Synthesis, crystal structures, DNA binding and cytotoxicity of two novel platinum(II) complexes containing 2-(hydroxymethyl)pyridine and pyridine-2-carboxylate ligands

Article abstract of DOI:10.1016/j.bmcl.2013.01.119

Two new platinum(II) complexes, trans-[Pt(2-mpy)₂] ·4H₂O (1) and [PtCl(2-pyc)(2-hmpy)]·H₂O (2), where 2-hmpy = 2-(hydroxymethyl)pyridine, 2-mpy = deprotonated 2-hmpy and 2-pyc = pyridine-2-carboxylate, have been synthesized and characterized by elemental analysis, IR, NMR, and X-ray crystallography. The DNA binding affinities of these complexes for Fish Sperm DNA (FS-DNA) were investigated using fluorescence, viscosity, thermal denaturation and gel electrophoresis measurements. Fluorescence analysis indicates that complex 1 binds to DNA by a single intercalative mechanism, while complex 2 exhibits two types of interactions such as intercalation and covalent binding. Gel electrophoresis assay demonstrates ability of the complexes to cleavage the supercoiled pBR322 plasmid DNA. The in vitro cytotoxicities of both complexes were preliminarily evaluated and the cytotoxicity of complex 1 against the human lung cancer cells (H1299) is similar to oxaliplatin, but higher than transplatin and carboplatin.

Full text of DOI:10.1016/j.bmcl.2013.01.119

Bioorganic & Medicinal Chemistry Letters 23 (2013) 2117–2122
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, crystal structures, DNA binding and cytotoxicity of two
novel platinum(II) complexes containing 2-(hydroxymethyl)pyridine
and pyridine-2-carboxylate ligands
b
c
d
Ceyda Icsel a, Veysel T. Yilmaz a, , Aysegul Golcu , Engin Ulukaya , Orhan Buyukgungor
⇑
a Department of Chemistry, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey
b Department of Chemistry, Faculty of Science and Arts, University of Kahramanmaraßs Sütçü Imam, Campuse of Avsar, 46100 Kahramanmaras, Turkey
c Department of Medical Biochemistry, Medical School, Uludag University, 16059 Bursa, Turkey
d Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayis University, 55139 Samsun, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new platinum(II) complexes, trans-[Pt(2-mpy)2]ꢀ4H2O (1) and [PtCl(2-pyc)(2-hmpy)]ꢀH2O (2), where
2-hmpy = 2-(hydroxymethyl)pyridine, 2-mpy = deprotonated 2-hmpy and 2-pyc = pyridine-2-carboxyl-
ate, have been synthesized and characterized by elemental analysis, IR, NMR, and X-ray crystallography.
The DNA binding affinities of these complexes for Fish Sperm DNA (FS-DNA) were investigated using fluo-
rescence, viscosity, thermal denaturation and gel electrophoresis measurements. Fluorescence analysis
indicates that complex 1 binds to DNA by a single intercalative mechanism, while complex 2 exhibits
two types of interactions such as intercalation and covalent binding. Gel electrophoresis assay demon-
strates ability of the complexes to cleavage the supercoiled pBR322 plasmid DNA. The in vitro cytotox-
icities of both complexes were preliminarily evaluated and the cytotoxicity of complex 1 against the
human lung cancer cells (H1299) is similar to oxaliplatin, but higher than transplatin and carboplatin.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 6 December 2012
Revised 25 January 2013
Accepted 27 January 2013
Available online 8 February 2013
Keywords:
Pt(II) complexes
2-(Hydroxymethyl)pyridine
Pyridine-2-carboxylate
DNA binding
Cytotoxic activity
Since the discovery that diamminedichloroplatinum(II) (cis-
[PtCl2(NH3)2], cisplatin) promotes cancer cell death by binding to
DNA,1 thousands of platinum(II) compounds have been synthe-
sized and screened in the last 30 years.2,3 In addition, great pro-
gress is being made towards examining interactions with DNA
