Histaminium decavanadate: a small biomimetic model to study non-covalent interactions between decavanadate and histidine side chains in proteins

Over the last 30 years, many studies have examined polyoxidometalates as a treatment for various illnesses. Many substances that contain decavanadate have been proposed as potential therapies for diabetes, cancer, and Alzheimer's disease. Currently, there are 8 functional proteins in the Protein Data Bank (PDB) that bind decavanadate (V 10). These are the human cell cycle protein CksHs1, the transient receptor potential cation channel (TRPM4), two ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), acid phosphatase, tyrosine kinase, and, more recently, HEWL (lysozyme) and RNase A. The interaction sites of the decavanadate anion with these proteins are mostly made up of side chains, such as arginine, lysine, and histidine. The histaminium dication served as a small biomimetic model to elucidate the noncovalent interactions between decavanadate and histidine residues in proteins. Here we report the synthesis and crystallization of histaminium decavanadate and its characterization using FTIR, Raman, 51 V-NMR, TGA, and X-ray diffraction. To gain insights into the non-covalent interactions of decavanadate in protein environments, the interaction energy between the decavanadate anion and histaminium counterions was calculated using DFT methods. To better understand the non-covalent interactions in these adducts, studies were carried out using the Quantum Theory of Atoms in Molecules (QTAIM) and Non-covalent Interaction-Reduced Density Gradient (NCI-RDG). Based on their interaction energies, decavanadate can interact with histaminium through hydrogen bonds, electrostatic forces, and van der Waals forces. The compound exhibits strong hydrogen bond interactions, which significantly enhance its stability. Decavanadate holds considerable promise as a potential treatment for diabetes, cancer, and neurological protection. Consequently, additional research is required to elucidate its interactions with proteins.

The interaction of polyoxidometalates (POM’s) with proteins has concentrated significant attention due to its critical role in the pathways governing POMs’ biological activity (Aureliano et al., 2021; Costa Pessoa et al., 2021; Ferraro et al., 2025). Non-covalent interactions are more common between biomolecules and POM’s, regardless of findings of covalent interactions (Gil and Carbó, 2022). Experimentally, there are limits to identifying binding modes, characterizing interactions, and evaluating the competition for binding sites between POM’s and other species in the medium. On the other hand, from a computational perspective, the initial docking studies examined the binding sites, revealing that POMs primarily interact in the positively charged regions of the protein where cationic and polar amino acids are predominant (Judd et al., 2001; Prudent et al., 2008; Narasimhan et al., 2014). There are currently 8 functional proteins that bind decavanadate (V 10) reported in the Protein Data Bank (PDB). These are the human cell cycle protein CksHs1, the transient receptor potential cation channel (TRPM4), two ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), acid phosphatase, tyrosine kinase, and, more recently, HEWL (lysozyme) and RNase. The interaction sites of the decavanadate anion with these proteins are mostly made up of side chains, such as arginine, lysine, and histidine (Aureliano et al., 2022a).

Decavanadate is a polyoxidovanadate that has been widely investigated due to its remarkable ability to interact with proteins. This property has been proposed as a potential therapeutic agent for the treatment of various diseases, including diabetes mellitus, Alzheimer’s disease, and cancer (Treviño et al., 2019; Sciortino et al., 2020a; Aureliano et al., 2025). Decavanadate has exhibited promising anticancer activity in different cell lines, demonstrating significant inhibition of tumor growth. Its mechanisms of action are multifaceted and involve interactions with key proteins and enzymes, as well as the disruption of fundamental cellular processes such as proliferation and metastasis (Sciortino et al., 2020b). The structural and electronic similarity between vanadium and phosphate constitutes a fundamental basis for the therapeutic interest in vanadium compounds, including decavanadate (Sánchez-Lara et al., 2018). This resemblance enables these compounds to interfere with phosphate-metabolizing enzymes, which play crucial roles in multiple cellular signaling pathways that are frequently dysregulated in cancer cells. Such interference suggests a primary mechanism through which decavanadate may exert its anticancer effects (Aureliano, 2011). In this context, decavanadate is a potent inhibitor of alkaline phosphatases (ALPs), enzymes that are often overexpressed in various types of cancer and are associated with tumor growth and metastasis. Inhibition of ALPs by decavanadate may disrupt tumor cell metabolism and functionality, thereby hindering their proliferation (Aureliano, 2017). Additionally, decavanadate interacts with actin, a fundamental cytoskeletal protein, inhibiting its polymerization into filamentous actin (F-actin). Actin dynamics are essential for cellular processes such as cell division, migration, and metastasis; therefore, their disruption by decavanadate may impede cancer progression. Research has shown that decavanadate causes changes in the shape of globular actin (G-actin) and stops it from polymerizing. Furthermore, decavanadate has been observed to bind to the catalytic site of G-actin, which coincides with the ATP-binding site, indicating possible competition with this nucleotide (Sciortino et al., 2020a).

