Structural assignment of 6-oxy purine derivatives through computational modeling, synthesis, x-ray diffraction, and spectroscopic analysis

Article abstract of DOI:10.1021/jp100039p

6-Oxy purine derivatives have been considered as potential therapeutic agents in various drug discovery efforts reported in the literature. However, the structural assignment of this important class of compounds has been controversial concerning the speci

Full text of DOI:10.1021/jp100039p

6968
J. Phys. Chem. B 2010, 114, 6968–6972
Structural Assignment of 6-Oxy Purine Derivatives through Computational Modeling,
Synthesis, X-ray Diffraction, and Spectroscopic Analysis
Xinyun Zhao,†,‡ Xi Chen,†,‡ Guang-Fu Yang,† and Chang-Guo Zhan*,‡
Key Laboratory of Pesticide and Chemical Biology of the Ministry of Education of China, College of
Chemistry, Central China Normal UniVersity, Wuhan 430079, P. R. China, and Department of Pharmaceutical
Sciences, College of Pharmacy, UniVersity of Kentucky, 725 Rose Street, Lexington, Kentucky 40536
ReceiVed: January 4, 2010; ReVised Manuscript ReceiVed: February 26, 2010
6-Oxy purine derivatives have been considered as potential therapeutic agents in various drug discovery efforts
reported in the literature. However, the structural assignment of this important class of compounds has been
controversial concerning the specific position of a hydrogen atom in the structure. To theoretically determine
the most favorable type of tautomeric form of 6-oxy purine derivatives, we have carried out first-principles
electronic structure calculations on the possible tautomeric forms (A, B, and C) and their relative stability of
four representative 6-oxy purine derivatives (compounds 1-4). The computational results in both the gas
phase and aqueous solution clearly reveal that the most favorable type of tautomeric form of these compounds
is A, in which a hydrogen atom bonds with the N1 atom on the purine ring. To examine the computational
results, one of the 6-oxy purine derivatives (i.e., compound 4) has been synthesized and its structure has been
characterized by X-ray diffraction and spectroscopic analysis. All of the obtained computational and
experimental data are consistent with the conclusion that the 6-oxy purine derivative exists in tautomer A.
The conclusive structural assignment reported here is expected to be valuable for future computational studies
on 6-oxy purine derivative binding with proteins and for computational drug design involving this type of
compounds.
Introduction
SCHEME 1: Three Possible Types of Tautomeric Forms
of 6-Oxy Purine Derivativesa
Purine derivatives are widely used as the common core
structures in design and synthesis of lead compounds for drug
discovery. Depicted in Scheme 1 are the common core structures
of the 6-oxy purine derivatives, with four representative
compounds (1-4). A variety of compounds with the common
core structures have been identified as potentially valuable
therapeutic agents, such as specific immunomodulators,1 antiviral
agents,2 inhibitors of Multidrug Resistance Protein 4,3 and
phosphodiesterase 2 (PDE2), for the treatment of inflammation,
thromboembolism, and diseases of cardiovascular or urogenital
system.4
Although a variety of 6-oxy purine derivatives have been
synthesized and their biological activities have been tested, the
structural assignment of the compounds with these common core
structures has been controversial. For example, the hydrogen
atom was assigned to the N1 atom on the purine ring (structure
A in Scheme 1) in some reports.5–7 However, in other reports,8–10
the hydrogen atom was assigned to the O10 atom (structure B,
including B-1 and B-2, in Scheme 1). According to another
study,11 N3 atom protonation (structure C in Scheme 1) is also
possible. So, a total of three different types of tautomeric forms
(A-C) have been used for the compounds with the common
core structure depicted in Scheme 1.
a Tautomer B may take two different types of conformations (B-1
and B-2).
tautomeric forms would be remarkably different for these
compounds. If a wrong site was assigned for the hydrogen, the
structure-based computational design would be meaningless and,
therefore, could be misleading. A meaningful structure-based
drug design and discovery must be based on reliable structural
assignment.
