Accepted Manuscript

Title: 2,4-Ditellurouracil and its 5-fluoro derivative:

Theoretical investigations of structural, energetics and ADME
parameters

Authors: Ibrahim A. Alswaidan, Kritish Sooknah, Lydia

Rhyman, Cemal Parlak, Derek T. Ndinteh, Mohamed I.
Elzagheid, Ponnadurai Ramasami

PII: S1476-9271(16)30288-2
DOI: http://dx.doi.org/doi:10.1016/j.compbiolchem.2017.02.002
Reference: CBAC 6646

To appear in: Computational Biology and Chemistry

Received date: 11-6-2016

Revised date: 17-12-2016
Accepted date: 2-2-2017

Please cite this article as: Alswaidan, Ibrahim A., Sooknah, Kritish, Rhyman,
Lydia, Parlak, Cemal, Ndinteh, Derek T., Elzagheid, Mohamed I., Ramasami,
Ponnadurai, 2,4-Ditellurouracil and its 5-fluoro derivative: Theoretical investigations
of structural, energetics and ADME parameters.Computational Biology and Chemistry
http://dx.doi.org/10.1016/j.compbiolchem.2017.02.002

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<AT>2,4-Ditellurouracil and its 5-fluoro derivative: Theoretical investigations of
structural, energetics and ADME parameters
<AU>Ibrahim A. Alswaidana, Kritish Sooknahb, Lydia Rhymanb, Cemal Parlakc, Derek
T. Ndintehd, Mohamed I. Elzagheide, Ponnadurai Ramasamib,f*
##Email##ramchemi@intnet.mu##/Email##
<AFF>aDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud
University, Riyadh 11451, Saudi Arabia
<AFF>bComputational Chemistry Group, Department of Chemistry, Faculty of Science,
University of Mauritius, Rduit 80837, Mauritius
<AFF>cDepartment of Physics, Science Faculty, Ege University, Bornova, Izmir, 35100,
Turkey
<AFF>dDepartment of Applied Chemistry, University of Johannesburg, P.O. Box 17011,
Doorfontein, Johannesburg 2028, South Africa
<AFF>eDepartment of Chemical and Process Engineering, Jubail Industrial College,
Jubail Industrial City 31961, Saudi Arabia
<AFF>fDepartment of Applied Chemistry, University of Johannesburg, P.O. Box 17011,
Doorfontein, Johannesburg 2028, South Africa
<ABS-Head><ABS-HEAD>Graphical abstract
<ABS-P>
<ABS-P><xps:span class="xps_Image">fx1</xps:span>
<ABS-HEAD>Highlights Tautomers of 2,4-ditellurouracil and 5-fluorotellurouracil
were studied using DFT method. The keto-enol tautomerism was studied in the gas
phase. The diketo form is the most stable tautomer. Substitution of hydrogen by
fluorine causes a decrease in the interconversion barriers. The ADME parameters of
the most stable diketo and dienol tautomers were predicted.
<H1>4 <ABS-HEAD>Abstract
<ABS-P>2,4-Ditellurouracil exhibits keto-enol tautomerism via different pathways
resulting in seven tautomers. These pathways were studied in the gas phase using density
functional theory method. The functionals used were BLYP, B3LYP and BHLYP and the
basis sets were 6-311++G(d,p) for all atoms except that LanL2DZ ECP was used for
tellurium atom only. The results indicate that the diketo form is more stable as observed
for uracil and its sulfur and selenium analogues. The effect of introducing fluorine at
position 5 was also investigated and the energy difference between the diketo and dienol
forms is reduced. 2,4-Ditellurouracil and its 5-fluoro analogue are expected to exist
exclusively as the diketo form due to the high interconversion energy barrier. We
extended the investigation to predict ADME parameters of the most stable diketo and
dienol tautomers in view of understanding their biological properties. This research
enlightens keto-enol tautomerism of 2,4-ditellurouracil and its 5-fluoro derivative with
additional insights to biological functions.
<KWD>Keywords: keto-enol tautomerism; tellurouracil; DFT; COSMO-RS; ADME

