New bioconjugated rhenium carbonyls by transmetalation reaction with zinc derivatives

Article abstract of DOI:10.1021/om300394v

The transmetalation reaction between zinc dithiocarbamates and rhenium carbonyls has been used as a new strategy to link biomolecules to transition metals. The zinc(II) dithiocarbamate of isonipecotic acid (1) and the succinimidyl ester derivative (2) were prepared by straightforward procedures and were fully characterized by spectroscopic and X-ray diffraction methods, showing in both cases the presence of dinuclear complexes. Complex 2 reacted with all the primary and secondary amines studied (glycine methyl ester, β-alanine methyl ester, 1-(2-methoxyphenyl)piperazine, and d-(+)-glucosamine) through the activated succinimidyl ester group, linking the metallic fragment with the biomolecule by the formation of a peptidic bond and leading to the respective bioconjugated zinc complexes 3-6. In all cases, these zinc complexes could be isolated from the reaction medium by simple precipitation. These results evidence the potential of complex 2 to be used as a synthon to link the zinc dithiocarbamate fragment to biomolecules that contain an amine group. Complexes 3-6 were characterized by the usual spectroscopic methods, and all data agree with the proposed structures, which do not contain significant interactions between the zinc fragment and the functional groups of these biomolecules. The transmetalation reaction between the zinc complexes 3-6 and the rhenium carbonyl [ReBr₃(CO)₃]^2- led to the expected rhenium dithiocarbamates 7-10 with no change in the organic dithiocarbamate fragments, confirming the viability of this reaction as a tool for linking biomolecules to transition elements. All complexes were characterized by spectroscopic methods, and the crystal structure of 8 was studied by X-ray diffraction analysis. All data demonstrated that the biomolecule is positioned far away from the fac-{Re(CO)₃} fragment, and the octahedral coordination around the metal is completed by the functionalized dithiocarbamate and a phosphine ligand. Finally, analysis by ESI-MS spectrometry of the reaction between the zinc complex 4 and a water solution of [Re(H₂O)₃(CO)₃]⁺ at a very low concentration (10 ppm) showed that the transmetalation reaction took place, even though the solubility of the zinc complex in water medium was as low as 0.66 ppm. This preliminary result supports the viability of this approach for the preparation of rhenium and technetium target-specific radiopharmaceuticals, since the preparations of these compounds are always performed in water medium.

Full text of DOI:10.1021/om300394v

Article
pubs.acs.org/Organometallics
New Bioconjugated Rhenium Carbonyls by Transmetalation Reaction
with Zinc Derivatives
†
‡
§
‡
∥
,†
́
J. Lecina, A. Carrer, A. Alvarez-Larena, U. Mazzi, L. Melendez-Alafort, and J. Suades*
†
́
̀
Departament de Quımica, Edifici C, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain
‡Department of Pharmaceutical Sciences, University of Padova, 35131 Padova, Italy
§X-ray Diffraction Service, Universitat Auton
̀
oma de Barcelona, 08193 Bellaterra, Spain
∥Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy
S
* Supporting Information
ABSTRACT: The transmetalation reaction between zinc
dithiocarbamates and rhenium carbonyls has been used as a
new strategy to link biomolecules to transition metals. The
zinc(II) dithiocarbamate of isonipecotic acid (1) and the
succinimidyl ester derivative (2) were prepared by straightfor-
ward procedures and were fully characterized by spectroscopic
and X-ray diffraction methods, showing in both cases the
presence of dinuclear complexes. Complex 2 reacted with all the primary and secondary amines studied (glycine methyl ester, β-
alanine methyl ester, 1-(2-methoxyphenyl)piperazine, and D-(+)-glucosamine) through the activated succinimidyl ester group,
linking the metallic fragment with the biomolecule by the formation of a peptidic bond and leading to the respective
bioconjugated zinc complexes 3−6. In all cases, these zinc complexes could be isolated from the reaction medium by simple
precipitation. These results evidence the potential of complex 2 to be used as a synthon to link the zinc dithiocarbamate fragment
to biomolecules that contain an amine group. Complexes 3−6 were characterized by the usual spectroscopic methods, and all
data agree with the proposed structures, which do not contain significant interactions between the zinc fragment and the
functional groups of these biomolecules. The transmetalation reaction between the zinc complexes 3−6 and the rhenium
carbonyl [ReBr3(CO)3]2− led to the expected rhenium dithiocarbamates 7−10 with no change in the organic dithiocarbamate
fragments, confirming the viability of this reaction as a tool for linking biomolecules to transition elements. All complexes were
characterized by spectroscopic methods, and the crystal structure of 8 was studied by X-ray diffraction analysis. All data
demonstrated that the biomolecule is positioned far away from the fac-{Re(CO)3} fragment, and the octahedral coordination
around the metal is completed by the functionalized dithiocarbamate and a phosphine ligand. Finally, analysis by ESI-MS
spectrometry of the reaction between the zinc complex 4 and a water solution of [Re(H2O)3(CO)3]+ at a very low concentration
(10 ppm) showed that the transmetalation reaction took place, even though the solubility of the zinc complex in water medium
was as low as 0.66 ppm. This preliminary result supports the viability of this approach for the preparation of rhenium and
technetium target-specific radiopharmaceuticals, since the preparations of these compounds are always performed in water
medium.
