X-ray structure, NMR and stability-in-solution study of 6-(furfurylamino)-9-(tetrahydropyran-2-yl)purine - A new active compound for cosmetology

Article abstract of DOI:10.1016/j.molstruc.2010.05.013

The crystal and molecular structure of 6-(furfurylamino)-9-(tetrahydropyran-2-yl)purine (1) was determined at 150(2) K. The compound crystallizes in monoclinic P2₁/c space group with a = 10.5642(2), b = 13.6174(3), c = 10.3742(2) ?, V = 1460.78(5) ?³, Z = 4, R(F) = for 3344 unique reflections. The purine moiety and furfuryl ring are planar and the tetrahydropyran-2-yl is disordered in the ratio 1:3, probably due to the chiral carbon atom C(17). The individual ¹H and ¹³C NMR signals were assigned by 2D correlation experiments such as ¹H-¹H COSY and ge-2D HSQC. Stability-in-solution was determined in methanol/water in acidic pH (3-7).

Full text of DOI:10.1016/j.molstruc.2010.05.013

Journal of Molecular Structure 975 (2010) 376–380
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
X-ray structure, NMR and stability-in-solution study of
6-(furfurylamino)-9-(tetrahydropyran-2-yl)purine – A new active compound for
cosmetology
a
a,
b
a
a
a
*
ˇ
ˇ
´
ˇ
Jan Walla , Lucie Szücová , Ivana Císarová , Tomáš Gucky , Marek Zatloukal , Karel Dolezal ,
Jarmila Greplová a, Frank J. Massino c, Miroslav Strnad a
a
´
˚
Laboratory of Growth Regulators, Palacky University & Institute of Experimental Botany AS CR, Šlechtitelu 11, 783 71 Olomouc, Czech Republic
b Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 2030, 128 40 Prague, Czech Republic
c Senetek PLC, 831A Latour Court, 94558 Napa, CA, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The crystal and molecular structure of 6-(furfurylamino)-9-(tetrahydropyran-2-yl)purine (1) was deter-
mined at 150(2) K. The compound crystallizes in monoclinic P21/c space group with a = 10.5642(2),
b = 13.6174(3), c = 10.3742(2) Å, V = 1460.78(5) Å3, Z = 4, R(F) = for 3344 unique reflections. The purine
moiety and furfuryl ring are planar and the tetrahydropyran-2-yl is disordered in the ratio 1:3, probably
due to the chiral carbon atom C(17). The individual 1H and 13C NMR signals were assigned by 2D corre-
lation experiments such as 1H–1H COSY and ge-2D HSQC. Stability-in-solution was determined in meth-
anol/water in acidic pH (3–7).
Received 6 April 2010
Accepted 8 May 2010
Available online 19 May 2010
Keywords:
Kinetin derivative
X-ray structure analysis
Cytokinin
Ó 2010 Elsevier B.V. All rights reserved.
Aging
Stability-in-solution
NMR analysis
1. Introduction
compared to those of the free bases [6,7,21]. 6-(Furfurylamino)-
9-(tetrahydropyran-2-yl)purine (1) was tested for its anti-senes-
Purine based derivatives called cytokinins have received consid-
erable attention since the discovery of N6-furfuryladenine (kine-
cent activity on detached soya leaves [6]. Later, it underwent a
series of cytokinin assays and its biological effects were described
in detail [21]. Due to structural similarity between kinetin and 1,
the compound was also tested on human fibroblasts within the
frame of the anti-aging assay and it was shown to be much more
effective than kinetin [21]. A clinical study of topical use of 1,
including in vitro studies of attachment frequency, cellular growth
curves, mitochondria activity, lysosomes, accumulation of intracel-
lular debris and overall rejuvenation, has been published recently
[22]. It was established that treatment of the skin with a 0.1% con-
centration of this compound improved roughness and skin mois-
turization as well as mottled hyperpigmentation and fine
wrinkles, and therefore it can serve as an anti-aging treatment
[22]. The substance is currently used in several compositions for
treating skin, for example in Pyratine 6 anti-aging cream and lotion
[23]. This paper reports the results of long-term research on this
particular cytokinin derivative, 6-(furfurylamino)-9-(tetrahydro-
pyran-2-yl)purine (1), during which not only the biological
properties of the compound were studied, but also its stability-
in-solution and its solid state structure. The solid state structure
of the compound as well as its stability-in-solution, has not previ-
ously been described.
tin),
a very important representative of this group [1,2].