From the thermodynamic point of view, all three types of
tautomeric forms (A-C in Scheme 1) could coexist in solution,
but with different relative concentrations. The question is which
type of tautomeric form is dominant or more favorable in
solution. To address this crucial question, we first performed
first-principles electronic structure calculations on the molecular
structures and energetics of four representative compounds (1-4
in Scheme 1). The first-principles electronic structure calcula-
tions were performed on all three possible types of tautomeric
forms for each of these four compounds. The computational
results led to the prediction of the most favorable type of
tautomeric form. To test the computational prediction, com-
It is crucial to correctly assign the molecular structures of
this important type of compound (with the hydrogen atom on
the right site) for structure-based drug design and discovery, as
the binding of a drug target (say protein) with different
* Corresponding author. Tel: 859-323-3943. Fax: 859-323-3575. E-mail:
zhan@uky.edu.
† Central China Normal University.
‡ University of Kentucky.
10.1021/jp100039p  2010 American Chemical Society
Published on Web 04/30/2010

Structures of 6-Oxy Purine Derivatives
J. Phys. Chem. B, Vol. 114, No. 20, 2010 6969
SCHEME 2: Synthesis of Compound 4a
a Reagents and conditions: (a) pyridine, acetonitrile, reflux 1 h and then 15 min; (b) methyl 3-methoxyphenylacetate, CH3ONa, reflux.
pound 4 was synthesized and its structure was characterized by
X-ray diffraction technology and 1H NMR and IR spectra. The
combined computational and experimental studies consistently
demonstrate that the dominant type of tautomeric form is always
A in the gas phase, solution, and crystal. The conclusive
assignment of the proton for 6-oxy purine derivatives provides
a solid basis for future structure-based drug design and discovery
associated with 6-oxy purine derivatives.
mercially available. Solvents were dried in a routine way and
redistilled. The H NMR spectrum was recorded at 400 MHz
1
in DMSO on a Varian 400 MHz NMR spectrometer. The mass
spectrum was determined using a Trace MS 2000 organic mass
spectrometry. Melting points were recorded on a Bu¨chi B-545
melting point apparatus. Elemental analysis (EA) was carried
out with a Vario EL III CHNSO elemental analyzer. The crystal
structure of the title compound was determined on the Bruker
Smart Apex CCD X-ray instrument.
Compound 4 was prepared by using a route (Scheme 2)
Computational and Experimental Methods
modified from that described in the literature.27
Computational Modeling. The initial structures of all
compounds were built with GaussView 3.0. All of the molecular
geometries were first optimized by using the density functional
theory (DFT) with the B3LYP functional and the 6-31G* basis
set. Harmonic vibrational frequency analysis was performed at
the same level of theory (B3LYP/6-31G*) to make sure that
each geometry optimized is indeed associated with a local
minimum on the potential energy surface and to estimate the
thermal correction to the Gibbs free energy in the gas phase.
Then the optimized geometries were employed to performed
single-point energy calculations at the B3LYP/6-311++G**
level.
The geometries optimized in the gas phase were also used
as the initial structures for further geometry optimizations in
aqueous solution using self-consistent reaction field (SCRF)
theory at the B3LYP/6-31G* level. The quantum Onsager
solvation model12 was chosen for the geometry optimizations
in aqueous solution (with a dielectric constant of 78.5). The
radius of the cavity used in the quantum Onsager model was
estimated from the molecular volume calculation at the B3LYP/
6-31G* level on the gas phase geometry. The geometry
optimization was followed by the harmonic vibrational fre-
quency calculation at the same SCRF level of theory for the
thermodynamic correction to the Gibbs free energy in aqueous
solution. Further, the geometries optimized in aqueous solution
were employed to calculate the solvent shifts of the free energies
by using the surface and volume polarization for electrostatic
(SVPE)13–15 implemented recently in Gaussian03 program.16 The
SVPE model is also known as the fully polarizable continuum
model (FPCM),17–24 because it fully accounts for both surface
and volume polarization effects in determination of the
solute-solvent electrostatic interaction. Finally, the nonelec-
trostatic contributions to the solvation free energy of the solutes
were estimated semiempirically by using IEFPCM model25
implemented in the Gaussian03 program.
At room temperature, 1.02 g (56 mmol) if methyl 3-meth-
oxyphenylacetate and 0.24 g (14 mmol) of 5-amino-1-(2-
hydroxyethyl)-1H-imidazole-4-carboxamide (5) were desolved
in 10 mL of warm pure methanol to obtain a solution (solution
A), and 0.15 g (63 mmol) of sodium was desolved in 10 mL of
pure methanol to obtain another solution (solution B). Then,
the mixture of the solutions A and B was heated under refluxing
for 15 h. The methanol was distilled off using a rotary
evaporator, and then 30 mL of water was added to the residue
and the mixture was extracted by dichloromethane (3 × 40 mL).