and understanding the mechanism of anticancer activity of plati-
num compounds.4,5 Anticancer drugs that target DNA have two dif-
ferent interaction mechanisms such as covalent binding or
noncovalent interactions. It is well established that cisplatin binds
to DNA through covalent bonding via chloride ligand exchange by a
nitrogen base of DNA such as guanine N76 and forms mostly 1,2-
intrastrand cross-link that kinks the DNA structure. Noncovalent
interactions between DNA and anticancer drugs were classified
into three modes:7–9 (i) electrostatic interactions with the nega-
tively charged phosphate backbone of DNA, (ii) binding interac-
tions to the minor and major grooves of DNA double helix and
(iii) intercalation of a planar aromatic ligand between two base
the activation of the trans geometry since transplatin, the trans iso-
mer of cisplatin, is inactive as an antitumor agent and significantly
higher doses must be applied before any therapeutic effect oc-
curs.10 Platinum(II) complexes containing pyridine11–14 and a ser-
ies of monosubstituted py ligands such as hydroxypyridines,15,16
methylpyridines,12,14,17–19 hydroxymethylpyridines,14,20–24 acetyl-
pyridines,25–28 pyridine carboxylic acids24,29,30 and pyridine car-
boxamide31 have received great attention as potential anticancer
platinum(II) complexes. In some cases, the activity of these com-
plexes was comparable to that of cisplatin.
As a part of our interest in the synthesis, characterization and
anticancer activities of palladium(II) and platinum(II) complexes
containing py-based ligands,32–35 in the present letter, we report
preparation, structures and DNA binding properties of two new
platinum(II) complexes containing 2-substituted py ligands such
as 2-(hydroxymethyl)pyridine (2-hmpy) and pyridine-2-carboxyl-
ate (2-pyc), namely trans-[Pt(2-mpy)2]ꢀ4H2O (1) and [PtCl(2-
pyc)(2-hmpy)]ꢀH2O (2). The structures of both complexes were
identified by elemental analysis, IR, NMR and single crystal X-ray
techniques. Interaction of these complexes with Fish Sperm DNA
(FS-DNA) was studied by fluorescence spectroscopy, thermal dena-
turation, viscosity and gel electrophoresis measurements.
pairs via p-stacking.
Synthesis, DNA-binding and cytotoxic activity of platinum(II)
complexes with substituted pyridine (py) derivatives have been
well documented. Most of these complexes were in the configured
form of the trans isomer and the studies were mainly focused on
As shown in Scheme 1, previously prepared trans-[PtCl2(2-
hmpy)2]35 was used in the synthesis of complex 1, while complex
2 was obtained from the direct reaction of K2[PtCl4] with 2-hmpy
⇑
Corresponding author. Tel.: +90 224 2941749; fax: +90 224 2941898.
E-mail address: vtyilmaz@uludag.edu.tr (V.T. Yilmaz).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.01.119

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C. Icsel et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2117–2122
OH
O
O
N
O
Cl
N
HN
HN
N
70 °C
·4H O
Pt
2
2
Pt
+
+
2
- 2 NaCl
N
O
Cl
N
O
N
H
O
O
O
Na
Complex 1
HO
OH
N
OH
N
Cl
Cl
Cl
Cl
50 °C
Pt
K
2
2
+
·H O
2
Pt
- 2 KCl
-HCl
N
O
Cl
O
Complex 2
Scheme 1. The synthetic route of complexes 1 and 2.
at 50 °C. Both complexes were fully characterized by microanaly-
sis, IR and NMR.36 The characterization studies showed that one
of the 2-hmpy ligands was oxidized to produce the pyc ligand dur-
ing the complexation reaction of complex 2. X-ray quality yellow-
orange crystals of 1 were obtained by diffusion, while those of 2
were formed by slow evaporation of the solution at room temper-
ature. Crystal data and structure refinement details of the two
complexes are summarized in Table S1. Selected bond lengths
and angles were listed in Table S2.