Cytokinins are plant growth regulators that promote cell division,
prevent leaf senescence and participate in almost all stages of plant
development [3]. Moreover, kinetin delays the onset of aging char-
acteristics in human fibroblasts [4] and therefore is currently in-
cluded as an active agent in many cosmetic compositions [5]. Up
to now, a number of cytokinin derivatives have been prepared,
their biological properties have been studied and some interesting
structure and activity relationship data have been obtained [6–9].
Considering particularly N(9) substitution of kinetin, various alkyls
[10–13], aryls [14,15], or miscellaneously substituted ribosides
[16–19] have been used as substituents. 6-(Furfurylamino)-9-(tet-
rahydropyran-2-yl)purine was prepared by Robins et al. (1960) by
the reaction of 6-chloro-9-tetrahydropyran-2-ylpurine with N6-
furfurylamine [20]. It was later demonstrated that tetrahydropyr-
anylation very often improves the anti-senescent properties
* Corresponding author. Tel.: +420 585634940; fax: +420 585634870.
ˇ
E-mail address: lucie.szucova@upol.cz (L. Szücová).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.05.013

J. Walla et al. / Journal of Molecular Structure 975 (2010) 376–380
377
150(2) K on a Nonius Kappa CCD diffractometer with graphite-
monochromatised Mo K radiation, k = 0.71073 Å. The structure
2. Experimental
a
was solved by direct methods (SIR97) [24] and refined by a full-
matrix least-squares routine based on F2 (SHELXL97) [25]. Non-
hydrogen atoms were refined with anisotropic displacement
parameters. Except for the one at N(10), the hydrogen atoms were
placed in their calculated positions and refined using a riding mod-
el with Uiso(H) = 1.2 Ueq of their bonding atom. The hydrogen atom
on N(10) was identified on a difference Fourier map and was re-
fined isotropically. The refinement converged (D/rmax = 0.001,
232 parameters) to R = 4.95% for the observed, and R = 5.53%,
wR = 12.23%, GOF = 1.100 for all diffractions. The final difference
2.1. General
3,4-Dihydropyrane and kinetin were purchased from Sigma Al-
drich and were used without further purification. Formic acid,
ethyl acetate, ammonia, magnesium sulphate and methanol were
purchased from Lachema and were used without further purifica-
tion. Evaporation of solvents was carried out under vacuum using
a rotary evaporator. Elemental analyses were determined on an EA
1112 Flash analyzer (Thermo-Finnigan). The melting point was
determined on a Büchi Melting Point B-540 apparatus and was
uncorrected. Thin layer chromatography (TLC) was carried out
using silica gel 60 WT254 plates (Merck Co.). CHCl3:MeOH (9:1,
v:v) was used as mobile phase. The CI + mass spectra were re-
corded using a Polaris Q (Finnigan) mass spectrometer equipped
with a Direct Insertion Probe (DIP). Compound 1 was heated in
an ion source with a temperature gradient from 40 °C to 450 °C
over 5 min, the mass monitoring interval was 50–1000 amu, and
spectra were collected using 1.0 cyclical scans, applying 70 eV elec-
tron energy. Isobutane was used as a reagent gas at a flow-rate of
2 l/h. The mass spectrometer was directly coupled to an Xcalibur
data system. 1H, 1H–1H COSY, 13C and 1H–13C heteronuclear single
quantum coherence edited GP (ge-2D HSQC) experiments were re-
corded on a Bruker Avance 300 FT NMR spectrometer operating at
a temperature of 300 K and at a frequency of 300.13 Hz. Samples
were prepared by dissolving the substances in DMSO-d6. Tetra-
methylsilane (TMS) was used as the internal reference standard.
