Collaborative Chemistry

Chemistry is all around us and even within us. Everything is made up of atoms consisting of neutrons, protons and electrons. When a molecule, or group of bonded atoms, has an unpaired electron, it is called a free radical. Due to its high reactivity and instability, a free radical will steal electrons from other molecules, causing an ongoing and potentially dangerous cycle to occur within the human body. Free radicals are often created by metal ions and can cause severe DNA damage, resulting in mutations and cancer, tissue damage in heart attack and stroke and neurodegenerative diseases. To prevent this cycle and gain insight into the environment around the metal ions, the Imaginative Ligands and Unique Metal Complexes: A Marriage of Organic and Inorganic Chemistry Creative Inquiry project, led by Drs. Julia Brumaghim and Modi Wetzler from the Department of Chemistry, is designing ligands—molecules that bind metal ions to prevent radical generation and more broadly control metal reactivity.

To function properly, the body needs an appropriate amount of metals such as iron and copper. With Brumaghim’s expertise in bioinorganic chemistry, she and the students investigate how these metals generate free radicals and damage DNA. “It turns out that there are a lot of antioxidants, either ones that occur naturally in your cells or ones you eat in your diet (fruits, vegetables, green tea and all those things that people tell you [that] you should eat) that can prevent cancer and degenerative diseases,” Brumaghim said. Many of the antioxidants that the Creative Inquiry team observes are coordination compounds, which are bonded metals and ligands—some of which are the ligands Wetzler mentors the students in designing.

The students in this Creative Inquiry project recently worked to develop a ligand that can completely encapsulate a metal ion and prevent or slow down generation of radicals. Two versions of a ligand were designed using four hydroxamic acid arms branching from a common backbone. The first, a hydroxamic acid analog of ethylenediaminetetrapropionic acid (EDTP), a chemical used to bind calcium, was made by a former graduate student through a five-step process. Each of the four arms of this ligand has three carbons, and it proved to be too big and did not bind well to the metal. This led Maclean Hutmacher, a junior chemistry major, on a mission to produce a smaller ligand.

For several months, Hutmacher and Wetzler followed the graduate student’s methodology, but this time used a hydroxamic acid analog of ethylenediaminetetraacetic acid (EDTA). Like EDTP, EDTA, a chemical agent used to bind iron, also has four arms. However, it is significantly smaller in size due to each of its arms only having two carbon atoms rather than the three carbon atoms of EDTP. “The process was painful for a while. Our chemical products kept decomposing and requiring purification steps. It was super tedious and took a super long time,” Hutmacher said. With no luck, they decided to try a different method that would convert the EDTA’s acetic acid arms into hydroxamic acid arms, resulting in a more direct, two-step process. “Wouldn’t you know it, the easier and more direct route worked the first time we tried it,” Wetzler exclaimed. With the successful development of this ligand, the bioinorganic team can observe and better understand how the binding of the antioxidant ligand with the metal controls free radical formation and damage.

Though preventing DNA damage and degenerative diseases is the Creative Inquiry project’s current focus, the team has ambitious goals. In the future, Brumaghim and Wetzler hope to explore antioxidants and other ligands that can separate nuclear waste, by pairing their ligands with the larger, riskier lanthanide and actinide metals. After seeing how uniting their perspectives and expertise succeeds on the smaller scale, they can only imagine what great things collaborative chemistry will accomplish on a larger scale.