By Lam Vo
On Thursday, Oct. 2, Dr. J. Thomas Ippoliti of University of St. Thomas in Minnesota led the Chemistry department’s weekly seminar. His talk was titled “Synthesis of Novel Blood Sugar Lowering Compounds.”
Ippoliti received his Bachelor’s degree from State University of New York at Potsdam, his Master’s degree from University of Wyoming and his PhD from University of Wisconsin-Madison. He completed his Postdoctoral research at Exxon Research and Engineering, and started teaching at University of St. Thomas in 1989.
“This is a project in which the original goal is way different from the final outcome,” Ippoliti started. Instead of finding blood sugar lowering compounds, he set off his research looking for ones that had a strong antibacterial effect. It was no easy task, provided that the connection between a compound’s atomic structure and its biological activities is usually hard to predict. Ippoliti used a powerful technological tool called Forward Engineering that helped make the search for these compounds easier.
Developed by Medisyn Technologies, Forward Engineering is a unique prediction platform capable of quickly designing novel or improved molecules based on pre-specified properties. Using topology, a mathematical theory that studies geometric properties and spatial relations, this technology encodes the structural elements of a molecule and biological activities into the same kind of data, called topological indices. Thus, this technology enables scientists to identify molecules that possess desired properties, such as efficacy in treating a certain kind of disease, and assess the potential to act as a drug of new compounds.
In the words of David Land, President of Medisyn Technologies, Forward Engineering allows “discovery of new chemical entities and bioactives in new chemical classes not previously known to possess the desired properties. It is the extrapolation from known chemical space to novel chemical space.”
With Forward Engineering, Ippoliti came up with an entirely new structure that was predicted to possess an extremely strong antibacterial effect, which is designated as compound X. He then advanced to synthesize it. The first synthesis scheme he used, though, turned out to be a failure. Instead of the expected product, the reaction sequences he used yielded an entirely different compound.
The mechanism of reactions involved was carefully scrutinized, and doing so revealed a very fundamental step that was unnoticed. His group’s second attempt succeeded as he learned from his mistakes. They managed to successfully make compound X.
Yet, the project continued in an unanticipated direction. As compound X was sent out for further bioactivity testing, an unexpected conclusion came back to Ippoliti’s group. Compound X did not display any of the antibacterial effect that it had been predicted to have.
It appeared that the group’s years of careful planning and painstaking synthesis did not pay off.
However, to Ippoliti’s surprise, after another few rounds of tests, compound X was proved to be useful for medical use. It is Glucagon-like Peptide-1 (GLP-1) active. GLP-1 is a hormone that increases insulin secretion from the pancreas in a glucose-dependent manner.
Thus, it is the subject of intensive investigation as a potential treatment of diabetes mellitus. In other words, compound X has the capability of lowering the sugar level in human blood and may be an effective drug in treating diabetes.
After the discovery of compound X’s power, the research group continued to synthesize approximately a dozen of the compound’s derivatives, whose structures varied slightly from the original.
Undergraduate students, who worked in his group, made many of the derivatives. These compounds are being tested as possible drug lead compounds.
According to Ippoliti’s website, his research group is composed of entirely undergraduate students. The research has a primary focus in the field of organic synthesis.
Ippoliti’s website also states that there are currently six areas of research that the Ippoliti group is actively involved in: synthesis of novel antimicrobial molecules, synthesis of luminol derivatives, synthesis of radioopaque polymers, new synthetic methodology for reduction of amides, synthesis of thermochromic molecules and synthesis of antimalarial molecules.
The story of Ippoliti’s discovery of a novel blood sugar is a perfect example of how important discoveries are made with logical deductions as well as an openness to unexpected twists and turns along the way.