During the extraction, the product was precipitated out, and
filtration by suction and silica gel chromatography gave 0.32 g
of compound 4 (yield 76%) as a white solid (melting point:
199.1 °C). Compound 4 was characterized by 1H NMR and IR.
IR (KBr/cm-1): 3313 (N-H), 3089, 2950, 2841, 1673 (CdO),
1589, 1535, 1475, 1436, 1378, 1260, 1186, 1167, 1076, 1048,
1034, 875, 767, 710, 648. EI-MS: m/z (%) 300.1 (M+, 86.11),
269.2 (100.00), 255.1 (64.16), 109.1 (86.43), 91.1 (43.17), 77.1
(45.45), 65.1 (27.19), 45.2 (41.11). 1H NMR (400 MHz, DMSO-
d6): δ 12.32 (s, NH, 1H), 7.96 (s, CH, 1H), 6.80-7.24 (m, ArH,
4H), 4.98 (t, OH, 1H, 2J ) 5.6 Hz), 4.14 (t, CH2, 2H, 2J ) 5.2
Hz), 3.94 (s, CH2, 2H), 3.32-3.75 (m, 5H, OCH3, CH2). Anal.
Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66; O, 15.98.
Found: C, 59.96; H, 5.34; N, 18.98.
For the purpose of determining an X-ray crystal structure, a
single crystal of compound 4 suitable for X-ray analysis was
grown from methanol at 293 K. The crystal structure was
determined by X-ray crystallography, and the determined crystal
structure was shown in Figure 2. Crystal data obtained for
compound 4: triclinic; a ) 7.2840(10) Å, b ) 8.9089(12) Å, c
) 13.7793(19) Å, ꢀ) 76.153(2)°; V ) 843.7(2) Å3, T ) 295(2)
3
j
K, space group P1, Z ) 8, Dc ) 1.308 g/cm , µ(Mo KR) )
0.096 mm-1, F(000) ) 352. A total of 5660 reflections
measured, 3439 unique, R(int) ) 0.0511, which were used in
all calculations. Fine R1 ) 0.0532, wR2 ) 0.1316, R1 ) 0.0805,
wR2 ) 0.1594 (all data).
The SVPE calculations were carried out by using a local
version16 of the Gaussian03 program26 on a 34-processors IBM
Linux cluster in our own laboratory. All of the other calculations
were performed using the Gaussian03 program on an IBM
supercomputer (X-series Cluster with 340 nodes or 1360
processors) at the University of Kentucky Center for Compu-
tational Sciences.
Results and Discussion
Geometries and Energetics from First-Principles Elec-
tronic Structure Calculations. The geometries of various
tautomeric forms of compounds 1-4 optimized in the gas phase
are depicted in Figure 1. Table 1 collects the key bond lengths
in the optimized geometries. The corresponding bond lengths
Experimental Details. Triethyl orthoformate, 2-cyano-2-
aminoacetamide, and other chemical reagents were com-

6970 J. Phys. Chem. B, Vol. 114, No. 20, 2010
Zhao et al.
TABLE 2: Calculated Relative Gibbs Free Energies (∆G in
kcal/mol) of Different Molecular Structures/Conformations
of Compounds 1-4a
structures
compound
phase
A
B-1
B-2
C
1
∆G(gas)
∆G(sol)
∆G(gas)
∆G(sol)
∆G(gas)
∆G(sol)
∆G(gas)
∆G(sol)
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
5.4
10.2
5.0
11.4
7.5
10.7
5.8
11.7
4.0
9.1
3.8
8.8
5.3
9.8
4.9
8.0
18.9
8.5
19.7
9.4
18.6
12.0
18.9
8.1
2
3
4
a The energy calculations were performed at the B3LYP/
6-311++G** level by using geometries optimized at the B3LYP/
6-31G* level. Thermal corrections to Gibbs free energies were
estimated at the B3LYP/6-31G* level.
tautomeric form A of compounds 1-4, the C6-O10 bond length
is 1.222-1.223 Å, the C6-N1 bond length is 1.430-1.434 Å,
and the C2-N3 bond length is 1.301-1.309 Å. In the optimized
geometries of tautomeric form B (including conformations B-1
and B-2) of compounds 1-4, the C6-O10 bond length is
1.342-1.351 Å, the C6-N1 bond length is 1.325-1.333 Å,
and the C2-N3 bond length is 1.331-1.340 Å. In the optimized
geometries of tautomeric form C of compounds 1-4, the
C6-O10 bond length is 1.224-1.230 Å, the C6-N1 bond
length is 1.421-1.427 Å, and the C2-N3 bond length is
1.373-1.383 Å. The largest difference between different
compounds for a given bond length does not exceed 0.01 Å.