Decavanadate has demonstrated antiproliferative effects in various cancer cell lines, resulting in the inhibition of cell growth. It has been demonstrated that both decavanadate and the metformin–decavanadate complex exerts antiproliferative effects in melanoma cells at concentrations approximately tenfold lower than those required for monomeric vanadium (De Sousa-Coelho et al., 2022). Moreover, preclinical studies using animal models have been conducted to evaluate the antitumor activity of decavanadate in vivo. Administration of a magnesium and sodium decavanadate compound in mice bearing melanoma allografts prevented and significantly suppressed tumor growth by up to 70% (Essid et al., 2025). In general, the anticancer mechanism of action of decavanadate appears to be quite complex, involving interactions with multiple cellular targets rather than a single specific pathway. Therefore, a detailed investigation of the mechanisms leading to cancer cell death is crucial for its potential therapeutic application. In this regard, comprehending the stability of decavanadate in biological settings is essential for its advancement as a therapeutic agent (Aureliano, 2017). For this reason, new decavanadate-based compounds are being explored that combine the decavanadate anion with various organic and inorganic cations, as the chemical structure and associated counterions can significantly influence its anticancer activity. These approaches aim to modulate the physicochemical properties of decavanadate, such as solubility, stability, and cellular uptake, which may result in enhanced therapeutic efficacy and reduced toxicity (Sánchez-Lara et al., 2018). As a follow-up to our work with guanidinium and spermidinium decavanadates (Paredes- Pérez et al., 2024), histaminium is proposed to mimic the interactions of histidine side chains in proteins (a biomimetic compound is a synthetic (man-made) molecule designed to imitate the structure, function, or behavior of a natural biological molecule). Histamine is a biogenic amine that plays a role in many bodily functions, such as the immune system, neurotransmission, and the release of stomach acid. Decavanadate, a representative POM, is known for its structural versatility and redox activity, which may influence its interactions with biomolecules. Therefore, the non-covalent association between decavanadate and histamine could modulate histamine’s biological activity or stability, which may in turn impact cellular processes; additionally, the stability of decavanadate could also be affected, thus impacting its pharmacological activity. In the present article, we investigate the non-covalent interactions of histaminium decavanadate as a small biomimetic model of the histidine decavanadate interaction in proteins, with the purpose of identifying the type and strengths of such interactions. The theoretical methodology used, based on DFT calculations and the topological electron density parameters, allows us to identify the main bond critical points corresponding to the non-covalent interactions involved in the complex stability. Values of interaction energy and kinetic energy density functionals were measured to classify the type of non-covalent interaction and quantitatively characterize their properties. Such analyses showed that mainly hydrogen bonds and van der Waals interactions are responsible for the binding of decavanadate to highly positively charged pockets, and with that information, one could predict important pharmacological targets or carrier proteins that could protect decavanadate from decomposition in biological environments.

Synthesis of histaminium decavanadate

The reagents used were purchased from the supplier Sigma-Aldrich (Darmstadt, Germany), and no additional purification was performed. The solids were weighed on an OHAUS AX223 electronic balance with a sensitivity of up to 1 mg. In a 50 mL beaker, 20 mL of distilled water was placed. To this beaker, 138 mg of potassium metavanadate (1 mmole) were added, and the solution was stirred constantly with the help of a magnetic stirrer for a period of 5 min. Once dissolved, it was acidified with 4 drops of glacial acetic acid, and the solution turned yellow-orange as described by Rossotti and Rossotti (1956), Swallow and Barnes (1964), and Evans Jr (1966). Using a pH meter, the pH was adjusted to 4.3. In another beaker of the same volume, 20 mL of distilled water was added, and 184 mg of histamine dihydrochloride (1.66 mmole) C 5 H 9 N 3 • 2HCl was added. This solution was kept under constant agitation for 5 min. Then the histamine dihydrochloride solution was slowly dripped onto the yellow-orange decavanadate solution; however, the reaction occurred too quickly, forming a precipitate almost instantly. Therefore, to obtain high-quality crystals, it was decided to carry out the synthesis in the cold. That is, once both reactants were dissolved and the decavanadate was formed, they were taken inside a refrigerator set at 8 °C. After a brief period of 15 min, with the help of a micropipette, all the histamine dihydrochloride solution was slowly added to the decavanadate solution. Finally, the mixture was left inside the refrigerator for 24 h, after which the crystals began to appear. The reaction yield was 74%. Synthesis and crystallization are presented in Scheme 1 as follows.