Figure 1 represents the molecular structures of complexes 1 and
2. In complex 1, the platinum(II) ion lies on the inversion center
and is coordinated by two deprotonated hmpy ligands (mpy) to
form a distorted square-planar geometry of PtN2O2. The mpy an-
ions act as bidentate ligands, creating five-membered trans chelate
rings. The whole molecule, including the py ring, the –CH2–O group
and the platinum(II) ion is planar. The individual molecules are
linked by strong O–Hꢀ ꢀ ꢀO hydrogen bonds between the deproto-
nated O atom of the complex and crystal water molecules, leading
to a two-dimensional supramolecular network (Fig. S1). In com-
plex 2, the platinum(II) ion is coordinated by one hmpy, one pyc
and one chloro ligands, in a distorted square-planar arrangement
of PtN2OCl. Hmpy acts as a monodentate ligand via the py nitrogen
atom, while the the pyc anion behaves as a bidentate ligand. The py
rings of hmpy and pyc occupy the cis positions. They are not copla-
nar and the dihedral angle between them is 77°. The molecules of 2
are connected by O–Hꢀ ꢀ ꢀO hydrogen bonds, involving the hydroxyl
group of hmpy, carboxyl group of pyc and water molecules
(Fig. S1). The Pt-N(pyc), Pt-O(pyc) and Pt-Cl bond distances are in
the expected region,29,37 while the Pt-N(mpy or hmpy) bond dis-
tances in both complexes are comparable to that of trans-
[Pt(NH3)(2-hmpy)Cl2]23 and trans-[PtCl2(2-hmpy)2].35
Competitive ethidium bromide (EB) binding studies were
undertaken to monitor the binding affinity of the complexes to
DNA. Fluorescence intensities between 600–620 nm (kex = 290 nm)
were measured at different complex concentrations. EB is a planar
conjugate molecule and fluoresces weakly, but its emission inten-
sity at around 610 nm increases sharply in the presence of DNA,
Figure 1. Molecular structures of (a) trans-[Pt(2-mpy)2]ꢀ4H2O (1) and (b) [PtCl(2-
pyc)(2-hmpy)]ꢀH2O (2).

C. Icsel et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2117–2122
2119
in which the complex concentration is the value at a 50% reduction
due to the strong stacking interaction (intercalation) between the
DNA base pairs.38 Addition of a new metal complex, which may re-
place EB, results in a decrease in the fluorescence intensity. The
emission spectra of the EB–DNA solutions in the presence of com-
plexes show that the emission intensity of the EB–DNA solutions
gradually decreases on adding both complexes in increased
amounts (Fig. 2). These observations indicated that EB was par-
tially replaced by the complexes intercalating in to DNA. The
quenching ability of both complexes is evaluated by the Stern–Vol-
mer constant (KSV):39
of the fluorescence intensity of EB and KEB = 1.0 ꢂ 107 Mꢃ1
([EB] = 5.0
l
M). The Kapp values are estimated as 1.0 ꢂ 106 Mꢃ1 for
1 and 5.0 ꢂ 105 Mꢃ1 for 2. The Kapp values of the present complexes
compare well with those of platinum(II) complexes, acting as
metallointercalators.6,41,42 The binding constant of 1 is only twice
larger than that of 2. This may be due to the planar arrangement
of 2-mpy ligands around platinum(II) and as a result, complex 1
can readily intercalate into the base pairs of DNA. However, the
py rings in complex 2 are not planar and the intercalation of this
complex is prevented to some extent.
