Water‐Soluble μ‐oxo triruthenium Compound of Biological Interest: H‐Bonds Network and Interaction with HSA

• Published in: European journal of inorganic chemistry Vol. 27; no. 13
• Main Authors: Pinheiro, Bruno F. A., Fernandes, Nathan C., Chaves, Otávio A., Ellena, Javier A., De Queiroz, Mariana S., Tedesco, Antônio C., De Araujo‐Neto, João H., Nikolaou, Sofia
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 02.05.2024
• Subjects: aminopyridine; Chemical bonds; HSA interaction; Hydrogen bonding; Hydrogen bonds; Molecular docking; non-conventional hydrogen bonding; Protonation; Serum albumin; water solubility; μ-oxo triruthenium cluster
• ISSN: 1434-1948; 1099-0682
• DOI: 10.1002/ejic.202300617

The water‐soluble compound [Ru3O(CH3COO)6(4‐ampy)3]Cl (1, 4‐ampy=4‐aminopyridine) was evaluated in terms of its biologically relevant properties. Compound 1 participates in a hydrogen bonding network which includes the NH2 substituents of the ancillary ligands, methanol molecules, the Cl− counter‐ion, and a non‐conventional hydrogen bond with the neighboring 4‐ampy molecules′ π‐cloud, as determined by X‐ray measurements. One protonation equilibrium was observed at pH values below 2.3. Additionally, the compound exhibited a partition coefficient value of −0.86 (±0.07), indicating that it is highly hydrophilic. At 37 0C and pH=7.4 (phosphate buffer), compound 1 shows moderate (Ksv=2.4 104 M−1) and spontaneous (ΔG=−26.4 kJ mol−1) binding to human serum albumin (HSA) through ground‐state association, which involves formation of hydrogen bonds (ΔH=−35.7 kJ mol−1 and, ΔS=−29.8 J mol−1 K−1). Molecular docking calculations support the formation of hydrogen bonds between 1 and HSA, and suggest subdomain IIA (site I), which contains the Trp‐214 residue, as the primary interactive pocket, in agreement with the experimental static fluorescence quenching mechanism. Furthermore, a preliminary assay reveals that 1 has low cytotoxicity towards human glioblastoma U87‐MG cells. The fully water‐soluble compound [Ru3O(CH3COO)6(4‐ampy)3]Cl (1) engages in a hydrogen‐bonds network involving the 4‐ampy ligands and methanol, Cl‐, and the π‐cloud of neighboring 4‐ampy molecules. 1 has pKa=2.25 and logP=−0.86, showing its high hydrophilicity. 1 interacts with HSA by static mechanism through hydrogen‐bonds formation, which was confirmed by molecular docking calculations.