The individual 1H and 13C signals were assigned by 2D correlation
experiments including 1H–1H COSY and ge-2D HSQC.
map displayed no peaks of chemical significance (Dqmax = 0.40,
D
q
min = ꢁ0.27 e Åꢁ3).
2.4. Stability of 1 in acidic solution
The pH stability of compound 1 in methanol was analyzed by
HPLC–PDA (System Gold, Beckman Instruments, Fullerton, USA)
and the analytes were monitored at 270 nm. 10ꢁ2 M solutions of
compound 1 in methanol were prepared and diluted to 10ꢁ4
M
using McIlvaine buffer solution for the appropriate pH (3–7) [26].
One hour after incubation at 25 °C, 5 l of each prepared solution
was directly injected onto a reversed phase column (Symmetry
C18, 5
l
lm, 150 ꢀ 2.1 mm, Waters, Milford, USA). The following
binary gradient was used at a flow-rate of 0.3 ml/min: 0 min, 10%
A, 0–25 min, a linear gradient to 90% A, followed by 5 min isocratic
elution of 90% A, where A was 100% methanol and B was 15 mM
formic acid adjusted to pH 4 with ammonium. HPLC measurement
of the solutions was repeated after a 24 h incubation at 25 °C. The
analyses were repeated at least three times.
2.2. 6-(Furfurylamino)-9-(tetrahydropyran-2-yl)purine (1) synthesis
3. Results and discussion
The compound was prepared by a previously published proce-
dure [20] with slight modifications. 3,4-Dihydropyrane (5.4 ml,
0.059 mol), and formic acid (5 ml) were added to a stirred suspen-
sion of kinetin (5 g, 0.023 mol) in ethyl acetate (40 ml), heated to
reflux (78 °C) and stirred for 3 h. The reaction mixture was cooled
to 20 °C, and 25% aqueous ammonia solution (10 ml) was added to
neutralize the formic acid. The organic phase was washed with
water (2 ꢀ 20 ml), dried with anhydrous magnesium sulphate
(5 g), and evaporated to a yellow residue (9.5 g) that was crystal-
lized from methanol (50 ml). The resulting white crystalline prod-
uct was washed with cold methanol (5 °C, 2 ꢀ 10 ml), and dried
under vacuum. Yield: 5.0–5.5 g (73–80%), m.p. 135.8–137.8 °C, ele-
mental analysis, calculated for C15H17N5O2 (299.34), %C 60.19, %H
5.72, %N 23.40. Found: %C 60.20, %H 5.65, %N 23.42, CI + mass spec-
tra: [M]+ = 300.35, 1H NMR (300 MHz, DMSO-d6): d = 1.48–1.60 (m,
2H, C21Ha, C21Hb), 1.63–1.77 (m, 1H, C20Ha), 1.88–1.95 (m, 2H,
C20Hb, C22Ha), 2.30 (dq, 1H, J = 11 Hz, J0 = 1.9 Hz, C22Hb), 3.61–
3.70 (m, 1H, C19Ha), 3.95–4.02 (m, 1H, C19Hb), 4.71 (s, 2H,
C11H), 5.63 (dd, 1H, J = 11 Hz, J0 = 1.9 Hz, C17H), 6.23 (d, 1H,
J = 3.0 Hz, C16H), 6.35 (t, 1H, J = 3.0 Hz, C15H), 7.53 (d, 1H,
J = 3.0 Hz, C14H), 8.24 (bs, 1H, N10H), 8.27 (s, 1H, C8H), 8.37 (s,
1H, C2H).