I0=I ¼ 1 þ KSV ½complexꢁ
where I0 and I are the emission intensities in the absence and pres-
ence of the complexes, respectively. KSV is also called as the quench-
ing constant. From the insets in Figure 2, the KSV values are
The fluorescence Scatchard plot was performed to determine
the binding modes of the two complexes. Fixed amounts of DNA
complex were titrated with increasing amounts of EB. Binding data
were obtained from a Scatchard plot using the equation:43
estimated as 3.07 ( 0.11) ꢂ 104 Mꢃ1 for
1
and 9.79
r
EB=CEB ¼ Kobs ðn ꢃ rEBÞ
( 0.12) ꢂ 103 Mꢃ1 for 2. These values indicate that the quenching
efficiency of complex 1 is about three times higher than 2. In addi-
tion, from the plot of intensity against complex concentration, the
values of the apparent DNA binding constant (Kapp) were calculated
using the equation:40
where rEB is the ratio of bound EB to total nucleotide concentration;
CEB is the concentration of free EB, n is the number of binding sites
per nucleic acid (maximum value of rEB); Kobs is the binding con-
stant. The concentration of the free EB was calculated using the fol-
lowing equation:44
KEB ½EBꢁ ¼ Kapp ½complexꢁ
Figure 2. Emission spectra of EB–DNA in the presence of increasing amounts complexes 1 (a) and 2 (b). [EB] = 5.0
intensity upon increasing amounts of 1 and 2. Insets: Stern–Volmer plot of the fluorescence data.
lM, [DNA] 50.0 lM. The arrows show the changes in

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C. Icsel et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2117–2122
type B behaviour with large change in both the slope and the inter-
cept (0.201 < x2 < 0.169) (see Fig. 3 and Table 1) and does not bind
to DNA by a single intercalative mechanism.43 The type B com-
plexes exhibit both intercalative interaction and covalent bonding
with DNA. Complex 2 contains a relatively good leaving ligand
(Cl). The chlorido ligand can readily be hydrolyzed in the buffers
employed, forming a positively charged species that can assist the
electrostatic interaction of the metal complexes with the DNA
strand, followed by both coordination of the metal ions to DNA
through a nitrogen base of DNA such as guanine N76 and intercala-
tion of the planar ligand between the base pairs. Therefore, the
combined effect of intercalation and covalent bonding is most likely
for [PtCl(2-pyc)(2-hmpy)]ꢀH2O (2), resulting in an effective DNA
interaction.
Additional evidence for intercalation into the DNA was obtained
from viscosity studies. An increase in relative viscosity reflects an
increase in apparent molecular length. A molecule bound to DNA
by intercalation will cause lengthening and unwinding of the
DNA helix, thus led to significant increase of viscosity of DNA solu-
tion. By contrast, groove binding and electrostatic interactions only
cause slight or no changes of viscosity.45 The viscosity experiments
were carried out by addition of increasing amount of the com-
plexes on FS-DNA and the corresponding data were illustrated in
Fig. 4. The specific viscosity of the DNA solutions increases obvi-
ously with the addition of both complexes. These results also sug-
gest that both complexes can bind to DNA in an intercalative mode.
Notably, the viscosity increase of FS-DNA is more pronounced in
the case complex 1 over r ¼ ½complexꢁ=½DNAꢁ ¼ 1.
Thermal denaturation profiles provide a convenient way for
detecting binding and also assessing relative binding strengths of
molecules. The temperature at which half of the total base pairs
is unpaired is defined as the DNA melting temperature (Tm). Tm is
strictly related to the stability of the double helix, and binding of
molecules to DNA alters the Tm values depending on its strength.
In the case of complex 1, the thermal denaturation of FS-DNA
was shown to occur in two steps, indicating that a part of the
DNA, which was not bound to the complex, melted in the first tran-
sition, then the part containing the intercalated complex melted at
a higher temperature. However, complete denaturation occurred in
one-step in the case of complex 2. The Tm of FS-DNA in the absence
of the complexes is 62 °C. As can be seen from Figure 5, the Tm va-
lue of the FS-DNA solutions increased significantly with the addi-
tion of the complexes. For example, at r = 0.50, 4Tm values of 1
(5 °C) and 2 (9 °C) suggest that the insertion of these complexes en-
hanced the stability of the DNA double helix conformation and in-
creased the DNA melting temperature.
