Iron Chelation by thiocytosine: Investigating electronic and structural features for describing tautomerism and metal chelation processes

1 Introduction

By the pioneering work of Watson and Crick for characterizing structural features of DNA, the components of this building block of living system have become targets of several research works for developing further applications [1–4]. In this regard, each of purine and pyrimidine nucleobases have been analyzed for several times in the forms of pure of modified models to explore new features for employing in living systems [5–9]. To this aim, substituting oxygen atoms of such nucleobase by sulfur atoms has been a procedure for generating new structures as derivatives of original ones [10–12]. Considerable efforts have been dedicated to explore existence and features of thionucleobases for various goals, in which thiocytisine (TC) is one of those compounds obtained by the oxygen atom replacement by the sulfur atom (Fig. 1). This compound in addition to its other modifications has been seen available for performing further analysis about their nature and applications [13–16]. Existence of tautomerism could be also expected for such heterocyclic compounds by movement of one hydrogen atom from between the amine and thio groups arising new structures with the same formula but different in structural configurations in comparison with the parent model [17–20]. To this point, impacts of occurrence of tautomerism on electronic and structural features of the parent molecule are important to be recognized according to their expected roles in living systems [21–23]. In some cases, tautomerism could lead to occurrence of mutations in living systems with harmful impacts on the human life health status [24]. Therefore, exploring existence of such tautomers for nucleobases relatives have been seen important for developing their future applications [25–27]. Parallel to keto-enol tautomerism of the original cytosine, thio-thiol tautomerism could be also expected for the TC compound, which is the topic of current work. In addition to the parent TC compound, three other compounds were evaluated by movements of one hydrogen atom of amine group among another amine group or thio group (Fig. 2). Besides exploring tautomerism, possible role of such tautomers for chelating an iron (Fe) atom is also important regarding the expected pharmaceutical functions of nucleobases relatives in living systems [28–30]. Indeed, chelation or adsorption processes are types of molecular communications, which are playing important roles in living systems [31–33]. In this regard, not only Fe, but also several other metal types could be chelated in human body systems for playing their biological or pharmaceutical roles, in which Ferriprox and Desferal are the examples of metal chelators with pharmaceutical roles of medication in human body systems [34–36]. As a consequence, this work was done for exploring Fe decoration of TC to investigate electronic and structural features for occurrence of metal chelation process.

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Fig. 1

Thiocytosine (TC).

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Fig. 2

Optimized configurations of TC models, bond distances, NBO atomic charges, HOMO and LUMO distribution patterns and ESP surfaces.

Fe is a necessary element for running the cell growth of living systems, in which its level of magnitude is a crucial factor for cell safety [37]. By the importance of cancer and even COVID-19, metal chelation should be considered as an important task [38–41] Several attempts have been dedicated to explore how to remove the excess of Fe from the cell or how to supply Fe in the lack of this element for the cell to maintain the cell health and safety status for doing correct function [42–44]. In this regard, earlier works showed that the small heterocyclic compounds could work as possible Fe-chelators for the purpose [45–47]. Such mechanism of Fe-chelation is also investigated in this work by exploring formations of tautomers and examining their role for doing such metal chelation process (Fig. 3). To achieve this aim, density functional theory (DFT) computations are performed as a benefit of employing computational tools for systematically investigating the models systems at the smallest molecular and atomic scales [48–50]. In recent years, several procedures of computer-based approaches have been developed to provide insightful information especially for the complicated living systems prior to performing experiments [51–53]. The required results of investigated models were prepared to reach the goal of this work to show tautomerism processes and possible mechanism of metal chelation by formations of Fe-decorated TC compounds (Table 1 and Figs. 1–3).

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Fig. 3

Optimized configurations of FeTC models, bond distances, NBO atomic charges, HOMO and LUMO distribution patterns and ESP surfaces.

To approach the goal of this work, formations of tautomers of TC were investigated by performing DFT calculations at the level of B3LYP/6-31G^* using the Gaussian program [54]. Four optimized compounds were evaluated assigning by TC1-4, in which their configurations are shown in Fig. 2. By doing such calculations, four compounds of TC were available for participating the Fe-chelation processes resulting FeTC1-4 models as shown in Fig. 3. Individual optimization calculations were performed for the original TC and FeTC compounds to obtain minimized energy geometries, in which such geometries were confirmed by performing additional frequency calculations avoiding the existence of any imaginary frequency. As a consequence, four original structure and four Fe-decorated structures were obtained for the models of this work (Figs. 2 3). For evaluating additional electronic and structural features, several types of energies were evaluated including total energy (TE), deformation energy (DE) and chelation energy (CE) for the models. Moreover, frontier molecular orbitals features including energy levels of the highest occupied and the lowest unoccupied molecular orbitals (HOMO and LUMO) were obtained besides visualizing their distribution patterns. For showing variations of energy distances between HOMO and LUMO, energy gap (EG) was also evaluated. Electrostatic potential (ESP) surfaces, natural bond orbital (NBO) atomic charges and values of dipole moment (DM) were evaluated for the optimized models systems. All obtained quantitative values were summarized in Table 1 and all visualization were represented in Figs. 1–3 for further analyzing the electronic and structural features of tautomers and Fe-decorated models of TC compounds.