Experimental characterization

The characterization was carried out using the available spectroscopic techniques. For infrared spectroscopy, the samples were measured directly without the need for special treatment under the following conditions: using a Bruker ALPHA II Platinum model in the range of 4,000 to 400 cm -1 (24 scans/sample with a resolution of 4 cm -1). The Raman spectroscopy measurements were performed using a LabRAM®-HORIBA JOBYN YVON micro-Raman device in the range of 500–1,050 Raman shifts at ambient temperature, 25 °C. The amount of sample used was 5 mg, which was placed on a slide for direct measurement. The NMR spectra were obtained using a 500 MHz Bruker device in a region of 100–500 ppm. The samples were dissolved in deuterium oxide (D 2 O) and distilled water in a 10/90 percentage ratio, respectively. The total volume in which each compound was dissolved was 1 mL, of which 500 µL were placed in a resonance tube for measurement. Before this, the pH of the final solution was measured using pH strips, which was approximately 4.5. For X-ray diffraction, an Oxford Gemini-Atlas diffractometer equipped with a charge-coupled area detector and monochromatic Mo-Kα radiation from graphite (λ = 0.71073 Å) was used. Thermogravimetric analysis (TGA) with simultaneous differential thermal analysis (DTA) was carried out under an inert N 2 atmosphere using STA 2500 Regulus (Netzsch Instruments, Selb, Germany) equipment. The amount of sample used was ∼10 mg, and they were heated from 30 to 700 °C at a rate of 25 °C/min in alumina crucibles. An empty cuvette was used as a reference.

Software

The data were processed with the CrysAlisPro suite, and SCALE3 ABSPACK was used for absorption correction (CrysAlisPro Software System, version 171.43.1a, 2022) (CrysAlis Pro, 2013; Meskini et al., 2025). The structure was solved by direct methods using the ShelXT program and refined by full-matrix least-squares on F2 with SHELXL-2019 (Sheldrick, 2015). The positional and anisotropic atomic displacement parameters were refined for all non-hydrogen atoms. Hydrogen atoms were located in different Fourier maps and included as fixed contributions riding their parent atoms, with isotropic thermal factors chosen as 1.2 times their carrier atoms. The OLEX2 software (Dolomanov et al., 2009) was used as a graphical interface. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited in the Cambridge Crystallographic Data Center (CCDC number 2524228). Mercury 4.0 (Macrae et al., 2020) (Version 2025.3.3) was used to represent the crystallographic data.

Theoretical methodology

The structure of the compound was optimized using the hybrid functional PBE0 (Adamo and Barone, 1999), with the Def2-SVP basis set for the atoms of C, H, O, and N (Weigend and Ahlrichs, 2005) and the LANL2DZ basis set for the atom of V with an effective core potential (ECP) (Hay and Wadt, 1985). The implicit model CPCM was used with water as a solvent (Tomasi et al., 2005). The Frontier molecular orbitals (highest occupied molecular orbital, HOMO, and lowest unoccupied molecular orbital, LUMO) and the molecular electrostatic potential (MEP) map were illustrated. The calculations were carried out with the Gaussian16 program (Frisch et al., 2016), and the results were visualized with the Gaussian View 6.0.16 program (Dennington et al., 2016). The main non-covalent interactions were analyzed using the quantum theory of atoms in molecules (QTAIM) approach with AIMAll software (Keith, 2019) and Non-Covalent Interaction-Reduced Density Gradient (NCI-RDG) analyses with Multiwfn software (Lu and Chen, 2012) and VMD software (Humphrey et al., 1996).

Structural descriptions

The crystallization of the compound was carried out immediately after the synthesis reaction. The reaction mixture was allowed to slowly evaporate at 8 °C, yielding orange rhombohedral crystals. These crystals were analyzed by single-crystal X-ray diffraction, revealing a structure corresponding to (C 3 H 11 N 3) 3 [V 10 O 28 ]•2H 2 O. In Figure 1, the asymmetric unit is represented. It is important to note that the structure contains one histaminium ion and two superimposed histaminium ions with an occupancy of 0.5, presenting two different orientations. In the structure, each histamine cation contains two protonated nitrogen atoms, resulting in a +2 charge per histamine molecule. The hydrogen atoms participate in hydrogen bonding interactions. The decavanadate anion exhibits D 2 h symmetry, featuring eight terminal oxygen atoms (V=O t), fourteen bridging oxygens (μ 2), four triply bridging oxygens (μ 3), and two octahedral oxygen atoms (μ 6). The crystallographic parameters are listed in Table 1. The histaminium dication, which exhibits disorder, is refined with an occupancy factor of 1/2, such that in the asymmetric unit we see 1.5 histamine molecules and 0.5 decavanadate molecules. This is confirmed by the empirical formula obtained from the refinement and by the validation in the checkCIF report (V 10 O 28, 3(C 5 H 11 N 3), 2(H 2 O)) (see Supplementary Data). Furthermore, that histaminium molecule dication is located precisely at an inversion center, as is the decavanadate cage. In Figure 2 the numbering of the atoms is presented.

