Decavanadate Salts of Cytosine and Metformin: A Combined Experimental-Theoretical Study of Potential Metallodrugs Against Diabetes and Cancer

Abstract

Cytosine, a DNA and RNA building-block, and Metformin, the most widely prescribed drug for the treatment of Type 2 Diabetes mellitus were made to react separately with ammonium or sodium metavanadates in acidic aqueous solutions to obtain two polyoxovanadate salts with a 6:1 ratio of cation-anion. Thus, compounds [HCyt]6[V10O28]·4H2O, 1 and [HMetf]6[V10O28]·6H2O, 2 (where HCyt = Cytosinium cation, [C4H6N3O]+ and HMetf = Metforminium cation, [C4H12N5]+) were obtained and characterized by elemental analysis, single crystal X-ray diffraction, vibrational spectroscopy (IR and Raman), solution 51V-NMR, thermogravimetric analysis (TGA-DTGA), as well as, theoretical methods. Both compounds crystallized in Pfalsemml-overline1¯ space group with Z' = 1/2, where the anionic charge of the centrosymmetric ion [V10O28]6− is balanced by six Cytosinium and six Metforminium counterions, respectively. Compound 1 is stabilized by π-π stacking interactions coming from the aromatic rings of HCyt cations, as denoted by close contacts of 3.63 Å. On the other hand, guanidinium moieties from the non-planar HMetf in Compound 2 interact with decavanadate μ2-O atoms via N−H···O hydrogen bonds. The vibrational spectroscopic data of both IR and Raman spectra show that the dominant bands in the 1000-450 cm−1 range are due to the symmetric and asymmetric ν(V−O) vibrational modes. In solution, 51V-NMR experiments of both compounds show that polyoxovanadate species are progressively transformed into the monomeric, dimeric and tetrameric oxovanadates. The thermal stability behavior suggests a similar molecular mechanism regarding the loss of water molecules and the decomposition of the organic counterions. Yet, no changes were observed in the TGA range of 540–580°C due to the stability of the [V10O28]6− fragment. Dispersion-corrected density functional theory (DFT-D) calculations were carried out to model the compounds in aqueous phase using a polarized continuum model calculation. Optimized structures were obtained and the main non-covalent interactions were characterized. Biological activities of these compounds are also under investigation. The combination of two therapeutic agents opens up a window toward the generation of potential metalopharmaceuticals with new and exciting pharmacological properties.

The Aquaporin-3-Inhibiting Potential of Polyoxotungstates

“…Thus, POMs exhibit outstanding physical, chemical, and biochemical properties that remain to be completely understood and applied. Due to these properties, POMs are studied in environmental, chemical, and industrial fields, particularly in the areas of catalysis, corrosion prevention, smart glasses, and macromolecular crystallography, as well as in biology, such as for cancer treatment, bacterial infection, and diabetes, among others [1][2][3][4][5][6]. Although the number of POM studies with anticancer effects is increasing, their mechanisms of action in each type of cancer cell are still far from being understood [3].…”

Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus

“…At pH around 1 and 25 °C, the half-life of decavanadate drops to about 6 s. At such strongly acidic conditions, the vanadate cation, VO 2 (H 2 O) 4 + , is the thermodynamically favorable species. The nature and concentration of the counterion also have a significant influence on the stability of the decavanadate polyanion along the pH range and the medium conditions, as indicated by the change of its decomposition rates in works of Soares et al and Gândara et al [134–137].…”

“…Also, the ratio of vanadium in the plasma to vanadium in RBCs increased over time with metavanadate administration but remained constant for decavanadate administration [162, 163]. Although there is still some disagreement regarding the extent of the physiological importance of the decavanadate ion, multiple recent studies have conclusively demonstrated that decavanadate can induce changes in the biological activities of several enzymes, which underlines the importance decavanadate-based compounds in medicine [86, 87, 90–92, 134, 164–167].…”

Vanadium and Melanoma: A Systematic Review

“…The past decades have marked important advances in the traditional view of many roles that metals and their compounds play in biological systems. In fact, metals, inorganic compounds and/or metals-organic frameworks show a diversity of properties that allowed them to present several and distinct biological, environmental and health applications [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. Recent insights into metals applications includes for instance, zinc nanoparticles as feed additives showing more efficiency than zinc salts, increasing growth not only in fish [1] but also in plants [2], besides preventing metal contaminants accumulation [2] and normalizing antioxidant biomarkers [1,2].…”