The molecular structure of 6-(furfurylamino)-9-(tetrahydropy-
ran-2-yl)purine (1), including atom labeling, is given in Fig. 1. Crys-
tallographic data for 1 are given in Table 1 while the selected bond
lengths, angles and torsion angles are shown in Table 2. No solvent
molecules co-crystallized. We compared the structure of 1 to the
structure of kinetin [27] and kinetin riboside [28] to determine
the influence of the tetrahydropyran-2-yl substitution at the N(9)
atom of purine moiety. The bond lengths and angles are only
slightly influenced with the exception of the N(9)AC(8) and
C(8)AN(7) bonds that adjoin N(9) atom. N(7)AC(8) is 1.3245(8) Å
for kinetin and 1.290(1) Å and 1.312(2) for kinetin riboside and
for 1, respectively. The N(9)AC(8) bond is 1.3465(7) Å for kinetin
and 1.383(2) Å and 1.360(2) Å for kinetin riboside and for 1,
respectively. The N(9) substituent also influences the surrounding
angles. While the angle C(8)AN(7)AC(5) is 102.58° for kinetin, the
same angle is 103.14° and 104.0(1)° for kinetin riboside and 1,
respectively. N(9)AC(4)AC(5) is 104.05° for kinetin, 106.41° for
kinetin riboside and 105.6(1)° for 1. Whilst the bonds and angles
in the purine moiety are influenced only slightly, big differences
were obvious in the torsion angles. The torsion angle
C(6)AN(1)AC(2)AN(3) for kinetin is 0.84°, the same angle for kine-
tin riboside is 3.05° and 2.3(3)° for 1. C(11)AN(10)AC(6)AC(5) tor-
sion angle was found 174.27° for kinetin and 168.05° and 178.6(1)°
for kinetin riboside and for 1. The purine moiety is almost planar
with maximum deviation from the plane of 0.0161 Å. The dihedral
angle between the pyrimidine and imidazol rings in the purine
moiety is 1°. The furanyl ring is almost planar with maximal devi-
ation from the plane 0.0027 Å. Dihedral angle between furanyl ring
and purine moiety is 69° and dihedral angle between furanyl and
pyrimidine ring is 68.7°. The tetrahydropyran-2-yl substituent
contains a chiral carbon atom whereas the substance is a racemic
13C NMR (75 MHz, DMSO-d6): d = 22.4 (C20), 24.4 (C21), 29.9
(C22), 36.4 (C11), 67.6 (C19), 80.8 (C17), 106.5 (C16), 110.3
(C15), 118.91 (C5), 138.8 (C2), 141.7 (C14), 152.4 (C8), 152.9
(C4), 154.12 (C6).
2.3. Crystallography
Colorless crystals suitable for X-ray diffraction study were
grown by slow evaporation of an isopropanol solution at labora-
tory temperature. X-ray data collection was carried out at

378
J. Walla et al. / Journal of Molecular Structure 975 (2010) 376–380
Fig. 1. Molecular structure of 6-(furfurylamino)-9-(tetrahydropyran-2-yl)purine (1).
Table 1
Table 2
Crystal data and structure refinement for 1.
Selected bond lengths (Å), angles (°) and selected torsion angles for 1.