Figure 3. Fluorescence Scatchard plots for the binding of EtBr (2ꢃ10
lM) to DNA in
the presence (lines aꢃd) of increasing concentrations of complexes 1 and 2.
Table 1
Binding parameters for the fluorescence Scatchard plot of FS-DNA with EB in the
presence of complexes 1 and 2
Complex
rfa
Kobs (ꢂ 105 Mꢃ1
)
n
1
0.25
0.5
1.0
10.58
4.16
3.21
2.45
0.201 0.001
0.198 0.003
0.193 0.003
0.192 0.028
2.0
2
0.25
0.5
1.0
4.71
1.11
0.43
0.41
0.200 0.008
0.189 0.012
0.174 0.017
0.169 0.019
2.0
a
rf is the formal ratio of complex to nucleotide concentration with values ranging
from 0.25 to 2.0.
CEB ¼ ½ðF ꢃ F0Þ=ðFmax ꢃ F0ꢁ Ctotal
where Ctotal is the total ethidium bromide concentration, F0 is the
observed fluorescence emission intensity of EB in the absence of
DNA, Fmax is the intensity of EB–DNA in the absence of complex,
and F is the fluorescence of the totally bound EB–DNA-complex.
The fluorescence Scatchard plots obtained for competition of the
platinum(II) complexes with EB to bind with DNA are given in Fig-
ure 3. The binding parameters of the fluorescence Scatchard plot of
FS-DNA with EB in the presence of complexes are presented in Ta-
ble 1. Obviously, the plots display different affinity and binding
sites. Complex 1 produces a Scatchard plot in which the slope de-
creases in the presence of increasing amounts of complex, with lit-
tle change in the intercept on the abscissa (0.205 < x1 < 0.192). It
exhibits a type A behaviour, typical of intercalating agents and com-
petitive inhibition of EB binding.43 By contrast, complex 2 shows a
Figure 4. The relative viscosity of FS-DNA upon addition of increasing amounts of
complexes 1 and 2 (r = 0.2ꢃ3.0).
g is the viscosity of DNA in the presence of
complex, and g0 is the viscosity of DNA alone.

C. Icsel et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2117–2122
2121
Table 2
IC50 values of complexes 1 and 2, transplatin, cisplatin, carboplatin and oxaliplatin
against selected cancer cellsa after the treatment for 48 h
Complexes
IC50 (lM)
H1299
5RP7
1
2
124.9 2.2
166.5 2.6
136.2 2.4
20.9 1.2
>200
>200
185.2 8.0
122.8 6.8
12.2 0.8
68.7 8.8
9.3 1.1
transplatin
cisplatin
carboplatin
oxaliplatin
118.9 4.6
a
H1299 = human lung cancer cell line, and 5RP7 = rat transformed fibroblast
cancer cells.
Gel electrophoresis assay demonstrates that both complexes effi-
ciently cleavage the supercoiled pBR322 plasmid DNA without
any reducing and oxidizing agent.
Figure 5. Thermal denaturation profiles of FS-DNA (100
lM) in the absence and in
the presence of complexes 1 and 2 (50 M) in a Tris/HCl buffer solution.
l
Two malignant cell lines, of which one is epithelia-originated
(H1299 from lung) and the other is stroma-originated (5RP7 from
connective tissue), were used to investigate the cytotoxic activity
of the two complexes and their clinically-used variants as shown
in Table 2. It was found that cisplatin was the most cytotoxic agent
against the epithelial cell line while oxaliplatin was the most po-
tent against to stromal cell line. This shows that a powerful drug
does not necessarily show the same degree of cytotoxic activity
against all kinds of tumor. In the case of the H1299 cell line, com-
plex 1 showed better activity than complex 2, transplatin and car-
boplatin but it was much less active than cisplatin. For the same
cell line, the IC50 value of 2 was found to be markedly higher than
that of carboplatin. On the other hand, complex 2 is only slightly
more active than complex 1 against the 5RP7 cell line. However,
complex 2 did not seem to have a satisfactory cytotoxic activity
against this cell line, compared to transplatin and clinically-used
platinum-based anticancer drugs.