organometallic radiopharmaceuticals for nuclear medicine
applications. The transmetalation reaction is currently
employed in radiopharmacy to produce the organometallic
compound (99mTc)sestamibi.4 However, in our proposal we use
this reaction innovatively for a very different goal.
Molecular imaging methods are useful in medicine because
they allow the visualization of biochemical processes in living
organisms and can help the diagnosis of some diseases by
noninvasive techniques. The labeling of biologically active
molecules with a radionuclide is currently a topic of great
interest in radiopharmacy, because it can lead to specific tracers
with potential new applications in oncology,5,6 infection
INTRODUCTION
■
Transmetalation is one of the basic reactions in inorganic
chemistry that is defined as the exchange of ligands between
two metal atoms. It has been used since the beginnings of
organometallic chemistry as a practical tool to prepare new
compounds, being based on the substitution of a weak carbon−
metal bond such as Hg−C by a stronger bond such as Zn−C.1
Currently, this reaction continues to be extremely useful in the
synthesis of new compounds, and one pertinent example is the
use of silver N-heterocyclic carbenes (NHCs) for the
preparation of transition-metal carbenes.2
The use of organometallics in biology and medicine, and
particularly the search for organometallic pharmaceuticals, has
become a relevant research topic in the last few decades.3 In
this context, the goal of this study is to apply the
transmetalation reaction to improve the preparation of
Special Issue: Organometallics in Biology and Medicine
Received: May 10, 2012
© XXXX American Chemical Society
A
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Figure 1. Schematic representation of the competition between labeled and unlabeled molecules for receptor sites after a labeling reaction.
Scheme 1
Scheme 2
imaging,6 neuroreceptor imaging,7,8 and other medical special-
ties. Depending on the emission properties of the radionuclide,
either of two imaging methods can be used: positron emission
tomography (PET) or single photon emission computed
tomography (SPECT). The radionuclide mainly used for
SPECT is 99mTc,4,8 which gives rise to a wide range of
radiopharmaceuticals by simple preparation procedures and is
easily accessible by 99Mo/99mTc generators.
Furthermore, organometallic radiopharmaceutical chemistry
has been greatly stimulated in recent years after the
development of simple and convenient preparations of the
aqua ions fac-[99mTc(H2O)3(CO)3]+ and fac-[188Re-
(H2O)3(CO)3]+. The labile properties of water ligands in
these cations permit the straightforward preparation of new
rhenium and technetium radiopharmaceuticals with carbonyl
ligands, which exhibit small size, high thermodynamic stability,
kinetic inertia, and high in vivo stability.9 All these properties
make the fac-{M(CO)3} fragment (M = Tc, Re) an excellent
synthon for developing new specific tracers with biologically
active molecules. Therefore, most of the current research work
with this metal carbonyl is oriented toward the development of
new bioconjugated compounds.10 However, there are some
difficulties that are inherent to the preparation of specific
tracers with 99mTc carbonyls. A problematic point regarding the
preparation of such compounds for radiopharmaceutical
application is shown schematically in Figure 1.