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system, space group
Unit cell dimensions
C15H17N5O2
299.34
150(2) K
0.71073 Å
Monoclinic, P21/c
a = 10.5642(2) Å
b = 13.6174(3) Å
c = 10.3742(2) Å
1460.78(5) Å
4, 1.361 Mg/m3
0.095
Bond lengths
N(1)AC(2)
N(1)AC(6)
N(3)AC(2)
N(3)AC(4)
N(7)AC(8)
N(7)AC(5)
N(9)AC(8)
N(9)AC(4)
C(5)AC(4)
C(5)AC(6)
C(6)AN(10)
N(9)AC(17)
1.342(3)
1.346(2)
1.329(3)
1.340(2)
1.312(2)
1.386(2)
1.360(2)
1.380(2)
1.385(2)
1.411(2)
1.340(2)
1.454(3)
Volume
Z, calculated density
Absorption coefficient
F(0 0 0)
632
Index ranges
ꢁ13 6 h P 13
ꢁ17 6 k P 17
ꢁ13 6 l P 13
6547/3344 [R(int) = 0.031]
Full-matrix least-squares on F2
3344/0/232
1.100
R1 = 0.0495
R1 = 0.0553, wR2 = 0.1223
0.40 and ꢁ0.27 e Åꢁ3
0.01
Bond angles
C(2)AN(1)AC(6)
C(2)AN(3)AC(4)
C(8)AN(7)AC(5)
C(8)AN(9)AC(4)
N(3)AC(2)AN(1)
N(3)AC(4)AN(9)
N(3)AC(4)AC(5)
N(9)AC(4)AC(5)
C(4)AC(5)AN(7)
C(4)AC(5)AC(6)
N(7)AC(5)AC(6)
N(1)AC(6)AC(5)
N(7)AC(8)AN(9)
117.9(2)
110.3(2)
104.0(1)
106.0(1)
130.2(2)
127.7(2)
126.7(2)
105.6(1)
110.5(1)
117.0(1)
132.5(1)
117.8(1)
114.0(2)
Reflections collected/unique
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R(F) indices [I > 2
R indices (all data)
Largest diff. peak and hole
r(I)]
D/rmax
mixture. In the tetrahydropyranylated part of the molecule, there
are two possible positions of tetrahydropyran-2-yl ring (A and B)
in the structure with the probability ratio of 3:1. A and B positions
form optical antipods, both in chair conformation. Although the
oxygen atom is in stable position, stabilization by a hydrogen bond
was not observed. A and B rings of tetrahydropyran-2-yl are bound
in equatorial position holding the angle of 92.6° (A) and 64.3° (B) to
the plane of purine moiety. The mutual angle between the planes
of the spaced rings A and B is 35.4°. Only one intermolecular
hydrogen bond between N(10)AH(1) and N(7) was observed. 6-
(furfurylamino)-9-(tetrahydropyran-2-yl)purine was also investi-
gated by 1D and 2D NMR experiments in DMSO-d6. Chemical shifts
found for 1H and 13C NMR are given below the description of the
synthesis in Section 2 (above). 1H NMR chemical shifts were attrib-
uted to hydrogen atoms present in the molecule. N(10)H signal
broadening was probably caused by the exchange of the N(10)H
atom with H atoms of the solvent, but it could also be influenced
by the hydrogen interaction of the N(10)H with the N(7) atom of
the purine moiety. Between these two atoms was also found the
only intramolecular hydrogen bond in a solid state molecule. The
methylene protons on C(11) are activated by hyperconjugation
and are relatively acidic and therefore instead of a doublet, a broad
singlet was observed in the 1H NMR spectrum. Clear signal broad-
Torsion angles
C(6)AN(1)AC(2)AN(3)
C(11)AN(10)AC(6)AC(5)
C(6)AN(10)AC(11)AC(12)
N(10)AC(11)AC(12)AO(13)
ꢁ2.3(3)
ꢁ178.6(1)
ꢁ93.9(2)
ꢁ64.5(2)
ening is also apparent from the 13C NMR spectrum for C(11). Sim-
ilar results were described for analogous 6-benzylamino-9-
(tetrahydropyran-2-yl)purine [29]. The majority of the determined
chemical shifts of 13C NMR spectra were in agreement with the
data found in the literature [30] except for the chemical shifts that
represent quaternary carbon atoms C(4), C(5) and C(6), and their
assignment was made on the basis of the literature that describes
NMR spectral properties of purines [31]. Fig. 2 shows the 1H–13
HSQC edited GP NMR spectrum of compound 1.