So, the substituent effects on the bond lengths are all rather
small.
To determine the most favorable tautomeric form (A, B, or
C) of 6-oxy purine derivatives, we calculated the relative Gibbs
free energies, and calculated energetic results are summarized
in Table 2. For all compounds examined, tautomer A is always
associated with the lowest Gibbs free energy in both the gas
phase and solution. The Gibbs free energies of the other
tautomers are significantly higher, particularly for the results
calculated in solution. Thus, the computational data predict that
6-oxy purine derivatives should dominantly exist in tautomer
A, and the other tautomers are negligible in solution.
Figure 1. Geometries optimized at the B3LYP/6-31G* level for the
three possible types of tautomeric forms of 6-oxy purine derivatives
(compounds 1-4). Color codes: red, oxygen; blue, nitrogen; gray,
carbon; white, hydrogen.
TABLE 1: Key Bond Lengths (in Å) in the Geometries
Optimized for Various Possible Structures of Compounds
1-4, in Comparison with the Corresponding Experimental
Values in the X-ray Crystal Structure of Compound 4
structurea
r(C6-O10)
r(C6-N1)
r(C2-N3)
1A
1.217(1.223)
1.344(1.349)
1.339(1.344)
1.216(1.228)
1.218(1.223)
1.344(1.351)
1.340(1.346)
1.216(1.230)
1.219(1.222)
1.346(1.350)
1.341(1.344)
1.218(1.227)
1.218(1.222)
1.345(1.348)
1.340(1.342)
1.217(1.224)
1.242
1.436 (1.431)
1.328 (1.329)
1.333 (1.333)
1.436 (1.426)
1.437 (1.433)
1.328 (1.329)
1.334 (1.333)
1.436 (1.427)
1.438 (1.434)
1.324 (1.325)
1.330(1.330)
1.428 (1.421)
1.435 (1.430)
1.326 (1.326)
1.331 (1.330)
1.431 (1.425)
1.391
1.303 (1.301)
1.338 (1.335)
1.333 (1.331)
1.386 (1.375)
1.303 (1.301)
1.337 (1.334)
1.332 (1.331)
1.385 (1.373)
1.309 (1.309)
1.342 (1.340)
1.338 (1.337)
1.388 (1.380)
1.309 (1.309)
1.341 (1.340)
1.338 (1.337)
1.387 (1.383)
1.303
1B-1
1B-2
1C
2A
2B-1
2B-2
2C
3A
3B-1
3B-2
3C
4A
Results from Wet Experimental Studies. To test the
computational prediction, compound 4 was selected for wet
experimental study. The target compound was synthesized via
the route outlined in Scheme 2, and characterized by 1H NMR,
elemental analysis, mass spectroscopy, and IR spectroscopy.
Methyl 3-methoxyphenylacetate was obtained by 3-methox-
yphenylacetic acid with absolute methanol in the presence of
the catalyst concentrated sulfuric acid in 96% yield. The
intermediate 5-amino-1-(2-hydroxyethyl)-1H-imidazole-4-car-
boxamide (5) was prepared according to the procedure described
by Banerjee et al.,28 but we modified the procedure by adding
pyridine as a catalyst to increase the yield from 42% (reported
by Banerjee et al.) to 73.2% (this work). The 1H NMR spectrum
of 5 was consistent with that reported in the literature.28
Compound 4 was obtained by refluxing intermediate 5 with
methyl 3-methoxyphenylacetate under CH3ONa/CH3OH system.
The main difference between tautomers A, B, and C lies in
the position of a hydrogen atom that can bond to N1, O10, or
N3. Since the chemical environments of a hydrogen atom on
N1, O10, and N3 are different, one might expect to use nuclear
magnetic resonance (NMR) techniques to determine the position
4B-1
4B-2
4C
4 (expt.)b
a Unless indicated otherwise, all of the geometries were
optimized at the B3LYP/6-31G* level in the gas phase. The values
in parentheses were optimized at the B3LYP/6-31G* level in
aqueous solution. b Bond lengths in the X-ray crystal structure of
compound 4.
optimized in aqueous solution are also listed in Table 1 for
comparison. As one can see in Table 1, the optimized bond
lengths in the gas phase are all very close to the corresponding
values optimized in aqueous solution. The largest difference is
∼0.01 Å. For convenience, the discussion below will only refer
to the geometries optimized in aqueous solution, unless explicitly
indicated otherwise.
