DFT Study of Tautomeric Equilibria of 6-Hydroxy--Flourocytosine

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1 DFT Study of Tautomeric Equilibria of 6-Hydroxy--Flourocytosine BEHZAD CHAHKANDI, SOROUR HASANI Department of Chemistry Islamic Azad university,shahrood branch Tehran Street, Shahrood IRAN Abstract:-Tautomerism is of interest to many chemists and biologist.one sides of its importance is about nucleotid bases beacause tautomerization of nucleotid bases is one of possible causes of mutations in DNA.Tautomerization of 6-Hydroxy-5-Flucytosine(OHFC) that is one of the important and new metabolites of Flucytosine,an antifungal agents,were studied by using of quantum calculations at B3LYP level with the 6-31G* and 6-31G** basis sets. Optimized geometries and total energies for 17 possible tautomers of OHFC in the gas phase were determined and also thermodynamic properties ( for tautomeric equilibria between different tautomers were calculated with the frequency calculations.all calculations were performed at 298K and 1 at. Calculations of energies for these tautomers defined that OHFC14 is the most stable tautomer and it s energy is at the highest level and the most unstable tautomer is OHFC6 that has energy of Hartree.In any case,30 tautomeric equilibria were considered between 17 tautomers. Considering of tautomeric equilibria defines that equilibrium OHFC2 OHFC5(T7)) is the most stable equilibrium and it s is Kcal/mol. Key-Words: Tautomerism, 6-Hydroxy-5-Flucytosine, Nucleotid bases, Antifungul, Mutation, Metabolite.. 1 Introduction Tautomerism as one of the possible mechanism of mutation in DNA, has extended area for studies.therefor different theoretical and experimental studies were performed on this process[1]. Nucleic acids are polymer molecules composed of two kinds of bases, purine, and pyrimidine [2]. The parent structure for all purine contains a 6-membered imidazol (3 carbon : 2 nitrogen). Pyrimidines are closed ring organic compounds [3]. The purines include Adenin and Guanin the pyrimidines include thymine, cytosine and uracile [4]. Unique pyrimidines are formed by the addition of aunique side groups [5].In fact understanding of the hysicochemical properties and tautomeric behavior of purine and pyrimdine bases of the nucleic acids is of fundamental importance not only in relation to qualitative concepts of chemical binding and physical chemistry but also in relation to molecular biology and the presumed role of the so-called rare tautomers in mutagenesis[6]. Cytosine is the most unstable of DNA bases, deaminating to uracil with an ISSN: ISBN:

2 activation energy of kjmol -1 [7] there are different pyrimidine analoges used as prodrug for treatment of cancers like 5-flourouracile (fu) and 5-flucytosine that uses as antifungal agent [8]. At first flucytosine was synthesized in It is 4-amino-5-fluoro -2(1H)-pyrimdone[9].5FC itself has no antifungal activity. analysis of human biofluids by martino on patients who were treated by FC, provided the new information about the metabolism of FC in human [10]. Two compounds involving a direct metabolism of 5-FC were found that one of them is OHFC. Ab initio calcutions were performed on the tautomers of cytosine and flucytosine. One of these calcutions was water-mediated tautmerization of cytosine to the rare imino form that performed by geza fogarasi [11]. This investigation indicated that cytosine has 3 primery low energy forms. The amino-oxo (keto) tautomer is the canonical form, present in DNA in the gas phase, the amino hydroxy (enol) struture dominates. The imino-oxo tautomer is considered as the rare form, calculations with CCSD(T) method give following relative energies to enol form : E (keto)=1/2-1/6 kcalmol -1, E (imino-oxo)=1/3-2/1 kcalmol -1.[12]In the present work, optimized geometries of 17 possible tautomers of OHFC will be studied with the DFT quantum calcutaions at the 6-31G*, 6-31G** basis set levels and also 30 tautomeric equiblira are considered according to The presence of 17 possible tautomers. Thermodynamic properties of these equilibria will be calculated with the frequency calculations. According to the results, the most stable and unstable tauotomers and equilibrium will be investigated. 2 Computational Methods Fig.1In this paper for determinating of optimized geometries and energy of different tautomers of OHFC quantum calculation of DFT were used at B3LYP level with the 6-31G*, 631G** basis sets. The thermodynamic properties of tautomeric equilibria of OHFC were obtained by using of the frequency calculation at B3LYP level and 6-31G*, 6-31G* basis sets. All calculations were carried out by using Gussian Results and Discussion The 6-31G** optimized geometries and tautomeric equilibria process of OHFC are shown in scheme2. The optimized primary form of OHFC is shown in fig.1. According to that atom (H) is moving between which two atomis, we consider structural models of CO,CN,NN,NO that order of these models gives in scheme1. We mention the tautomers, From OHFC11 to OHFC17 and the equilibria, from T1 To T30. Schem 1. equilibria based on models (CO,CN,NO,NN) Tautomeric Structural CO CN NO NN T5 T3 T1 T16 T8 T12 T7 T2 T18 T9 T13 T17 T23 T19 T26 T14 T22 T4 T20 T28 T15 T25 T6 T21 T30 T10 T14 T11 T27 T Relative Stabilities The total energies corresponding to these structures, calculated with 2 basis sets at the B3LYP level are reported in table 1. Results show that the most stable tautemer is OHFC14 and its energy is-569/ Hatree and the most unstable tautome is OHFc6 and it s energy is 569/34064 Hartree. Relative energies of these 17 tautomers to OHFC14 are obtained. these results are given in table 2. according to these amounts, the most stable tautomer to OHFC14 is OHFC9 and the most unstable tautomer to OHFC14 is OHFC6. E (OHFC9)=-2/51317 kcalmol -1 E (OHFC4)=-41/41249 kcalmol -1 ISSN: ISBN:

3 Table 1. Total energies(hartrees)for optimized geometries atb3lyp level. Tautomers B3LYP/6-31G* B3LYP/6-31G** OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC Table2.relative stabilities(kcal/mol) for 17 Tautomers. Tautomers B3LYP/6-31G* B3LYP/6-31G** 0HFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC OHFC13 OHFC OHFC OHFC OHFC Thermodynamic Properties Thermodynamic properties ( G, H, E) were and + calculated according to values.in fact for calculating of + ( G, H, E) of each equilibrium we take the of the + and + difference of reactant and the products of each reaction. the most G and H is for (T7) OHF5 OHFC2.The least G is for T26 (OHFC16 OHF 17) that is Kcalmol -1. All quantieties at G and H are agree with E that are given in table 3.the results of stability of euilibria from ( G, H, E) at two basis set levels are the same. ISSN: ISBN:

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5 Table3.Thermodynamic properties for equilibria in(kcal/mol) Tautomeris m equbliria T T T T T T T T T T T T T T T T T T T T T T T T T T T T T T ISSN: ISBN:

6 5 conclusion All results show that OHFC14 is the most stable tautomer that has energy of andohfc6 is the less stable tautomer and its energy is Hartree.In (OHFC2 OHF5)has the negative value for G.With comparison of relative energies of tautomers, order of stabilities of tautomers is following: [9] Polak A, Eschenhoff E, Fernex M, Scholer HJ. Metabolic studies with 5-fluorocytosine-6-14C in mouse, rat, rabbit, dog and man. Chemotherapy 1976;22: [10]G. Fogarasi, J. Mol. Struct (1997) 271. [11] R. Kobayashi, J. Phys. Chem. 102 (1998) [12] M.D. Topal, J.R. Fresco, Nature 263 (1976) OHFC14>OHFC9>OHFC11>OHFC2>OHFC1> OHFC3>OHFC15>OHFC10>OHFC7>OHFC13 > OHFC16>OHFC12>OHFC17>OHFC8>OHFC4 >OHFC5>OHFC6. And the order of stability for these equilibria is this: T7>T6>T27>T29>T18>T9>T16>T23>T20>T3 >T11>T5>T14>T19>T24>T10>T13>T30>T25> T21>T12>T8>T4>T22>T17>T15>T28>T2>T1 >T26. And according scheme2 we can say that innn model the most stable equilibria is T9 and about NO case is T6,in the case of CO the most stable equilibria is T5 and finallaly about CN structural model it is T7. References: [1] J. S. KWIATKOWSKRI., J. B A R T L ~an,d W. B. PERSONJ.. Am.Chem. Soc. 110, 2353 (1988). [2] J.D. Watson, F.H.C. Crick, Nature 171 (1953) [3]Heterocyclic Chemistry (3rd Edition) Thomas. L. Gilchrist. [4]Organic Syntheses, Coll. Vol. 4, p.182 (1963); Vol. 35, p.34 (1955). [5]Organic Syntheses, Coll. Vol. 4, p.336 (1963); Vol. 35, p.58 (1955). [6]Organic Syntheses, Coll. Vol. 4, p.638 (1963); Vol. 35, p.80 (1955). [7] C. Flinn, R.A. Poirier, and W.A. Sokalski. J. Phys. Chem. A,107, (2003). [8] Diasio RB, Lakings DE, Bennett JE. Evidence for conversion of 5-fluorocytosine to 5-fluorouracil in humans: possible factor in 5- fluorocytosine clinical toxicity. Antimicrob Agents Chemother 1978;14: ISSN: ISBN:

J.Phys. & Theo.Chem.I.A.U. Iran M.Monajjemi et al. Vol.4, No.1, Spring 2007

J.Phys. & Theo.Chem.I.A.U. Iran M.Monajjemi et al. Vol.4, No.1, Spring 2007 Journal of Physical & Theoretical Chemistry Islamic Azad University of Iran 4 (1) (27) Science and Research Campus ISSN: 1735-2126 AB Initio Calculations and IR Studies of Tautometric forms of Uracil and