C
While the tetrahydropyran-2-yl group has been commonly used
in organic chemistry as a protective group readily removable under
acidic conditions [32], we performed a set of stability tests for 1 in
an acidic pH. We deliberately excluded alkali pH because the com-
pound was prepared in alkali reaction mixture and under alkali
conditions the compound is stable. We performed HPLC stability

J. Walla et al. / Journal of Molecular Structure 975 (2010) 376–380
379
Fig. 2. Heteronuclear single quantum correlation (HSQC) edited GP experiment for 1.
Table 3
2-yl group (A and B) can be explained by the chiral C(17) atom.
Knowledge of the crystal and molecular structure of 1 revealed
new information about structural arrangement and weak interac-
tions in the molecule. We also determined stability of the com-
pound in methanol solution in the pH range from 7 to 3 that can
be useful for cosmetic applications and it was found that the com-
pound is stable up to pH 5 and only slightly disintegrates to
N6-furfurylaminopurine at pH 4. The stability of the compound
at low pH decreases as a function of time.
The stability of 6-(furfurylamino)-9-(tetrahydropyran-2-yl)purine (1) in acidic
solutions.
pH
1 (%)
N6-furfurylaminopurine (%)
1 h after sample preparation
7
6
5
4
3
99.7
99.5
99.5
99.1
93.2
0.3
0.5
0.5
0.9
6.8
24 h after sample preparation
7
6
5
4
3
99.6
99.6
99.0
94.1
42.7
0.4
0.4
1.0
5.9
57.3
Supplementary material
The crystallographic data for (1) were deposited with the Cam-
bridge Crystallographic Data Centre, CCDC 753,419. Copies of this
information may be obtained free of charge from the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK.
measurements in 10ꢁ4 M stock solutions in methanol, in which is
compound perfectly soluble, with pH decreasing from 7 to 3. The
percentage release of kinetin (as determined by HPLC), is given
in Table 3 at each pH. One hour after sample preparation, the com-
pound is stable up to pH 4, where only 0.9% disintegration to kine-
tin was observed. The percentage of disintegration (at pH 4)
significantly increased (to 5.9%) after 24 h of standing. The com-
pound is unstable at pH 3 and lower: the amount of disintegration
of compound 1 to kinetin was 6.8% after 1 h and 57.3% after 24 h.
The results are summarized in Table 3.
Acknowledgements
This work was financially supported by the Czech Ministry of
Education Youth and Sports (MSM 6198959216) as well as by
Grant Agency of the Czech Republic by Grant No. 522/09/1576
and by Senetek PLC company as well as by MSM 0021620857.
We would like to thank Zdena Kamarádová for skilful technical
assistance and Dr. David Morris for helpful suggestions and critical
reading of the manuscript.
4. Conclusion
References
The changes in covalent geometry near the N(9) atom of purine
moiety were attributed to N(9) substitution by a tetrahydropyran-
2-yl group. Two positions of the chair conformed tetrahydropyran-
[1] C.O. Miller, F. Skoog, F.S. Okumura, M.H. Von Saltza, F.M. Strong, J. Am. Chem.
Soc. 78 (1956) 1375.
[2] J. Barciszewski, F. Massino, B.F.C. Clark, Int. J. Biol. Macromol. 40 (2007) 182.

380
J. Walla et al. / Journal of Molecular Structure 975 (2010) 376–380
[3] P.J. Davies, Plant Hormones. Biosynthesis, Signal Transduction, Action!, Kluwer
Academic Publishers, Dordrecht, 2004
[18] M.P. Gonzales, C. Teran, Y. Fall, M. Teijeira, P. Besada, Bioorg. Med. Chem. 13
(2005) 601.
[4] S.I. Rattan, B.F. Clark, Biochem. Biophys. Res. Commun. 201 (1994) 665.
[5] <www.kinerase.com>.
[6] R. Zhang, D.S. Letham, J. Plant Growth Regul. 8 (1989) 181.
