Synthesis and biochemical evaluation of ruthenium compounds

Bard College received a $427,016 Project Grant from the National Institute of General Medical Sciences (NIGMS) under the Biomedical Research and Research Training program (CFDA 93.859) effective September 1, 2025, through August 31, 2028. The award supports the synthesis, characterization, and biochemical evaluation of ruthenium-based compounds as potential pharmaceutical agents. The research addresses a significant gap in transition metal drug development by investigating how ruthenium complexes interact with ribonucleic acid (RNA) molecules—a largely unexplored area in pharmaceutical research. The compounds are being engineered to enhance nucleotide binding affinity, improve aqueous solubility, and demonstrate activity against bacterial infections, cancer cells, and diabetes.

The project deliverables include synthesized and characterized ruthenium complexes with documented binding mechanisms to various RNA molecules, identification of specific RNA binding sites and binding strength measurements, and assessment of how binding affects RNA structure and function. Additionally, the research will determine whether the newly synthesized ruthenium complexes inhibit dihydrofolate reductase (DHFR), a critical enzyme in the folic acid pathway. These research outputs are intended to establish a foundation for advancing ruthenium-based therapeutics as alternatives to existing transition metal drugs such as cisplatin, which face limitations including drug resistance and poor efficacy.

Abstract

Transition metal compounds have been used as therapeutic agents. However, treatment with these compounds, for example cisplatin, can lead to drug resistance and poor efficacy. Ruthenium has been studied as an alternative to other transition metals. The aims of this project are to carry out the synthesis, characterization, and biochemical evaluation of ruthenium-based compounds as potential pharmaceutical agents. Ruthenium compounds have gained attention as potential therapeutic agents having different modes of action against bacterial infections, cancer, diabetes and other diseases. The overwhelming majority of pharmaceutical agents, including transition metal drugs, either target DNA or proteins. RNA has recently received much attention as a biomolecule in the fields of public health, medicine, and biotechnology. The rich structural diversity of RNA and its role in numerous cellular functions have led to its emergence as an important biological target for pharmaceutical agents. Very few studies have explored how transition metal complexes bind to RNA molecules. The initial aim of this project is focused on the synthesis and characterization of ruthenium complexes. The second aim of this project will investigate the binding of ruthenium complexes to various RNA molecules. Results will reveal the specific RNA binding sites of ruthenium complexes, their binding strength, and the impact of binding on RNA structure and function. The ruthenium compounds synthesized in this project are designed with the purpose of enhancing their binding to nucleotides, improving aqueous solubility, and making them active against diabetes, and bacteria and cancer cells. Finally, this project will determine whether the newly synthesized ruthenium complexes bind to dihydrofolate reductase (dhfr) enzyme and inhibit its catalytic activity. Dhfr is a crucial enzyme within the folic acid pathway. The folic acid pathway is important in the synthesis of nucleotides, amino acids, and other cellular intermediates. Dhfr enzyme has been targeted extensively by antifolate drugs, like methotrexate, which have been on the market for decades. Compounds synthesized in this project incorporate architectures of different antifolate and antidiabetic drugs with the goal of improving their water solubility, hydrogen bonding capabilities, and overall specificity.