Since the concentration of radioactive metal in the labeling
reactions is very low (10−7−10−8 M), only a very small portion
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Scheme 3
Figure 2. Perspective view of the centrosymmetric dimeric anion [Zn2(S2CNC5H9COO)4]4− of complex 1. Hydrogen atoms have been omitted for
clarity.
of functionalized biomolecules are in fact labeled with the metal
carbonyl fragment (functionalized biomolecules have the ability
to bond to the metal fragment, as is shown in the figure).
Consequently, in the radiopharmaceutical preparation the ratio
of labeled to unlabeled biomolecules is very low, meaning that
the labeled biomolecules must compete with unlabeled
biomolecules for the receptor sites.11 In order to improve the
ratio of labeled to unlabeled biomolecules in radiopharmaceut-
ical preparations, we have designed a new approach that allows
two apparently contradictory objectives: (1) a high labeling
yield (nearly all radioactive metals should be linked to the
biomolecule) and (2) a low unlabeled biomolecule concen-
tration in the reaction mixture. This new strategy is based on
using a transmetalation reaction between a zinc complex of the
functionalized biomolecule which is sparingly soluble in water
and the radioactive metal in water solution (Scheme 1).
This reaction is shifted to the right by the higher
thermodynamic stability of bonds with the {M(CO)3} fragment
(M = Tc, Re) with respect to the zinc atom. Concurrently, the
concentration of unlabeled biomolecule in the reaction mixture
can be very low because it is limited by the low solubility of the
bioconjugate zinc compound in water.
dithiocarbamate of isonipecotic acid can act as a
bifunctional chelating agent16 (BFCA) because it can
work as a linker between the metal (bonded to the
dithiocarbamate function) and the biomolecule (bonded
by a peptidic bond).
(4) It is expected that the zinc dithiocarbamate derivative of
isonipecotic acid will show low toxicity. Indeed,
isonipecotic acid17 and zinc dithiocarbamates18 are
involved in pharmacological studies and the dithiocarba-
mate of isonipecotic acid exhibits anti-inflammatory
activity.19
RESULTS AND DISCUSSION
■
Zinc(II) Dithiocarbamate of Isonipecotic Acid (1). This
compound was prepared by the reaction between a solution of
the sodium dithiocarbamate of isonipecotate prepared “in situ”
from the amine12 and a water solution of zinc(II) acetate
(Scheme 3). Complex 1 was obtained in high yield (84%) and
high purity by simple crystallization from the reaction medium.
One interesting aspect is that this compound is scarcely soluble
in water and, as was stated in the Introduction, the low
solubility of zinc compounds may be useful to improve the
labeled/unlabeled ratio in radiopharmaceutical preparation.
Thus, the compound was characterized by NMR spectroscopy
in D2O but all spectra were recorded at a temperature of 40 °C
in order to improve the solubility of 1. All spectroscopic data
agree with the proposed structure. For instance, the character-
istic signals of the dithiocarbamate group observed in the 13C
NMR (201.8 ppm) and the IR spectra (1493 cm−1, ν(CN))
are consistent with reported data for bidentate metal
dithiocarbamates.20 The presence of the isonipecotic fragment
To this purpose, we designed a new compound based on a
derivative of isonipecotic acid (Scheme 2) as a key compound
in attaining our goal, given its following advantages.
(1) The dithiocarbamate of isonipecotic acid has been
reported.12 It displays an appropriate structure for our
purposes because it can lead to very stable, symmetric
compounds, since the amine group in isonipecotic acid is
a symmetric secondary amine.
(2) Zinc dithiocarbamates are stable compounds13 that
exhibit transmetalation14 reactions with transition metals.
Therefore, a zinc dithiocarbamate with the structure
shown in Scheme 2 can be useful for the transmetalation
reaction displayed in Scheme 1.
1
is evidenced by the H NMR spectrum, in which all observed
signals could be assigned to the hydrogen atoms of the
heterocycle by means of 2D experiments (COSY, HSQC, and
NOESY), and these assignments agree with reported data for
isonipecotic acid.21
The crystal structure of 1 (Figure 2) shows the formation of
the postulated zinc dithiocarbamate but also reveals that it is a
(3) The above structure contains an N-hydroxysuccinimidyl
ester group suitable for coupling reactions with amines in
order to link the metal to a biomolecule.15 Hence, this
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Scheme 4
Figure 3. Perspective view of the centrosymmetric dimeric complex 2. Hydrogen atoms have been omitted for clarity.