<H1>1. Introduction
Nucleic acids represent one of the most outstanding breakthroughs in biology since the
discovery of the structures of DNA and RNA. Uracil is one of the pyrimidine bases found
in RNA which forms base pair with adenine and thereby, substituting thymine of DNA

1
during the transcription mechanism. Uracil is important in the body as it aids in the
production of enzymes and other proteins [1]. It is also involved in the biosynthesis of
polysaccharides [2]. Substituted nucleic bases have received considerable attention due to
their various pharmacological, biochemical and biological capabilities [3-7]. Halogenated
pyrimidines have been synthesised and used as potential anti-tumor [8,9], anti-bacterial
[10,11] and anti-viral agents [12,13]. Their incorporation into DNA and RNA increases
the sensitivity of these biomolecules to ionising radiation such that the replication process
in tumor cells is halted. Among the 5-monohalogenated derivatives of uracil, fluorine is
similar in size to hydrogen and when it is substituted in uracil, 5-fluorouracil is formed
and it was first introduced in medicine in 1957 [14]. This transformation alters the
chemistry of uracil significantly and it inhibits enzymes from replicating. Consequently,
it prevents the growth of cancerous cells and hence, 5-fluorouracil is a widely used drug
in oncology and is also recognised as effective treatment of modalities [15].
In 1965, Lipsett [16] detected the presence of sulfur in natural tRNA and these
substituted compounds possess biological activities. In view of this fact, substitution of
oxygen by heavier atom in DNA has gained considerable attention [17] and several
sulfur-substituted bases have been used as drugs [18]. 2,4-Dithiouracil was found to be a
melanoma-seeking agent owing to its specific incorporation in nascent melanin [19].
Sulfur-substituted purines and pyrimidines have also found applications in clinically
useful drugs [20]. Selenium is the other member of the chalcogen group which was
regarded as highly toxic element until it was found in microorganisms and other species
[21]. Selenocysteine was discovered as the 21st amino acid whereby it acts as a co-factor
for reduction of anti-oxidant enzymes [22,23]. Tellurium faced the same prejudice as
selenium in terms of drugs capabilities until the biological activities of tellurium
compounds were proven [24,25]. Tellurium compounds have been employed as drugs in
the treatment of several diseases such as syphilis, leprosy, sickle cell anemia, AIDS. They
are also used as anti-bacterial agents [26].
Uracil is known to exhibit tautomerism and studies conducted both experimentally and
theoretically to evaluate the relative stabilities of the keto-enol tautomerism [27-30] as
illustrated in Scheme 1. Tautomerism plays an important role from the medicinal and
pharmacological point of views [31] as it is useful in understanding mutation which may
occur during DNA replication. Studies have been carried out in the gas phase, solid state
and in solution in order to investigate the behaviours of uracil and its tautomers [32-35]
during the proton transfer process. It was found that the diketo-form is the most stable
tautomer [27,28]. Similarly, tautomerism in thiouracils [36] and selenouracils [37] were
investigated and in general the diketo form is more stable.
To the best of our knowledge, tautomerism involving 2,4-ditellurouracil has not been
studied and this was the basis of our investigation of this compound and its 5-fluoro
derivatives. The title compounds and their tautomers were studied in the gas phase using
density functional theory (DFT) method so as to obtain their structural and spectroscopic
parameters. Some of the physicochemical and biological parameters for the most stable
tautomers were also calculated. The findings of this research are hereby reported and
compared with other uracil analogues.
<H1>2. Computational Methods

