out for years on how to blend my chemistry with useful target molecules.” Some of her early work intersected with cancer research at various points along the way. In her first independent position as an assistant professor at The Ohio State University, she received an American Cancer Society Institutional Seed Grant to apply her hydrogen bond donor catalysis techniques to drug discovery. She collaborated with the medical school on an inhibitor for a protein that has been linked to pediatric brain tumors. “Doesn’t that sound very noble?” she asks. “It was a good project, but the molecules were very simple. We could use very standard reactions. It wasn’t intellectually stimulating, from a synthetic standpoint, because the chemistry was very easy.”
On the synergistic collaborations at WPI and in Worcester she says, “I think a lot of people want to hear that maybe I planned the whole thing. But I couldn’t have predicted this. I think I’m lucky that I came to WPI and found Suzanne. She’s such a great mentor for me. for me. At a large state university with a dozen organic chemists,” she jokes, “we’d talk only to ourselves. Here, I’m forced to talk to others. Turns out that’s advantageous!
Speaking seriously about the collaboration, she says, “It’s a multifaceted approach that requires a lot of different kinds of expertise. That’s why so few people do this kind of work—because it requires such different skills. But I think that’s where all the great science is—on the interface! It’s in the two complementary skill sets coming together to solve a problem you couldn’t solve by yourself.”