In conclusion, two novel complexes trans-[Pt(2-mpy)2]ꢀ4H2O
(1) and [PtCl(2-pyc)(2-hmpy)]ꢀH2O (2) have been synthesized
and characterized. Their crystal structures were determined by sin-
gle crystal X-ray diffraction. The DNA binding properties of the
complexes were examined by fluorescence spectroscopy, viscosity
and thermal denaturation measurements. The observations show
that the complexes interact with FS-DNA by intercalation with dif-
ferent binding affinities. Complex 1 bind to DNA by a single inter-
The cleavage of plasmid pBR322 DNA is achieved by agarose gel
electrophoresis, monitoring the transition from the closed circular
supercoiled from (Form I) to the open circular relaxed form (Form
II). Figure 6 shows the results of gel electrophoretic separations of
pBR322 DNA induced by metal complexes at various concentra-
tions. The untreated DNA (lane 0) exhibits two clear bands, corre-
sponding to Forms I and II, as expected. The progress of the
cleavage reactions with different concentrations of each complex
was shown in lanes 1–4. It is clearly seen that both complexes
can induce the obvious cleavage of the plasmid DNA since the
intensity of Form I band decreases markedly with increasing
amount of the complexes. The change in mobility of Form I DNA
band with the increase in the concentration of the complexes is
due to unwinding of the supercoiled Form I DNA. In the case of
2, at high concentrations (Lanes 3 and 4), smearing begins to occur
due to the degradation of DNA. This may be explained by the dual
interaction (intercalation and coordination) of this complex with
DNA, since covalent binding causes oxidative damage to DNA.46
calative mechanism, while complex
2 shows two types of
interactions such as intercalation and covalent binding. The capa-
bility of cleavage of pBR322 DNA by the complexes was investi-
gated using agarose gel electrophoresis, and the results indicate
that all complexes exhibit efficient DNA cleavage. The cytotoxic
studies show that the complexes exhibit low cytotoxic activity
against different cell lines tested. However, complex 1 showed
IC50 values lower than those found for transplatin and carboplatin.
Acknowledgment
We thank Uludag University for the financial support given to
the project.
Supplementary data
CCDC 908442 (complex 1) and 908443 (complex 2) contain the
supplementary crystallographic data for this Letter. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data (experimental methods, tables and figures)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.bmcl.2013.01.119.
Figure 6. Cleavage of pBR322 DNA (10
complexes 1 and 2 at several reactive concentrations (lanes 1ꢃ4): lane 1, 50
lane 2, 100 M; lane 3, 200 M; lane 4, 400 M. Form I and II represent the
supercoiled form and the open circular form, respectively.
l
M) in the absence (lane 0) and presence of
lM;
l
l
l

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C. Icsel et al. / Bioorg. Med. Chem. Lett. 23 (2013) 2117–2122
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Biochem. 2009, 103, 1221.
36. Complex 1: Yellow crystals, yield 71%, mp 190–205 °C (decomp.). Anal. Calcd
for C12H20N2O6Pt: C, 29.8; H, 4.2; N, 5.8. Found: C, 29.9; H, 4.0; N, 6.0%.1H NMR
3
(400 MHz, DMSO-d6): d (ppm) 8.45–8.43 (d, 2H, JHH = 5.6 Hz, H6-py), 7.99–
7.94 (td, 2H, 3JHH = 8.0 Hz, H4-py), 7.49–7.47 (d, 2H, 3JHH = 7.2 Hz, H3-py), 7.34–
7.30 (t, 2H, 3JHH = 7.2 Hz, H5-py), 5.01 (s, 4H, –CH2).13C NMR (400 MHz, DMSO-
d6): d 174.67, 147.38, 138.00, 123.17, 119.95, 75.67. (solid KBr pellet):
m )
(cmꢃ1
3404bs, 3191bs, 2909vw, 2880vw, 2844vw, 1679w, 1610w, 1569w,1485m,
1444vs, 1368w, 1287m, 1217m, 1160w, 1046s,1026vs, 833m, 770vs, 712s,
667vs, 632bs, 524s, 434m.