2
The notations used for the tautomers and rotamers of ditellurouracil, denoted as TeU, are
based on Figure 2. The name of tautomer is derived from the atom numbering connected
to a hydrogen atom while for the rotamer, the position of the hydrogen of each OH group
is distinguished by subscript ``1'' or ``2'' such as 21,41-TeU and 22,41-TeU. 2,4-
Ditellurouracil (1,3-TeU), its possible tautomers (1,22-TeU, 21,3-TeU, 1,41-TeU, 21,41-
TeU, 22,41-TeU and 3,41-TeU) due to proton transfer and transition state structures
(TS(1,22 1,3), TS(21,31,3), TS(1,31,41), TS(1,4121,41), TS(21,4122,41) and
TS(22,413,41)) are illustrated in the energy profile of Figure 1. The 5-fluoro analogues
are also illustrated in Figure 2 and the acronym F is added, signifying that fluorine is
located at the 5-position. All the structures were fully optimised in the Cs symmetry in the
gas phase. The transition states involved during tautomerisation were also modeled. The
geometries were optimised using the hybrid DFT with three different functionals,
namely;
(a) Becke (B) half and half exchange functional (H) with Lee-Yang-Parrs correlation

functional (LYP) non-local correlation functional (BHLYP),

(b) Beckes three-parameter hybrid exchange (B3) with the LYP correlation

functional (B3LYP),

(c) Beckes 1988 exchange functional with LYP correlation functional (BLYP).

The basis sets employed for all atoms were 6-311++G(d,p) except that LanL2DZ ECP
was used for the tellurium atom only. All computations were carried out with the
Gaussian 09 program [38]. Frequency computations were performed by the optimised
structures in order to investigate the nature of the stationary points. All ground state
structures do not have imaginary frequencies while transition states have one imaginary
frequency. The energies were also corrected for zero-point energies (ZPE). The adiabatic
electron affinity (EA) and the adiabatic ionisation energy (IE) were determined at their
relaxed geometries as follows:
EA = [E(optimised neutral) + ZPE] [E(optimised anion) + ZPE] (1)

IE = [E(optimised cation) + ZPE] [E(optimised neutral) + ZPE] (2)

Optimised geometries were used to carry out conductor-like screening for real solvents
(COSMO-RS) calculations using COSMOtherm program [39]. ADME (Absorption,
distribution, metabolism, excretion) parameters were investigated for potential drug
activity. These parameters include solubility, lipophilicity, intestinal absorption, and
blood brain coefficient.
<H1>3. Results and discussion

The results of the electronic computations on the structural parameters are reported and
discussed. This is followed by analyses of the dipole moments, tautomer stability,
electron affinity and ionisation potential, COSMO-RS calculations, physicochemical and
physiological properties.

3
<H2>3.1 Structural parameters

The interconversion of the tautomers of 2,4-ditellurouracil and its 5-fluoro derivatives are
shown in Figures 1(a) and 1(b). The structures and atom labelling of 1,3-TeU, 21,41-TeU,
1,3-TeU-F and 21,41-TeU-F are displayed in Figure 2. The structural parameters of 1,3-
TeU, 1,41-TeU, 21,41-TeU, 21,3-TeU, 1,3-TeU-F, 1,41-TeU-F, 21,41-TeU-F and 21,3-TeU-
F are summarised in Tables SI1-2 (SI=supplementary information). An analysis of the
data from Tables SI1 and SI2 indicates that there is only a slight difference among the
optimised structural data obtained from the three functionals used. It is worth pointing out
that the structural features of the 2,4-ditellurouracil derivatives are in accordance with
known experimental data of their analogous uracil [40], 2,4-dithiouracil [20] and 2,4-
selenouracil [37] except for those parameters where the tellurium atom is involved. The
length of C-F bond is found to be longer in 5-fluorotellurouracil compared to 5-
fluorouracil where the experimental C-F bond length is 1.348 [41]. Moreover, the
telluro-tellurol tautomerisation is accompanied by significant changes whereby the C-Te
bond length is increased while the other bond lengths and bond angles of the pyrimidine
ring are decreased except that a pronounced elongation of the C5-C6 double bond is
observed. The decrease of the structural parameters may be interpreted by the increasing
aromatic character of the pyrimidine ring. Another trend observed is that the C2-Te2
bond length which is systematically shorter compared to the C4-Te4 bond length in the
2,4-ditelluro compounds. This observation can be explained based on electronegativity
enhanced by the nitrogen atoms. The C2 is more electronegative than C4 as it is
sandwiched between the two nitrogen atoms, resulting in greater polarisation of C2
around the Te and thus, resulting in shorter bond length.
<H2>3.2 Dipole moment