The crystal structure confirms the presence of three histaminium dications (C 3 H 11 N 3) 2+, one decavanadate anion [V 10 O 28 ] 6-, and two water molecules, exhibiting a wide range of non-covalent interactions. The V=O terminal bond lengths range from 1.596 (2) to 1.617 (2) Å, and for the bridging oxygens (μ 2), the V-O bond distances increase, ranging from 1.689 (18) to 2.052 (19) Å. In the case of triply bridging oxygens (μ 3), the V-O distances vary from 1.903 (17) to 2.024 (17) Å, whereas for octahedral oxygen atoms, the V-O distances range between 2.109 (17) and 2.319 (17) Å. All bond distances fall within the normal range when compared to other polyoxidovanadate compounds (Evans, Jr, 1966; Bosnjakovic-Pavlovic et al., 2011; Bruno et al., 2002). The hydrogen bonds observed in the X-ray structure are listed in Table 2. Figure 3 depicts a ball-and-stick representation of a decavanadate moiety surrounded by 6 histaminium dications. Figure 4 allows visualizing how the histaminium dication bridges two decavanadates and how the other histaminium dication and a water molecule fit in the hole between the two decavanadates. Supplementary Figures S1, S2 in the supplementary show the hydrogen bonds of the water molecules and the histaminium dications.

Infrared spectroscopy

The IR spectrum of the histaminium decavanadate is presented in Figure 5 and has a band at 1,157 cm -1 corresponding to a bending vibration of the C–C–N of the tail of the histaminium moiety. Bands at 935 cm -1 that correspond to the stretching vibration of the V=O t; the bands at 806 cm -1 and 717 cm -1 are assigned to the V–O b –V of antisymmetric and symmetric vibrations, respectively; however, they are split or broadened. The theoretical IR spectrum complements these assignations, showing two coupled modes of the tail of the histaminium moiety, of the ν as (C–N) and bending (H–N–C) at the 1,187–1,061 cm -1 region. Also, several coupled modes involving the (V–O b –V) are observed at the 712–687 cm -1 and 603–504 cm -1 regions. In this instance, there are clearly defined bands on either side of the strongest peaks. These results match earlier FT-IR spectra found for similar compounds (Rakovský et al., 2002; Biçer et al., 2017; Avila et al., 2019; Paredes-Pérez et al., 2024).

Raman spectroscopy

The Raman spectrum of histaminium decavanadate presented in Figure 6 shows five stretching vibrations in the range of 996 to 917 cm -1. Similarly to other decavanadates, the vibration at 821 cm -1 corresponds to a bending vibration with low intensity. Due to the significant symmetry of the decavanadate anion, a simple spectrum is expected. However, due to the hydrogen bond interactions of different magnitudes, it is challenging to simplify the assignment of each vibrational mode. Nevertheless, we see that modes with high frequencies (900 cm -1 and above) are predominantly characterized by V=O t stretching. At slightly lower frequencies, the v sym (O−V b −O) bending movement exhibits significant intensity (Todorović et al., 2005; Omri et al., 2015; Sánchez-Lara et al., 2015; Treviño et al., 2016; Aureliano, 2016; Baran, 2024). The theoretical Raman spectrum shows coupled modes of ν s (V=O) with stretching ν s (C–N) of the histaminium ring at 1,094 cm –1, and at 990–906 cm –1. The band at 820 cm –1 is assigned to coupled modes of ω (C–N–H) and ω (C–C–H) of histaminium. At the lower frequency regions of 564–520 cm –1, several in-plane bending coupled modes of oxygens in decavanadate, (V–O b –V), are observed.

51 V nuclear magnetic resonance

Figure 7 presents the 51 V NMR spectrum of the compound, recorded immediately after dissolving 5 mg in 450 µL of water (pH = 5) and 50 µL of D 2 O. The spectrum displays three principal signals corresponding to the decavanadate cluster. These are assigned to V10C at δ −422 ppm, which appears broad and of low intensity; V10B at δ −497 ppm, which is sharp; and V10A at δ −513 ppm, which is the most intense and also sharp. Additionally, a minor signal at δ −558 ppm, labeled as V1, is observed and attributed to the partial decomposition of decavanadate into its monomeric form (Crans and Tracey et al., 1998; Rehder, 2008; Omri et al., 2015). Overall, the spectral features are consistent with those expected for a non-protonated decavanadate anion (Gumerova and Rompel, 2020).

TGA and DTA studies

The TGA of histaminium decavanadate (Figure 8) shows two low-temperature exothermic processes (at ∼50 °C and ∼100 °C), probably related to humidity loss or recrystallization solvent but without significant mass loss (less than 2.7%, which may correspond to two water molecules). After that, an important thermal process (exothermic) occurs between 160 °C and 250 °C, with approximately 8.1% of mass loss, that is in agreement with the decomposition of one histaminium dication (C 5 H 11 N 3) 2+, probably weakly bound to the decavanadate anion. Next, another slow thermal process is observed occurring between 250 °C and 470 °C, with a mass loss of approximately 8.5%. This is most likely related to the loss of a second histamine dication unit, perhaps more strongly bound to the decavanadate anion by hydrogen bonds. Finally, after 470 °C, there is a continuous loss of mass (which stops at 600 °C, the final temperature of the TGA analysis performed), with a total mass loss of 14% (perhaps partial decomposition of the decavanadate anion and the third histamine cation in a combined process). This is also an exothermic process, indicating decomposition (Wery et al., 1996; Sánchez-Lara et al., 2018; Paredes-Pérez et al., 2024).