3 Results and discussion

Thiocytosine (TC) (Fig. 1) was targeted in this work for exploring features of tautomerism and Fe-chelation processes at the smallest molecular and atomic scales based on DFT calculations. Four models were obtained by performing optimization processes according to the movement of one hydrogen atom of amine group among two amine groups and one thio group (Fig. 2). As a consequence, existence of possible models of TC was recognized for participating in further investigations and analyses. TC1 and TC2 are thio conformations and TC3 and TC4 are thiol conformations as a result of thio-thiol conversion of tautomerism processes. In this case, stabilities of the resulted compounds were different by obtaining different values of total energies (TE) as listed in Table 1. TC3 was the most stable structure and TC1, TC4, and TC2 were placed at the next stabilities, respectively. Values of deformation energy (DE) were obtained by energy differences of between each conformation and the most stable conformation (TC3), in which the largest deformation was seen for TC2 model.

Analyses of energy values of HOMO and LUMO and also their differences could show significance of tautomerism processes for prturbating the molecular orbital features, in which different results were obtained for the investigated tautomers in both of magnitudes and distributions of HOMO and LUMO features. It is important to mention here that the levels of HOMO and LUMO and their localization at the molecular sites could define the tendency of a molecule for contributing to communications with other substances through formations of intermolecular interactions. In this regard, the level of HOMO could imply for tendency of a molecule for electron donating and the level of LUMO could imply for tendency of a molecule for electron accepting. Parallel to this concept, localization of HOMO and LUMO at the molecular site could indicate the path of molecule for contributing to such communications with other substances.

Formations of tautomeric conformations indicated that such tendency of molecular system was changed regarding the changes of hydrogen atom position, in which such changes were almost significant for estimating the position of molecule for participating in Fe-chelation. Higher concentration of localization of HOMO pattern was seen at the left side of molecule involving thio-thiol groups besides the neighboring amine groups. In this case, Fe-chelation could be expected to be occurred from this side of TC molecules in all four tautomeric forms. Moreover, yellow-red colors of ESP could show negative parts of molecules for candidating atomic sites to be involved in Fe-chelation mechanism and process. Other green-blue colors of ESP could show neutral and positive parts of the molecule. Indeed, this is an advantage of performing such quantum calculations to analyze electronic and structural features of the models prior to involving them in further processes as a type of computer-aided drug design. As a consequence, four models of TC were prepared in this part by more or less significant features for involving in next Fe-chelation processes. It is important to mention that the structural deformations could be also seen by different values of dipole moments (DM) affirming changes of electric charge distributions of the structures in different tautomeric conformations of TC.

As indicated by achievements of formations of TC tautomers, four models of Fe-chelation processes were expected for the models yielding FeTC1-4 as shown in Fig. 3. Hydrogen atom is a very slight atom with one electron only, but its movement among other atomic sites in tautomerism process could put significant impacts on variations of electronic and structural features as could be seen by changes of bond distances and NBO atomic charges in addition to the obtained values of TE. The models were obtained by performing optimization calculations for relaxing each of Fe and TC counterparts towards each other. Parallel to the original TC compounds, FeTC3 was found to be the most stable Fe-chelated structure; however, the order of other were changed in a new arrangement of FeTC4, FeTC1, FeTC2 showing impact of the hydrogen movement for yielding structural variations. As could be seen by the optimized bond distances and NBO charges, significant changes were found for the FeTC models in comparison with each other or with the original TC models. Values of DE of Table 1 could show energy magnitudes of such structural variations, in which the results affirmed the strength of FeTC3 model for the highest stability whereas that of FeTC2 model for the lowest stability. As a consequence, such results indicated that the models could be achieved by different structural and electronic features. The results here could emphasize on a point that the thiol tautomeric conformations could win the Fe-chelation competition better than the thio tautomeric conformations. In this regard, dominant roles of tautoemers for doing functions in biological systems could be known with their different tendency for participating in Fe-chelation processes. Further analyses of the obtained results could show variations of levels of HOMO and LUMO and their distances emphasizing on the capability of detection of Fe-chelated systems by measuring such changes of electronic features for molecular orbital levels. For sensor purposes, such measurement could provide a tool for detection of existence of Fe in the environment even its concentration. Therefore, such Fe-chelation process could be investigated for an additional role of TC for sensing of existence of Fe in the media. Values of DM affirmed also variations of features for the investigated models with more or less significant features. Localizations of HOMO and LUMO patterns in addition to ESP surfaces all approve formations of Fe-chelated systems for TC tautomers. There is a point to be mentioned here that the process of Fe-chelation could be done by combinations of TC tautomers with more or less significant strength revealing the role of TC for participating in such Fe-chelation processes.

4 Conclusion

In this work, details of Fe-chelation processes were investigated by assistance of formations of tautomers of TC, in which the results affirmed such capability for whole TC tautomers. Movement of one hydrogen atom among two amine groups and thio group yielded four tautomers with different stabilities, in which TC3 thiol tautomer was proposed as the structure with the highest stability. Analyzing obtained bond distances and NBO atomic charges indicated significant impacts on the structural and electronic features of the tautomeric models showing the dominant role of tautomers for doing functions in the biological systems. Further analyzing the results indicated variations of features for FeTC models with the highest strength of Fe-chelation process for FeTC3 model among all four models. Moreover, molecular orbital features of the original TC compounds showed the possible positions and atomic sites of TC for contributing to Fe-chelation processes in a predictive mode. As a consequence, the results of recognized models were in agreement with the earlier results of the original models. Variations of HOMO and LUMO features made possible a way of detection of existence of Fe in the media in addition to formations of chelated structures. As a consequence, the achievements of this work proposed TC models suitable for contributing to Fe-chelation processes.