Dipole moment is useful as a parameter in drug-receptor interaction as studied through

quantitative structure-activity relationship [42]. The dipole moments of the 2,4-
tellurouracil and 5-fluorotellurouracil tautomers are reported in Table 1.
The calculated dipole moments show little sensitivity to the functionals employed. For
both compounds, tautomer 21,41-TeU has the smallest dipole moment while the dipole
moment of the 1,22-TeU is the largest.
<H2>3.3 Tautomer stability

The relative energies with zero-point corrections of all the tautomers considered are
included Figures 1(a) and 1(b). As has been previously noted for uracil, thiouracil, and
selenouracils, the tellurone form 1,3-TeU is most stable. The energy difference between
1,3-TeU and the other tautomers is large. So it can be affirmed that this form can exist
almost exclusively in the gas phase as there would be a loss in stability changing from
one form to another. The activation barriers for the tautomerisation reactions are high and
thus, only tellurone form 1,3-TeU is found in the gas phase. Tautomers 21,41-TeU and
22,41-TeU are among the stable tautomers. This can be explained by the tendency of the
pyrimidine ring to adopt the aromatic structure and hence gain stability through
resonance. Tautomer 21,3-TeU is equally stable as tautomers 22,41-TeU or 21,41-TeU and
21,3-TeU is always more stable than 1,22-TeU. The lower stability of tautomer 1,22-TeU
can be explained by taking into consideration the repulsive interactions between the lone

4
pair of electron on the N3 atom and the lone pairs of tellurium. Hence the activation
barrier connecting the global minimum with 21,3-TeU is 6.20 to 6.44 kcal mol-1 lower
than that connecting the global minimum and 1,22-TeU. Tautomer 1,22-TeU is also lower
in energy than 3,41-TeU. In 1,41-TeU there is a stabilising non-bonded interaction
between the hydrogen atom of the Te-H group and lone pair of electron on the N atom. In
3,41-TeU there is a repulsive interaction between the hydrogen atom of the Te-H group
and the hydrogen attached to the N atom. Tautomers 21,41-TeU and 21,3-TeU are very
close in energy and have an energy gap of 0.48-0.73 kcal mol-1. This can be interpreted
by the tendency of the pyrimidine ring to adopt the aromatic structure. Tautomer 21,3-
TeU is more stable than 1,41-TeU and the tautomerisation barriers indicate that the
formation of tautomer 21,3-TeU is thermodynamically and kinetically favored compared
to tautomer 1,41-TeU. The analysis of the activation energies for the transition states
show that TS (1,321,3) is more stable than TS (1,31,41) by 2.63-2.93 kcal mol-1.
The energy barriers are not sensitive to the electron functions employed in the DFT
computations, as the change in the activation energy is marginal and the relative energies
decrease in the order BHLYP > B3LYP > BLYP.
On comparing the energy profile of 2,4-tellurouracil (TeU) and its 5-fluoro derivative
(TeU-F), a similar trend is observed. 1,3-TeU-F is still the global minimum on the
potential energy surface and the activation energies are still quite high. In general, it can
be observed that substitution of hydrogen by fluorine causes a decrease in the activation
energies. The energy difference of tautomers 21,41-TeU-F and 22,41-TeU-F is small
(0.98-1.81 kcal mol-1) compared to tautomer 1,3-TeU-F. Thus, interconversions between
these 3 tautomers are possible in the gas phase. The gain in stability can be explained by
the fact that fluorine further increases the aromatic nature of the pyrimidine ring of
structures 21,41-TeU-F and 22,41-TeU-F.
The effects of substituting oxygen in uracil by sulfur, selenium or tellurium follow a
similar trend except that a decrease in the energy gaps and tautomerisation barriers are
observed down the chalcogen group (Table 2).
Diketo, dithio, diseleno and ditelluro forms are found to be most stable. Derivative 21,3-
TeU of uracil was found to be the second most stable tautomer. For thiouracil, the
inclusion of ZPE tends to change the relative stability of the second and third most stable
tautomer. This is also the case with selenouracil but DFT computations showed that 21,3-
TeU and 2,41-TeU-F are almost isoenergetic. For tellurouracil, the 21,41-TeU-F tautomer
is found to be the second most stable tautomer. The energy differences between 2,4-
ditellurouracil and tautomer 21,41-TeU are 6.4, 5.8 and 6.4 kcal/mol, for B3LYP, BHLYP
and BLYP functionals respectively. Hence, moving from uracil to tellurouracil leads to a
change in the usual trend observed. This is because the tellurium atom enhances the
aromatic character of the pyrimidine ring thereby stabilising it.
<H2>3.4 Electron affinity and ionisation potential