Theoretical calculations

The molecular structure and electronic properties of the compound Histaminium Decavanadate were calculated on two representative systems obtained from the crystal structure (systems A and B), as shown in Figure 9. In systems A and B, the decavanadate anion [V 10 O 28 ] 6- was surrounded by six histaminium dications in a charge +6 and singlet multiplicity model in both cases. In system A, four histaminium dications participate in four hydrogen bonding interactions, while two histaminium dications participate in two hydrogen bonds each, all of them with the bridging oxygens μ 2 of the decavanadate anion. In system B, the six histaminium cations participate with one hydrogen bond each on the bridging oxygens μ 2 of the decavanadate; see Figure 10. Table 3 shows the values of interaction energy, E int, obtained for two fragments in the complex using the equation E int = E opt-complex -E frag1 -E frag2, where E opt-complex is the optimized energy for systems A and B. Which were calculated at the level of theory PBE0/Def2SVP-LANL2DZ using ECP = LANL2DZ for the V atom, E frag1 is the energy obtained in a single-point calculation of the decavanadate anion in each system at the same level of theory, and E frag2 is the energy also obtained in a single-point calculation of the fragment formed by six histaminum cations in each arrangement at the same level of theory. As shown in Table 3, the optimized structure of system A is 13.3 kcal/mol more stable than that of system B, and the E int is approximately better by 10 kcal/mol. This energy difference could be due to the stabilization from non-covalent interactions in each system. Several non-covalent interactions are observed for stabilizing the structure, mainly hydrogen bonds and van der Waals interactions.

Figures 10, 11 show the molecular graphs and Non-Covalent Interactions (NCI) and the Reduced Density Gradient (RDG) graphs of systems A and B, respectively. In molecular graphs, the green dots represent bond critical points (BCP), blue dots represent ring critical points (RCP), and orange dots represent cage critical points (CCP). In Figure 10A, the main BCPs are labeled as CP1–CP4, while in Figure 11A, the BCPs are indicated with CP1–CP3 for systems A and B, respectively, defining strong hydrogen bonds between O atoms μ 2 of the decavanadate anion and H atoms linked to donor N atoms of histaminium cations, –N–H, from the imidazole ring or protonated amino group. System A shows a histaminium cation linked to a decavanadate anion by two hydrogen bonds: N3–H3…O3 with the N of imidazole as donor atom and oxygen μ 2 as the acceptor and N4–H4…O4 with the N of the protonated amino group as donor and O t as acceptor. System B shows all the hydrogen bonds with oxygen μ 2 as the acceptor in the decavanadate anion. Furthermore, it is observed that system A is stabilized by a major number of RCPs (blue dots) compared to system B, external to the decavanadate anion. In addition, system A shows some CCPs (orange dots) formed between histaminium dications and decavanadate anions, while in system B, CCPs are not observed.

Figures 11, 12B,C show the Non-Covalent Interactions (NCI) and the Reduced Density Gradient (RDG) graphs for systems A and B, respectively. In both systems, A and B, the N–H…O hydrogen bonds between the N–H of the histaminium cations and the O atoms of the decavanadate anion are shown in blue regions labeled as CP1–CP4 (for system A) and CP1–CP3 (for system B), observed in the range of −0.05 to −0.02 a.u. in the RDG graph in Figures 11C, 12C. In addition, van der Waals interactions are observed as green surfaces in the range of −0.02 to 0.01 a. u. System A presents more van der Waals interactions distributed around the decavanadate anion than System B, as shown in Figures 11B, 12B. Finally, strong repulsive interactions are observed in both systems, in red regions in the range of 0.015–0.05 a. u., corresponding to the atoms in the decavanadate anion.

