5–Fluorouracil: Computational Studies of Tautomers and NMR Properties

Turkish Computational and Theoretical Chemistry Turkish Comp Theo Chem (TC&TC) Volume(Issue): 1(1) – Year: 2017 – Pages: 27-34 Received: 04.05.2017 Accepted: 07.05.2017 Research Article 5–Fluorouracil: Computational Studies of Tautomers and NMR Properties Mahmoud Mirzaei1 a Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran Abstract: Chemical computations were performed to investigate stabilities and properties for tautomers of 5–fluorouracil (5FU). In addition to optimized properties, nuclear magnetic resonance (NMR) parameters were calculated for all atoms of the stabilized structures. Di–keto form of 5FU is the most stable structure and keto–enol and di–enol structural forms are tautomeric structures. According to the results, the polar and non-polar solvents media and tautomeric forms are both important in characterizing 5FU structures. Keywords: 5–Fluorouracil; Tautomer; Chemical computations; Density functional theory; Chemical shift. 1. Introduction 5–Flourouracil (5FU), as an anticancer drug, is a fluorinated derivative of uracil nucleobase with the fluorination of carbon number five of pyrimidine ring [1]. 5FU has been used for therapies of several types of cancers for years; however, the side effects are still a considerable problem for this popular anticancer drug [2, 3]. Formations of tautomeric structures commonly for heterocyclic structures could be one of the reasons for appearing the side effects [4]. Tautomers are formed by the exchange of hydrogen atoms between nitrogen and oxygen atoms of the heterocyclic ring making high energetic unstable structures ready to destroy the neighborhood systems [5, 6]. Tautomers are also origins of mutations in genetics yielding several defects to living systems [7]. Considerable efforts have been dedicated to characterize and identify various aspects of tautomers especially for biological related counterparts up to now [8 – 11]. Computations are one of the proper techniques for systematic investigations of stabilities and 1 properties for tautomeric systems at the atomic and molecular scales [12]. Characterizations of tautomers of 5FU and other uracil derivatives are interesting for the scientists due to their importance in the living systems [13 – 16]. Within this work, we have performed quantum chemical computations to investigate the stabilities and nuclear magnetic resonance (NMR) properties of tautomers of 5FU in different solvent systems. According to the results of earlier works, 5FU could participate in tautomerization process similar to uracil nucleobase, in which the di–keto form is the most stable structure. Tautomers could be in keto– enol and di–enol forms according to the exchange of hydrogen positions between nitrogen and oxygen atoms. Although the di–keto form has been seen as the most stable one, but the existence of keto–enol and di–enol tautomers are still possible (Fig. 1) [17]. Chemical environments could employ effects on the initial properties of matters especially presence of hydrophobic or hydrophilic solvents. Hereby, effects of five solvents including water, methanol, ethanol, chloroform, and carbon Corresponding Author e-mail: 27 Turkish Comp Theo Chem (TC&TC), 1(1), (2017), 27 – 34 Mahmoud MIRZAEI tetrachloride have been investigated on the properties of 5FU and its tautomers within current research. In fact, the major question of this work is to investigate the properties of 5FU and tautomers in the conventional and mostly used solvent media. 2. Computational Details Density functional theory (DFT) calculations have been performed employing the B3LYP exchange–correlation functional and the 6–31G* standard basis set as implemented in the Gaussian 98 package [18]. First, the investigated molecular structures of 5FU including di–keto (Fig. 1, Panel a), keto–enol (Fig. 1, Panels b – e), and di–enol (Fig. 1, Panel f), totally six forms, have been optimized to achieve the optimized structures corresponding to minimum energies. Next, the presence of five conventional and mostly used solvents including water (H2O), methanol (MeOH), ethanol (EtOH), chloroform (CHCl3), and carbon tetrachloride (CCl4) have been considered in the calculations of atomic and molecular properties. The molecular properties including total energies, dipole moments, and energies for the highest occupied and the lowest unoccupied molecular orbitals (HOMO and LUMO) have been evaluated in different solvent systems (Table 1). Furthermore, chemical shielding (σiso) tensors have been calculated for the atoms of optimized structures based on the gauge–included atomic orbital (GIAO) approach [19] and they have been converted to chemical shifts (δ /ppm) using equation of δ = σiso, reference – σiso, sample (Tables 2 – 6). To obtain magnitudes of σiso, reference , tetramethylsilane (TMS) has been used for C and H atoms, ammonia (NH3) has been used for N atoms, and water (H2O) has been used for O atoms, details of evaluations are described elsewhere [20]. Nuclear magnetic resonance (NMR) spectroscopy is among the most versatile techniques to investigate the properties of matters especially in living systems [21]. Chemical shielding tensors are originated from the electronic sites of atoms capable of detecting any perturbations employed to these sites. It is worth noting that, the molecular properties (Table 1) are not enough to recognize the characteristics of matters whereas NMR properties could reveal insightful information at the atomic scale to better achieve the purpose [22, 23]. Due to the complexity of experiments, computations could predict or interpret the characteristics of matters, especially for unstable tautomeric structures. The combinations of results of molecular (Table 1) and atomic (Tables 2 – 6) parameters could very well describe the properties of investigated 5FU models (Fig. 1). 3. Results and Discussion The models of this work include various forms of 5FU including the initial di–keto form and the keto–enol and di–enol tautomers (Fig. 1). For a quick description of models, nitrogen atoms numbers one and three have their original hydrogen atoms in the initial di–keto form (Panel a, Fig. 1). To make the tautomers, first the position of hydrogen atom number one has been exchanged to oxygen atom number two then atom number four to make the keto–enol forms (Panels b and c, Fig. 1). Afterwards, the hydrogen atom number three has been exchanged to oxygen atom number two then atom number four to make the second set of keto– enol forms (Panels d and e, Fig. 1). For the di–enol form (Panel f, Fig. 1), both of hydrogen atoms have been exchanged to oxygen atoms to make the third set of tautomers for the investigated 5FU. 28 Turkish Comp Theo Chem (TC&TC), 1(1), (2017), 27 – 34 Mahmoud MIRZAEI Figure 1. (a) Di–keto, (b) – (e) keto–enol, and (f) di–enol forms of 5FU The optimization processes indicated that the magnitudes (...truncated)