The EA and IP were calculated for tautomers 1,3-TeU and 1,3-TeU-F only. The results

are presented in Table 3.

Contrary to the IPs, the EAs change considerably with the use of the different functionals,
The EAs increase in the order BLYP > B3LYP > BHLYP for both tellurouracil and its 5-

5
fluoro derivative. All the EAs are positive. This shows that the anions are stable since
they are lower in energy than their corresponding neutral molecules. The substitution of
hydrogen by fluorine increases the EA to a great extent. These results show that ionised
5-fluorotellurouracil is expected to be the major site for electron capture in modified
nucleobases. This is consistent with suggestion that 5-halouracils enhance the sensitivity
of DNA and RNA to radiation through electron capture.
<H2>3.5 COSMO-RS calculations
In order to investigate the potential drug activity related parameters, COSMO-RS
calculations were carried out. Tautomers 1,3-TeU and 1,3-TeU-F are found to exist
exclusively in the gas phase and thus, they have been considered for COSMO-RS
calculations. The in silico calculations done to study the ADME related properties have
been classified into two categories, namely physicochemical properties and physiological
properties.
As these calculations are being performed with molecules not found in the COSMOtherm

database, 5-methyluracil which in the program database has been cited for comparison.

<H3>3.5.1 Physicochemical properties

<H4>3.5.1.1 -profile
The -profile plots of 1,3-TeU and 1,3-TeU-F including octanol and water are given in
Figure 3. These plots are useful to understand their behaviour in solvents and give a
detailed and vivid description of molecules polarity properties. It is observed that the two
tautomers have an asymmetric distribution of charges. This gives an indication on how
these compounds may interact in presence of specific solvents in solution. Water gives a
symmetric distribution while octanol gives an asymmetric distribution of charges. It can
be deduced that the compounds should be more soluble in octanol and other solvents
having asymmetric distribution of charges rather than water. The -coloured surface of
the tautomers can help in understanding the physicochemical behaviour of the drug
compounds towards potential dimerisation or agglomeration tendencies.
<H4>3.5.1.2 Solubility
Solubility in water is an important biological parameter. The absolute solubility of the

two tautomers in water was calculated at room temperature (298.15 K). The results are

collected in Table 4.

<H4>3.5.1.3 Lipophilicity
Lipophilicity is typically quantified as an estimated logP such as AlogP or ClogP. logP is
defined as the log(Poctanol/Pwater) and P is a partition coefficient for a given compound in a
specific solvent. The coefficient P determines the hydrophobic and hydrophilic nature of
compounds. P gives an indication if a compound may be prone to bioaccumulate in
membranes of living organisms. Lipids are the main constituents of biological
membranes, hence the term lipophilicity. Hence a high value of P will indicate that a
compound would be present in high concentration in membranes. The tables below give
the estimated values of logP. Note that both dry octanol and wet octanol have been
considered.