Table 4 shows the topological electron density parameters, ⍴(r), the Laplacian of density, ∇ 2 ⍴(r), the potential energy density, V(r), the gradient kinetic energy density, G(r), and the total electronic energy density, H(r), the interatomic distance, D int, the interatomic angle, A int, and the energy of interaction, E H···Y. According to Bader (1985), bond critical points (BCPs) in the Quantum Theory of Atoms in Molecules (QTAIM) are defined as points where the gradient of the electron density is Ñr = 0, representing a minimum in electron density along the bond path and a maximum in all other directions, where a bond path is a ridge of density connecting two nuclei. The strength and type of bond are related to the values of the properties of the electron density, i.e., Laplacian sign of electron density, the total energy density H(r), etc., at the bond critical points. For system A, critical points CP1–CP4 show values of ⍴(r) in the range of 0.0541–0.0881 a.u. For system B, critical points CP1–CP3 show values of ⍴(r) slightly higher than system A, in the range of 0.0806–0.0938 a.u. All values of ∇ 2 ⍴(r) are positive, indicating a depletion of density in the region of contact between the two atoms, which characterizes the non-covalent interactions as hydrogen bonds and van der Waals interactions. The total electronic energy density, H(r), is obtained from the equation H(r) = G(r) + V(r). H(r) is associated with covalency. ∇ 2 ⍴(r)>0, but H(r)<0, with D int between 1.2 and 1.8 Å, indicating H-bonding regions are partially covalent. The values of A int for the different BCPs between 161.15° and 178.41° indicate medium to strong H bonds. The values of interaction energy, obtained from V(r) values with the equation E H···Y = 1/2V(r), are in the range of 14.24–30.69 kcal/mol (for A) and 27.23–33.95 kcal/mol (for B), with the highest value for CP2, indicating the strongest hydrogen bond interaction in both systems (see Table 4). Stable rings are formed by the interactions between histaminium cations and decavanadate anions with RCPs with ⍴(r) of 0.0020–0.0078 a. u. and CPCs with ⍴(r) of 0.0020–0.0040 a. u. for system A (see Figure 10). System B presents fewer RCPs with higher values of ⍴(r) between 0.0028 and 0.0069 a. u., but no CPCs are observed with respect to system A (see Figure 11).

In 1973, an article identified decavanadate (V 10) as a micromolecular inhibitor of rabbit muscle adenylate kinase (DeMaster and Mitchell, 1973), marking the beginning of an exponential increase in research on vanadium compounds in biological systems (Rehder, 2008; 2015; 2017; 2023a; 2023b). Polyoxidometalates (POMs) are becoming significant because of their interesting architectures and characteristics (Gumerova and Rompel, 2018). The anion decavanadate is the most studied due to its capacity to interact with proteins (Aureliano and Gândara, 2005; Krivosudský et al., 2019; Patel et al., 2019). In this regard, it is important to mention Debbie Crans’ groundbreaking research on small models for the interaction of decavanadate and proteins. The article “X-ray Structure of (NH 4) 6 (Gly-Gly) 2 V 10 O 28 •4H 2 O: Model Studies for Polyoxidometalate-Protein Interactions” initiated the investigation into the function of non-covalent interactions in polyoxidometalates and proteins (Crans et al., 1994). Also, Decavanadate is a potent inhibitor of alkaline phosphatases (ALPs), and other phosphatases, including (PTP1B) (McLauchlan et al., 2010; Turner et al., 2012; Dorsey et al., 2018). Decavanadate also inhibits mycobacterial growth more potently than other oxovanadates (Samart et al., 2018). Furthermore, researchers have been looking into decavanadate and how it works with proteins in membrane receptors that make them act like noradrenaline (Venkataraman et al., 1997). Decavanadate and other POMs function as indirect activators of a G protein-coupled receptor (Althumairy et al., 2020). However, not only V 10 but also monostituided V 10 ´s have been found to affect signaling, interacting with CHO cell plasma membrane lipids, causing aggregation and activation of a G protein-coupled receptor (Kostenkova et al., 2023). Recently, research has expanded into several fundamental and applied domains. Numerous studies have been published on different aspects and applications of POVs, including industrial chemistry, materials science, catalysis, environmental chemistry, electronics, neuromorphic computation, biology, biochemistry, pharmacology, and medicine (Mizuno and Kamata, 2011; Rehder, 2017; Samart et al., 2018; Missina et al., 2018; 2020; Bijelic et al., 2019; Aureliano et al., 2021; 2022b; 2023; 2024; 2025; Diaz et al., 2021; 2023; Budych et al., 2023; Carvalho and Aureliano, 2023; Rehder, 2023a; Ścibior et al., 2024; Crans et al., 2004; Casarrubias-Tabarez et al., 2023; Dridi et al., 2024; Sanchez-Lara et al., 2024; De Souza-Camilo et al., 2026; Lopez-Valdez et al., 2025; Hu et al., 2026; Brito et al., 2025).

V 10 is a simple anion compared to other POMs, but it can show how highly charged and hydrated metal oxide clusters interact with biomolecules (Aureliano and Crans, 2009). Its effects on proteins are significant. How specific V 10 -induced structural modifications affect native proteins is crucial to understanding the mechanism of V 10 -protein interaction. In the long term, it could help reduce V 10 ’s adverse effects on proteins in vanadium poisoning. Decavanadate, a charge-6 anion, is one of the most studied polyoxidovanadates. Eight proteins that are significant for biological processes—acid phosphatase, tyrosine kinase, two ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), the human transient receptor potential cation channel (TRPM4), and the human cell cycle protein CksHs1 (Aureliano et al., 2022a)—and, more recently, HEWL lysozyme (Paolillo et al., 2025) and RNase A (Gutierrez et al., 2025) have been crystallized containing decavanadate. The binding sites of these proteins show how they interact with positively charged amino acids like lysine and arginine and hydrogen-binding forms like histidine and serine. Although arginine and lysine make up most of the side chains that interact with decavanadate, there are examples where histidine plays a significant role, such as in acid phosphatase A and TRPM4 (Aureliano et al., 2022a). Because the proteins are so big, it is difficult to analyze how they interact with the decavanadate without forming covalent bonds. Decavanadate is thermodynamically stable in acidic conditions (pH 3–6); however, it exhibits kinetic stability, which enables it to remain in physiological environments long enough to produce specific biological effects. Several studies have demonstrated a potent antitumor activity of decavanadate against various cancer cell lines, including breast cancer, melanoma, and glioblastoma, with mechanisms of action mainly associated with the inhibition of key ATPases and the induction of programmed cell death (Aureliano et al., 2022a; De Sousa-Coelho et al., 2022; Dridi et al., 2024).