Complex 2: Yellow–orange crystals, yield 55%, mp 216–225 °C (decomp.). Anal.
Calcd for C12H13ClN2O4Pt: C, 30.0; H, 2.7; N, 5.8. Found: C, 29.8; H, 2.9; N, 6.1%.
3
1H NMR (400 MHz, DMSO-d6): d (ppm) 9.12–9.11 (d, H, JHH = 5.6 Hz, H6-pyc),
3
3
8.35–8.30 (td, H, JHH = 7.6 Hz, H4-pyc), 8.16–8.12 (t, H, JHH = 7.6 Hz, H5-pyc),
7.90–7.87 (d, H, 3JHH = 7.6 Hz, H3-pyc), 7.82–7.80 (d, H, 3JHH = 8.0 Hz, H4-hmpy),
3
3
7.63–7.60 (t, H, JHH = 7.6 Hz, H3-hmpy), 7.52–7.48 (t, H, JHH = 7.6 Hz, H5-
hmpy), 7.45–7.44 (d, H, 3JHH = 5.6 Hz, H6-hmpy), 5.34–5.12 (dd, 4H, –CH2), 4.66
(s, H,–OH). 13C NMR (400 MHz, DMSO-d6): d 174.87, 164.34, 154.45, 149.29,
147.02, 141.12, 140.30, 130.63, 127.97, 125.38, 124.52, 64.33. (solid KBr
pellet):
m
(cmꢃ1) 3436b, 3138vw, 3097vw, 3069w, 3003vw, 2921vw, 1692vs,
1609s, 1577w, 1540w, 1479w, 1327s, 1280s, 1268m, 1155m, 1062m, 870m,
765s, 727w, 683s, 649vw, 568vw, 535vw, 479m.
37. Annibale, G.; Cattalini, L.; Canovese, L.; Pitteri, B.; Tiripicchio, A.; Camellini, M.
T.; Tobe, M. L. J. Chem. Soc. Dalton Trans. 1986, 1101.
38. LePecq, J.-B.; Paoletti, C. J. Mol. Biol. 1967, 27, 87.
39. Stern, O.; Volmer, M. Z. Physics 1919, 20, 183.
40. Lee, M.; Rhodes, A. L.; Wyatt, M. D.; Forrow, S.; Hartley, J. A. Biochemistry 1993,
15, 4339.
41. Gao, E. J.; Liu, L.; Zhu, M. C.; Huang, Y.; Guan, F.; Gao, X. N.; Zhang, M.; Wang, L.;
Zhang, W. Z.; Sun, Y. G. Inorg. Chem. 2011, 50, 4732.
42. Howe-Grant, M.; Lippard, S. J. Biochemistry 1979, 18, 5762.
43. Howe-Grant, M.; Wu, K. C.; Bauer, W. R.; Lippard, S. J. Biochemistry 1976, 15,
4339.
44. Kumar, C. V.; Asuncion, E. H. J. Am. Chem. Soc. 1993, 115, 8547.
45. Suh, D.; Chaires, J. B. Bioorg. Med. Chem. 1995, 3, 723.
46. Richards, A. D.; Rodger, A. Chem. Soc. Rev. 2007, 36, 471.
28. Rakic, G. M.; Grguric-Sipka, S.; KaluCerovic, G. N.; Gomez-Ruiz, S.; Bjelogrlic, S.
K.; Radulovic, S. S.; Tesic, Z. L. Eur. J. Med. Chem. 1921, 2009, 44.