6
The results of the calculated octanol-water partition coefficients indicate that the two
tautomers are more hydrophobic than hydrophilic. This is in accordance with the -
profile plots. The tautomers have asymmetric charge distribution and hence prefer to be
surrounded by octanol which has an asymmetric charge distribution profile. In addition,
the tellurium atoms being large make the molecule hydrophobic and the replacement of
one hydrogen atom by fluorine also makes the molecules more hydrophobic. Analysis of
the data in dry octanol indicates that tautomer 1,3-TeU optimised with the BHLYP
functional has a negative value. This is not consistent with the -profile plots. However,
this outlying result can be explained by the fact with the BHLYP functional results are
constantly underdetermined as observed for other parameters.
<H3>3.5.2 Physiological properties
<H4>3.5.2.1 Intestinal absorption
Once a drug is ingested, it encounters several membranes such as gut wall, intestinal wall
and cellular membrane before reaching the target site. Hence, the drug bioavailability can
be limited. The permeability of the drug across the intestinal epithelium is an important
parameter to consider. The percentage absorbance across the intestine of the two
compounds studied was determined (Table 6). It is observed from the results that the two
tautomers pass quite easily across the lining of the intestine. Hence it can be said that
they would be available for cellular membranes found after the intestine in quite a large
amount.
<H4>3.5.2.2 Blood-Brain barrier permeability
The blood brain barrier consists of a complex system that acts as a checkpoint to regulate
the traffic of nutrients and substances that enter the brain from the blood. Drug molecules
are selectively allowed to enter the central nervous system through passive diffusion and
through active transporters. The relatively affinity for the blood or brain tissue of a drug
can be expressed in terms of the bloodbrain partition coefficient,
logP(BB)=log(Cbrain/Cblood), where Cbrain and Cblood are the equilibrium
concentrations of the drug in the brain and the blood respectively. Table 7 reports the
values of logP(BB) of the two tautomers. The tautomers appear to be unable to pass into
the brain via the blood. So, it can be deduced that they are not appropriate for
physiological system disorders.
<H1>4. Conclusions

Seven different tautomers of 2,4-ditellurouracil and 5-fluorotellurouracil were studied

theoretically using DFT method. The ditellurone form was found to be the most stable
tautomer. The energy difference with other tautomers was so large that it was concluded
that this form existed almost exclusively in the gas phase. The fluoro tautomers were
found to have lower energy than the corresponding ditelluro tautomer. It is observed that
the substitution of hydrogen by fluorine causes a decrease in the activation energies. In
silico computations were further done on the tellurone form and its fluoro derivative to
investigate potential drug activity. The COSMO-RS calculations show that the two
tautomers can be further investigated, most probably in vitro as potential drugs.
<H1>5. Acknowledgements

The authors acknowledge the facilities from their respective Universities. The authors
extend their appreciation to the Deanship of Scientific Research at King Saud University

7
for the research group Project No. RGP VPP-207. The authors acknowledge the
anonymous reviewers for their comments to improve the manuscript.
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</BIBL>
<Figure>Figure 1(a). Interconversion of the tautomers of 2,4-ditellurouracil (relative

energies are in kcal mol-1).

<Figure>Figure 1(b). Interconversion of the tautomers of 5-fluoro-2,4-ditellurouracil

(relative energies are in kcal mol-1).

<Figure>Figure 2. Structures and atom labelling of 2,4-ditellurouracil and its 5-fluoro

derivatives.
<Figure>Figure 3. Sigma profile for tautomers 1,3-TeU and 1,3-TeU-F.
<Figure>Scheme 1: Tautomerism of uracil

Tables
<Table>Table 1. Dipole moments (Debye) of the tautomers.
2,4-Ditellurouracil (TeU)
Functional
21,3-TeU 1,22-TeU 1,3-TeU 1,41-TeU 21,41-TeU 22,41-TeU 3,41-TeU
B3LYP 4.334 8.010 4.811 6.784 1.964 2.042 7.819
BHLYP 4.890 8.503 5.236 7.392 2.055 2.115 8.402
BLYP 4.003 7.688 4.538 6.398 1.875 1.964 7.477
5-Fluoro-2,4-ditellurouracil (TeU-F)
21,3-TeU- 1,22-TeU- 1,3-TeU- 1,41-TeU- 21,41- 22,41-TeU- 3,41-TeU-
F F F F TeU-F F F
B3LYP 5.060 8.127 3.906 5.467 0.692 1.068 6.960
BHLYP 5.543 8.561 4.209 6.026 0.512 0.905 7.434
BLYP 4.782 7.776 3.701 5.094 0.668 1.079 6.643