[19] M. De Zwart, R. Link, D.K. Von Frijtag, K. Jacobien, G. Cristalli, K.A. Jacobson, A.
Townsend-Nicholson, A.P. Ijzerman, Nucleos. Nucleot. 17 (1998) 969.
[20] R.K. Robins, E.F. Godefroi, E.C. Taylor, L.R. Lewis, A. Jackson, J. Am. Chem. Soc.
83 (1960) 2574.
ˇ
ˇ
[7] L. Szücová, L. Spíchal, K. Dolezal, M. Zatloukal, J. Greplová, P. Galuszka, V.
Kryštof, J. Voller, I. Popa, F.C. Massino, J.-E. Jörgensen, M. Strnad, Bioorg. Med.
Chem. 17 (2009) 1938.
ˇ
ˇ
[21] L. Szücová, M. Zatloukal, L. Spíchal, L. Fröhlich, K. Dolezal, M. Strnad, F.J.
Massino, WO 2008/008770 and US 2008009508, 2008.
[22] J.L. McCullough, R.L. Garcia, B. Reece, J. Drugs Dermatol. 7 (2008) 131.
[23] <www.senetek.com>.
[8] F. Skoog, H.Q. Hamzi, A.M. Szweykowska, N.J. Leonard, K.L. Carraway, T. Fujii,
J.P. Helgeson, R.N. Loeppky, Phytochemistry 6 (1967) 1169.
[9] S. Matsubara, Phytochemistry 19 (1980) 2239.
[10] N.P. Ramzaeva, M. Lidaks, Y.S. Goldberg, M.V. Shimanskaya, Zh. Org. Khim. 24
(1988) 1090.
[24] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M.C. Burla, G. Polidori,
M. Camalli, J. Appl. Cryst. 27 (1994) 435.
[25] G.M. Sheldrick, Acta Cryst. A 64 (2008) 112.
ˇ
[11] D. Moravcová, V. Kryštof, L. Havlícek, J. Moravec, R. Lenobel, M. Strnad, Bioorg.
[26] T.C.J. McIlvaine, J. Biol. Chem. (1921) 183.
Med. Chem. Lett. 13 (2003) 2989.
[12] N.P. Ramzaeva, I.N. Goncharova, M. Lidaks, Y.S. Goldburg, M.V. Shimanskaya,
Khim. Geterotsiklicheskikh Soedinenii 1 (1987) 113.
[13] R. Czerpak, A. Krotke, A. Mical, Polskie Arch. Hydrobiol. 46 (1999) 71 (in
Polish).
[27] M. Soriano-Garcia, R. Parthasarathy, Acta Crystallogr. B, Struct. Crystallogr.
Cryst. Chem. 33 (1977) 2674.
[28] R. Walker, P. Tollin, Cryst. Struct. Commun. 11 (1982) 399.
[29] A. Huertas, F. Espejo, C. Rojas, Universitas Scientiarum (Pontificia Universidad
Javeriana, Facultad de Ciencias), vol. 9, 2004, p. 29.
[14] E. Hayashi, N. Shimada, Yakuga. Zasshi 99 (1979) 201 (in Japanese).
[15] K. El-Bayouki, A.M. Haggag, W.M. Basyouni, Egypt. J. Chem. 33 (1991) 243.
[16] D.M.J. Wright, S.P. Stephen, S.G. Stewart, J. Peter, Bioorg. Med. Chem. Lett. 8
(1998) 3647.
[30] J.D. Figueroa Villar, M.A. Motta, Nucleos. Nucleot. Nucleic Acids 19 (5,6) (2000)
1005.
ˇ
[31] R. Marek, V. Sklenár, Ann. Rep. NMR Spectrosc. 54 (2005) 201.
[32] T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley
& Sons, New York, 1999.
[17] P. Fishman, I. Lorber, I. Cohn, T. Reitblat, PCT Int. Appl. (2006) 32.