On April 12, SUNY Oswego welcomed Bruce Ellsworth, a 1987 alumni of the university to present the Augustine Silveria Jr. Distinguished Lecture Series, “Becoming a Scientist: The Path from Curiosity into Academics and a Career in Drug Discovery, Including the Invention of Farxiga for the Treatment of Diabetes.”

Having studied chemistry during his time at Oswego, Ellsworth, accompanied by his wife, began the day by speaking with students in a variety of classes, including the 9:10 a.m. majors-only organic chemistry section led by associate professor Matthew Baker. Their early introductions were not only to encourage students to attend the afternoon presentation but to inspire them to continue with their studies in the discipline.

Either Ellsworth’s early morning guest talks were successful or interest was already brewing in anticipation of his arrival; Shineman 175, the room where the presentation was held, was at borderline capacity come 2:50 p.m. Professors across all disciplines of chemistry, from organic to analytical and physical, along with their undergraduate and graduate students, sat intently, waiting to hear about the career pathway Ellsworth took preceding the synthesis of Farxiga.

Dapagliflozin, also known by its brand name Farxiga, is a medication used primarily to treat Type 2 diabetes but may be utilized to treat adults with heart failure and chronic kidney disease. Its market availability is a testament to the success of Ellsworth and the team behind the drug’s creation at Bristol Myers Squibb, the pharmaceutical company Ellsworth joined following his post-doctoral degree at the University of California at Irvine.

Ellsworth began the presentation with an overview of his life and the time spent at SUNY Oswego, noting the faculty that assisted him throughout his undergraduate chemistry career. Of significance were Richard Shineman, Ellsworth’s general chemistry professor, and Augustine Silveira, a former chemistry professor at the university who not only taught but also captured Ellsworth’s attention with graduate-level organic chemistry courses.

Ellsworth ultimately did not take the higher level courses and turned down a graduate school acceptance after his time at Oswego, rather going on to work in a biochemistry laboratory in 1987 where he modified DNA and later went on to work with applied biological systems and polymerized chain reactions.

“It was a really, really cool time,” Ellsworth said. “I mean, I’m not saying I invented anything, I was just there and got to see what people were doing. But I will say that in terms of the ways my brain operates, biochemistry was not it for me, I was back to organic chemistry. And that’s because I can’t let go of the atomic level. And so, even when I’m working on a protein, in my head, I’m actually imagining every atom in that protein.”

“And that’s one of the things that drove me back to my Ph.D.; the other was I realized that I actually wanted more [knowledge] in physical organic chemistry and some of the principles that really allow you to understand how to optimize your reactions,” Ellsworth said. “What are those side products telling you, and how do I then convert those into a more successful reaction?”

Ellsworth then transitioned to his time working at the University of California at Berkeley, where he was able to hone in on his interests in organic chemistry through “non-bonded molecular dissociations” and build a foundation for his future career in chemistry. Ellsworth admits, however, that his plan at the time was to continue into academia, not the pharmaceutical industry. Nonetheless, he continued his Ph.D. under Scott Rychnovsky’s laboratory at the University of California at Irvine, where he “studied the formation and trapping of oxacarbenium ion intermediates via Prins reaction” and “routes to the natural product, phorboxazole, via a Mukaiyama aldol-Prins cascade.”

Ellsworth found it necessary, however, to address his long path of education and the flexibility chemistry and adjacent fields of study have to offer future workers. 

“But I wanted to stop for a second before I go on to my career transition and say that it is not necessary to go out and get a Ph.D.,” Ellsworth said. “That’s not actually, despite what I was told when I was young, what makes you a scientist. Curiosity is what makes you a scientist.”

“For me, it was just really that realization that I felt I was lacking in some aspect of the scientific method that I really wanted to strengthen and bring forward,” Ellsworth said. “So that’s what I did in my Ph.D. and post-doc.”

The presentation then moved to Ellsworth’s time at Bristol Myers Squibb and the derivation of Farxiga, including the countless chemical mechanisms and procedures required to synthesize the drug. In addition, Ellsworth mentioned the nerve-wracking uncertainty that comes with creating a medication that, assuming it passes all other barriers to market entry, humans will ingest and need to tolerate in the body.

“The first time the compound I was working on went into humans, I was scared,” Ellsworth said. “You just really don’t want somebody to be harmed by something that you have discovered. Not only do you have to worry about [the medication] on its own, but then about the combination [of] other drugs the patient may be taking.”

While Ellsworth has an unshakable ethos on the topic of organic and drug synthesis, he was adamant about the development of his skill at the university and how basic chemistry courses shaped his inevitable success. 

“My job is to come up with stuff that has never been known before and never been synthesized before,” Ellsworth said. “And once again, that draws upon the skills that started right here at SUNY Oswego in my chemistry classes.”

The remainder of the presentation reviewed the literature, mechanisms and techniques employed throughout the fabrication process of Farxiga, including the retrosynthesis pathways necessary to arrive at certain drug intermediates, Friedel-Crafts alkylation for the incorporation of certain functional groups and the cost-minimizing reagents utilized for the final product. 

Ellsworth ensured to go through each step meticulously to provide a clear image of the laboratory’s work and dedication to the creation of the medication.

“Lastly, from what was known in the literature, was that you can buy this 

tetrabenzyl-protected glucose and then oxidize it to this carbonyl,” Ellsworth said. “So when you take an aryl lithium or aryl Grignard and add it into this carbonyl, [then you see that] ‘Wow, we’re pretty close to the structure we need.’”

After reviewing the complete molecular synthesis of the medication, Ellsworth finished his presentation by acknowledging the culminated efforts of Bristol Myers departments in Farxiga’s synthesis and the collaborative nature students need to have to be successful in chemistry.

“I think one plus one equals more than two when you work well together,” Ellsworth said.

Photo via: SUNY Oswego