A previous study conducted by our research group showed that noncovalent interactions of decavanadate with organic cations, such as guanidinium and spermidinium, can be used as small biomimetic models of arginine and lysine side chains in proteins (Paredes-Pérez et al., 2024). The results obtained demonstrated that these interactions occur mainly through hydrogen bonding and electrostatic interactions. From the theoretical perspective, the compound histaminium decavanadate is more stable than analogous complexes with guanidinium by 53 kcal/mol and with spermidinium cations by 76 kcal/mol, as previously reported by our group (Paredes-Pérez et al., 2024). It could be attributed to the non-covalent interactions with higher interaction energy, E H···Y, between 14.24 and 33.95 kcal/mol, compared to values of 7.81–13.68 kcal/mol and 6.34–23.31 kcal/mol for strong N−H···O hydrogen bonds of guanidinium and spermidinium decavanadates, respectively. Hydrogen bonds N−H···O and van der Waals interactions highly stabilize the supramolecular network between organic cations and the decavanadate anion, as shown in several previous works (Sánchez-Lara et al., 2018; Sánchez-Lara et al., 2019; García-García et al., 2021; Corona-Motolinia et al., 2022; Paredes-Pérez et al., 2024). These studies served as a model to understand the interaction of decavanadate with basic amino acids such as lysine and arginine, which are essential for biological processes including protein synthesis, tissue repair, and immune response.

As an example of histidine interaction with decavanadate, a 2006 publication details the characteristics of Francisella tularensis acid phosphatase A (AcPA), a member of a unique superfamily of acid phosphatases and phospholipases C. The structure of AcPA was crystallized at pH 6.0 with decavanadate (V 10), revealing binding alongside another form, V 1, which influences its active site. Crystallographic analysis of (AcPA) (PDB 2D1G) reveals a dual-binding phenomenon. While the active site is occupied by a monomeric V 1 species, a V 10 cluster interacts with a patch of positively charged residues on the surface, made by a triad of histidines and capped by a lysine residue. This suggests V 10 may act as a structural modulator while smaller species handle catalytic inhibition (Felts et al., 2006). So far, AcPa is the best example of a histidine biosite, since the decavanadate is hydrogen-bonded to histidines 455, 456, and 457, as shown in Figure 12. It is important to point out that distances (D-A)-A of the title compound range from 2.609 to 2.887 Å, while in the protein, they go from 2.437 to 2.815 Å. Also, the peptide bonds between the histidines are in one case trans, but the other is cis, indicating a change of conformation to maximize the strength of the hydrogen bonds. This opens the possibility for decavanadate to help crystallize, immobilize, or purify recombinant proteins with 6His-tags.