As one can see in Table 1, the optimized geometric
parameters for different tautomeric forms are remarkably
different. However, for a given type of tautomeric form, the
optimized bond length values for each bond in different
compounds are very close. In the optimized geometries of
1
of the hydrogen atom. On the H NMR spectrum (Supporting

Structures of 6-Oxy Purine Derivatives
J. Phys. Chem. B, Vol. 114, No. 20, 2010 6971
in the compound, the IR spectrum can exclude tautomer B and,
thus, supports tautomer A.
Conclusion
First-principles electronic structure studies on the possible
tautomeric forms (A, B, and C) and their relative stability of
four representative 6-oxy purine derivatives (compounds 1-4)
have demonstrated that the most favorable type of tautomeric
form of these compounds in both the gas phase and aqueous
solution should always be A, in which a hydrogen atom bonds
with N1 atom on the purine ring. To examine the computational
results, one of the 6-oxy purine derivatives (i.e., compound 4)
has been synthesized and its structure has been characterized
by X-ray diffraction and 1H NMR and IR spectroscopy. All of
the obtained computational and experimental data are consistent
with the conclusion that the 6-oxy purine derivative exists in
tautomer A. The conclusive structural assignment is expected
to be valuable for future computational studies on 6-oxy purine
derivative binding with proteins and for computational drug
design involving this type of compounds.
Figure 2. Intermolecular interaction in the X-ray crystal structure of
compound 4. Color codes: red, oxygen; blue, nitrogen; gray, carbon.
Information) of compound 4, a single peak at 12.32 ppm (1H)
was found. This absorption is attributed to the resonance of the
hydrogen atom on the -NH or -OH group. However, as each
of the three possible tautomers, i.e., 4A, 4B (4B-1 or 4B-2),
and 4C, has a -NH or -OH group, it is difficult to determine
which tautomer is the right one for compound 4.
The X-ray diffraction technique is a powerful tool to
determine molecular structures. Figure 2 depicts the intermo-
lecular interaction in the X-ray crystal structure of compound
4. Since X-ray diffraction itself cannot directly determine the
positions of hydrogen atoms, only heavy atoms are shown in
Figure 2. As shown in Figure 2, the N1 atom in one molecule
is only ∼2.8 Å away from the O10 atom of the other molecule
in the X-ray crystal structure. There must be a hydrogen atom
between the N1 atom of one molecule and the O10 atom of the
other molecule of compound 4. In other words, the hydrogen
atom to be assigned should covalently bond to either the N1 or
O10 atom in compound 4. So, in the X-ray crystal structure,
only tautomers A and B are possible, and tautomer C can be
excluded. Further, the C6-O10, C6-N1, and C2-N3 bond
lengths in the X-ray crystal structure are 1.242, 1.390, and 1.303
Å, respectively. The C6-O10 bond length of 1.242 Å clearly
reveals that the C6-O10 bond should be a typical CdO double
bond, suggesting that the hydrogen atom to be assigned should
covalently bond to the N1 atom, rather than the O10 atom, in
compound 4. In other words, the tautomer observed in the X-ray
crystal structure should be A. As seen in Table 1, within all of
the optimized geometries of compound 4, only tautomer A has
all bond lengths consistent with the corresponding experimental
values. The C6-O10, C6-N1, and C2-N3 bond lengths in
the optimized geometry of 4A are 1.222, 1.430, and 1.309 Å,
respectively, in good agreement with the corresponding bond
lengths in the X-ray crystal structure.
Acknowledgment. The research was supported in part by
National Institutes of Health (grant RC1MH088480) and
National Natural Science Foundation of China (grants 20602014,
20503008, and 20372023). We also acknowledge the Center
for Computational Sciences (CCS) at the University of Kentucky
for supercomputing time on IBM X-series Cluster with 340
nodes or 1360 processors.
1
Supporting Information Available: Two figures for H
NMR and IR spectra of compound 4. This material is available
free of charge via the Internet at http://pubs.acs.org.
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