<Table>Table 2. Relative energy of tautomers for uracil and its chalcogen analogues.
1,3- 1,41- 21,41- 21,3- 1,22- 22,41-
TeU TeU TeU TeU TeU TeU
Uracil MP2a 0 11.8 10.9 10.6 18.7 12.1

12
 CCSD(T)a 0 11.6 10.8 10.2 18.2 11.9

2,4-Dithiouracil MP2b 0 15.2 21.2 11.5 25.7 11.6

MP2+ZPEb 0 12.5 18.4 8.9 22.8 6.7

2,4- MP2 0 15.9 21.4 11.5 22.3 12.9

Diselenouracil
MP2+ZPE 0 12.9 18.2 7.9 19.0 7.1

MP4(SDQ)c 0 16.3 21.4 11.8 22.3 13.8

MP4(SDQ)+ZPE 0 13.9 18.2 9.0 19.0 8.1

B3LYPd+ZPE 0 11.3 16.1 8.0 17.6 7.9

2,4- B3LYP+ZPE 0 11.3 14.4 7.14 16.9 6.4

Ditellurouracil
BHLYP+ ZPE 0 11.8 14.7 7.1 18.0 5.8

BLYP+ZPE 0 10.5 13.6 6.8 15.8 6.4

a
MP2/6-31+G(d,p) and CCSD(T)/6-31+G(d,p) computations [27]
b
MP2/6-31G(d)//HF/3-21G(d) level, frozen core approximation [36]
c
MP4(SDQ)/6-31G(d)//HF/3-21G(d) + Huzinaga partially uncontracted basis set [43]
d
B3LYP/6-31G(d) [37]

<Table>Table 3. EA and IP (eV) of tautomers 1,3-TeU and 1,3-TeU-F.

Tautomer B3LYP BHLYP BLYP
IP EA IP EA IP EA
1,3-TeU 7.34 1.70 7.40 1.77 6.96 1.44
1,3-TeU-F 5.28 4.14 5.17 4.35 5.00 3.75

<Table>Table 4. Solubility of tautomers 1,3-TeU and 1,3-TeU-F and 5-methyluracil

Tautomer log s(water)
1,3-TeU (B3LYP) -1.267
1,3-TeU (BHLYP) -1.007

13
 1,3-TeU (BLYP) -1.501
1,3-TeU-F (B3LYP) -1.591
1,3-TeU-F (BHLYP) -1.401
1,3-TeU-F (BLYP) -1.813
5-Methyluracil 0.321

<Table>Table 5. Lipophilicity parameters of tautomers 1,3-TeU and 1,3-TeU-F and 5-

methyluracil
Tautomer logP

Dry octanol Wet octanol

1,3-TeU (B3LYP) 0.775 1.071

1,3-TeU (BHLYP) -0.128 0.310

1,3-TeU (BLYP) 1.233 1.460

1,3-TeU-F (B3LYP) 1.316 1.555

1,3-TeU-F (BHLYP) 0.560 0.919

1,3-TeU-F (BLYP) 1.728 1.906

5-Methyluracil -1.954 -1.262

<Table>Table 6. Intestinal absorption of tautomers 1,3-TeU and 1,3-TeU-F and 5-

methyluracil.
Tautomer Intestinal absorption (%)
1,3-TeU (B3LYP) 82.4
1,3-TeU (BHLYP) 75.4
1,3-TeU (BLYP) 86.2
1,3-TeU-F (B3LYP) 80.9
1,3-TeU-F (BHLYP) 74.6
1,3-TeU-F (BLYP) 84.8
5-Methyluracil 67.6

<Table>Table 7. logP(BB) of tautomers 1,3-TeU and 1,3-TeU-F and 5-methyluracil.

14
 Tautomer logP(BB)

1,3-TeU (B3LYP) -0.803

1,3-TeU (BHLYP) -1.182
1,3-TeU (BLYP) -0.590
1,3-TeU-F (B3LYP) -0.774
1,3-TeU-F (BHLYP) -1.111
1,3-TeU-F (BLYP) -0.569
5-Methyluracil -1.407

TDENDOFDOCTD

15