Researchers at CEPID CancerThera are exploring a new path for the development of therapies for oncological tumors and bacterial infections: the use of copper(II) complexes formed from the isomers 5-(trifluoromethyl)uracil and 6-(trifluoromethyl)uracil.
Isomers are molecules that have the same chemical formula (i.e., the same types and amounts of atoms), but are organized in different ways. This variation in organization can cause each isomer to have unique properties and behaviors, such as different flavors, melting points, or biological activities. This diversity is fundamental to the field of Chemistry and to many of its applications, including the creation of new drugs.
Dr. Pedro Paulo Corbi, chemist, professor at the Institute of Chemistry of the State University of Campinas (IQ/Unicamp) and principal investigator at CancerThera, reports what motivated the choice of these materials in conducting the studies: “Nucleobase analogs have been extensively studied as potential agents for cancer treatment. 5-fluorouracil is an example of this class of molecules used in cancer treatment, with which our group has been working for almost a decade.” Nucleobases are the organic compounds that contain nitrogen and form cellular structures such as deoxyribonucleic acid (DNA), a molecule known to carry biological information of the cell and to be a kind of “instruction manual”.
The group led by Corbi in this investigation was formed by the following researchers: MSc. Gabriele de Menezes Pereira, Dr. Julia Helena Bormio Nunes, Dr. Silmara Cristina Lazarini Frajácomo, Dr. Wilton Rogério Lustri, Dr. Fernando Rodrigues Goulart Bergamini, MSc. Josélia Cristina de Oliveira Moreira, BSc. Robson da Silva Pontes, Dr. Ana Lucia T. G. Ruiz, Dr. João Ernesto de Carvalho and Dr. Wdeson Pereira Barros.
The results of the study were published in the journal Chemistry Select (2025, v. 10, n. 6; DOI: 10.1002/slct.202405096) under the title “Investigating the antibacterial and antitumoral activities of new copper(II) complexes with trifluoromethyluracil isomers”.
How does chemical structure influence biological activity against cancer?
Researchers are seeking to understand which “doors” – possibly proteins or enzymes – these complexes may be opening or blocking to interfere with cell proliferation. The choice of 5-(trifluoromethyl)uracil and 6-(trifluoromethyl)uracil isomers for the synthesis of copper(II) complexes was motivated by the continuity of the group’s studies with compounds analogous to nitrogenous bases.
(a) 5-(trifluoromethyl)uracil and (b) 6-(trifluoromethyl)uracil.
The main objective was to evaluate the combination of these bioactive compounds with copper, seeking to enhance their activity in treatments against bacteria and the proliferation of tumor cells. The selection of these isomers, which have trifluoromethyl groups in different positions, allowed to investigate the possible differences in the interaction with copper(II) and in the biological effects, and the preliminary results showed that this approach was effective.
Researchers explain that the chemical structure of the studied complexes directly influences their biological activity, as it determines how the compound interacts with cells, both bacterial and tumor. In copper(II) complexes, the way copper atoms and ligands (such as nucleobases in the case of trifluoromethyluracil isomers) are organized can affect how the complex binds to structures within the cell, with DNA being one example among many.
“In the case of cisplatin, a platinum(II) complex, the metal binds to the DNA bases and creates crosslinks that ‘lock’ the DNA, preventing it from dividing correctly. This leads to the breakage of DNA chains and, eventually, to cell death,” explains MSc. Gabriele de Menezes Pereira, a doctoral researcher at IQ/Unicamp who is part of Corbi’s team and is the lead author of the study. When working with copper(II) complexes, the goal is to investigate whether they have a similar mechanism, binding to DNA in a similar way, and whether they cause similar damage, leading bacterial or tumor cells to death.
These copper complexes may have a different structure from cisplatin, which can alter how they interact with cells. The presence of the trifluoromethyl group in uracil isomers, for example, can influence how the copper complex binds to DNA or other proteins important for cell functioning.
DNA is not the main target
So far, based on initial results, researchers have identified that DNA is not the main target of these compounds. And since there is still no hypothesis formed about the cellular mechanism involved in the action of the complexes being investigated, they are planning to carry out assays with other biomolecules.
“These new experiments will help us better understand how the compounds interact with cells and what is the exact mechanism of action. From these data, we will be able to direct our investigations and form a more accurate hypothesis about how the complexes exert their biological effects,” explains Pereira.
Corbi says his team intends, then, to expand the studies to identify other possible targets: “Our group has experience in evaluating the interaction of different compounds with proteins, such as albumin and lysozyme, and these assays can give us an idea about whether proteins or enzymes can be targets for these new molecules that we are developing.”
The team used its vast repertoire of 5-fluorouracil-related compounds to explore the potential therapeutic benefits of these new complexes. “In this case, our expectation is that there is an additive effect between the properties of 5-(trifluoromethyl)uracil and 6-(trifluoromethyl)uracil isomers and copper in blocking cell proliferation at different stages of tumor cell replication,” says Corbi.
Pre-clinical and clinical trials are needed
Studies with these metal complexes are just beginning, and pre-clinical and clinical trials will also be necessary. To understand their forms of action, the next step is to finalize the more detailed in vitro assays, evaluating the interaction of the compounds with different cellular targets and biomolecules. “Only after this more detailed analysis could we advance to in vivo assays, to verify the efficacy and safety of the compound in a more complex biological environment. These additional studies are crucial to confirm their therapeutic potential and their possible clinical applications in cancer treatment,” Pereira points out.
Then, with robust data on the efficacy and safety of these complexes, it will be possible to plan in vivo assays, which simulate the behavior of the compounds in animals. Clinical trials with humans can only be conducted if the pre-clinical stage is successful.
Text: Romulo Santana Osthues