Regarding cancer, Zhai et al. (2009) reported the properties of decavanadate as a potential anticancer metallodrug. In this context, the study and understanding of noncovalent interactions between decavanadate and histamine are particularly relevant, as these interactions could modulate the biological activity or stability of histamine and potentially influence cellular processes associated with anticancer activity. For this reason, our research group has developed a wide variety of studies focused on the interaction of decavanadate with different organic ions (Sánchez-Lara et al., 2018; Sánchez-Lara et al., 2019; García-García et al., 2021; Corona-Motolinia et al., 2022). The main reason for doing these studies is to learn about these interactions so they can possibly be used to help develop anticancer agents, leading to important findings to understand the bioinorganic chemistry of decavanadate. As for histaminium dihydrochloride, it was authorized by the FDA in 1983 as an active ingredient for topical analgesic use (Federal Register, 1983). However, its main use is administered with minimal quantities of the immune-activating cytokine interleukin-2 (IL-2) following the initial cycle of chemotherapy for acute myeloid leukemia (AML) during the remission phase of the disease. This combination is reported to significantly reduce the likelihood of AML recurrence (Brune et al., 2006). The effect is particularly pronounced in patients under 60 who are experiencing their initial remission (Romero et al., 2009). In October 2008, the European Union authorized the concurrent use of histamine dihydrochloride and interleukin-2 for individuals with AML. The Swedish pharmaceutical firm Meda distributes the medication within the USA with the trade name Ceplene. Histamine dihydrochloride enhances the efficacy of IL-2 in augmenting the immune system. Laboratory studies have shown that this combination can eradicate leukemic cells via the immune system (Hellstrand et al., 1994). Recently, research has examined the interactions between segments of antimicrobial peptides modified with fatty acid chains and vanadate anions, particularly decavanadate ([V 10 O 28 ] 6−). The researchers used methods including calorimetry, spectroscopy, and molecular simulations to find out that these interactions are mostly electrostatic and change the peptide’s secondary structure, making it less stable and less likely to form an alpha-helix. The research elucidates the binding mechanisms of these compounds and the implications of such interactions for prospective biological or medicinal uses (Kapica et al., 2025). In a report by Aissa in 2024 a new compound (C 4 H 7 N 2) 4 [H 2 V 10 O 28 ] could be a suitable choice for making a new, more selective, and highly active chemotherapy drug for skin cancer. It could also be used in combination with other chemotherapy drugs to make tumor cells more sensitive and improve the effectiveness of the drugs that already treat melanoma (Aissa et al., 2024). A recent report of decavanadate (C 9 N 2 H 24) 3 [V 10 O 28 ]•7H2O, using two cancer cell lines (IGR39 and MDA-MB-231), indicates its anti-tumor activity. The decavanadate compound inhibited cell proliferation in a dose-dependent manner, showing most activity against the IGR39 cell line (Louati et al., 2026). Altogether, recent results indicated that new decavanadate derivatives might represent novel potential compounds for the development of active molecules against cancer. The decavanadate anion is a changing species due to the complexity of factors, namely, protonation, redox processes, hydrolysis, aging, counterions, and composition of the biological medium (Ždrnja et al., 2024; Dinda et al., 2025; Costa-Pessoa et al., 2025). Therefore, new strategies to protect its integrity are required to advance useful formulations and delivery systems for the treatment of different illnesses (Sedgwick et al., 2009). Small proteins or peptides containing arginine, lysine, and histidine can be used as carrier compounds, acting like chaperones to protect decavanadate from premature speciation before reaching special biological targets (Peña-Rosas et al., 2026; Ilari et al., 2026).

In this work, we successfully synthesized and crystallized a novel decavanadate compound employing the dicationic histaminium ion as a biomimetic model for histidine side chains in proteins. The compound was comprehensively characterized, with single-crystal X-ray diffraction analysis revealing that it crystallizes in the monoclinic system, space group P2 1 /n. The asymmetric unit comprises one decavanadate anion located at an inversion center, one and a half histaminium dications (with one exhibiting orientational disorder and refined with an occupancy of 0.5), and one lattice water molecule, leading to the empirical formula (C 5 H 11 N 3) 3 [V 10 O 28 ]•2H 2 O. The crystal structure was refined to final R indices of R1 = 0.0462 and wR 2 = 0.0933, confirming the reliability of the structural model. The structural analysis confirmed the expected D 2 h symmetry of the [V 10 O 28 ] 6- anion, with V–O bond distances falling within characteristic ranges for terminal (V=O t), doubly (μ 2), triply (μ 3), and sextuply (μ 6) bridging oxygen atoms. These values are consistent with those reported for other polyoxidovanadate compounds, validating the integrity of the decavanadate cluster within the crystal lattice. The protonation states of the histaminium cations, bearing two positive charges each, were corroborated by the identification of all hydrogen atoms from Fourier maps, which actively participate in an extensive network of non-covalent interactions.

The IR and Raman spectra are typical of decavanadate in the region below 1,000 cm -1; however, the vibrations associated with t are split, which means that there are hydrogen bonds of different strengths. Theoretical studies support the characterization of IR and Raman spectra obtained experimentally, adequately describing the assignment of the normal vibrational modes involved in these spectra. Likewise, DFT calculations using QTAIM theory and NCI-RDG analyses are carried out to accurately describe the non-covalent interactions involved in the stability of the formed complex. In a similar form to their analogous complexes with guanidinium and spermidinium cations, the histaminium decavanadate structure is highly stabilized by strong hydrogen bond interactions N−H···O characterized by high interaction energies (E H···Y) and their distances and valence angles between the H-donor and oxygen acting as the H-acceptor (D int and A int). Additional weak non-covalent interactions, such as van der Waals and electrostatic interactions, as well as several rings and cage structures, favor the complexes’ stability.

Decavanadate and its derivatives represent a novel class of metal-based compounds demonstrating considerable antiproliferative and anticancer activity against melanoma in preclinical models. It is important to mention that our compound, metforminium decavanadate (Treviño et al., 2016; González-Vergara et al., 2020) and similar compounds reported by (Chatkon et al., 2013; 2014) have such properties. While initial mechanistic insights are encouraging, extensive research is necessary to confirm safety, mechanism specificity, and translational feasibility. To make decavanadate a promising treatment for melanoma, it will be important to fill in the gaps that have been found using various experimental and theoretical methods. Another area of opportunity is the treatment of diabetic foot, taking advantage of the antibacterial and antifungal activities of decavanadate hybrid compounds. Therefore, a promising future for pharmacologic applications of hybrid decavanadates is now an open field.