Scheme 5
dinuclear centrosymmetric compound in the solid state. This is
a common arrangement for zinc dithiocarbamates,22 although
monomeric compounds have also been reported.23 The analysis
of this structure shows that bond distances and angles of the
core {Zn2S8} are very similar to previously reported data for
dinuclear zinc dithiocarbamates with simple alkyl groups such
as ethyl24 and isopropyl.25 The geometry around the zinc atom
is intermediate between trigonal bipyramidal and tetragonal
pyramidal, with four similar Zn−S distances (Zn−S21 =
2.3433(5) Å, Zn−S12 = 2.3457(6) Å, Zn−S22i = 2.3972(5) Å,
Zn−S11 = 2.4780(5) Å; i denotes an equivalent atom by an
inversion center), whereas one Zn−S bond is significantly
D
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Scheme 6
longer (Zn−S22 = 2.8162(5) Å). Similar values have been
reported for zinc diethyldithiocarbamate (2.331, 2.355, 2.383,
2.443, 2.815 Å)24 and zinc diisopropyldithiocarbamate (2.335,
2.342, 2.377, 2.454, 2.815 Å).25
reaction to the preparation of bioconjugated Zn(II) dithio-
carbamates (Scheme 5).
The NMR analysis of the reaction mixture showed that the
reaction of 2 with the methyl esters of glycine and β-alanine is
nearly quantitative after a few hours at room temperature.
Thus, complexes 3 and 4 could be isolated from the reaction
mixture by the simple addition of an ethanol/water mixture.
This very direct procedure gives pure compounds that can be
used without recrystallization in subsequent reactions.
Once the viability of this approach was established with the
model compounds 3 and 4, 1-(2-methoxyphenyl)piperazine
was chosen as the next reagent to be studied. This amine can be
viewed as a small biomolecule, because compounds with an
Succinimidyl Ester of Zinc(II) Dithiocarbamate of
Isonipecotic Acid (2). Although the preparation of
succinimidyl ester derivatives from carboxylic acid is a well-
known process, in most synthetic pathways reported the
starting reagent is carboxylic acid; this route is not feasible in
our case, since dithiocarbamates are not stable in acidic
medium. This problem was solved by using the peptide
coupling reagent TSTU (N,N,N′,N′-tetramethyl-O-(N-
succinimidyl)uronium tetrafluoroborate; CAS 105832-38-0),
since it can react directly with the carboxylate group and it
avoids working in acid media (Scheme 4). Furthermore, the
preparation procedure by this way is very straightforward and
convenient because compound 2 can be isolated from the
dimethylformamide reaction medium by simple precipitation
after addition of an ethanol/water mixture, allowing us to
obtain 2 in high yield (above 95%) and purity.
Spectroscopic data of 2 are fully consistent with the proposed
structure. Thus, ESI-MS shows a molecular weight increase due
to the formation of the succinimidyl ester group and NMR
spectroscopy displays all signals of the succinimidyl fragment,
as well as the shift of resonances of the isonipecotic fragment
atoms closer to the ester group such as the carbonyl carbon and
the hydrogen in position 4 of the piperidine ring. Single crystals
of 2 could be obtained by recrystallization from acetonitrile.
The X-ray diffraction analysis corroborated the proposed
structure, represented in Figure 3.
When this structure is compared with that of compound 1,
the strong similarity between the {Zn2S8} cores in both
complexes is obvious. This result evidences that the conversion
of the carboxylate group in 1 to the corresponding succinimidyl
ester has a minimum influence on the dithiocarbamate group.
The coordination around the zinc atoms is analogous in both
complexes, with one Zn−S distance being significantly longer
than the others (Zn−S distances for 2: Zn−S21 = 2.369(2) Å,
Zn−S12 = 2. 2.364(3) Å, Zn−S22i = 2.371(2) Å, Zn−S11 =
2.413(2) Å, Zn−S22 = 2.753(2) Å; i denotes an equivalent
atom by an inversion center).
Bioconjugated Zn(II) Dithiocarbamates (3−6). As
stated in the Introduction, complex 2 was designed with
activated ester groups with the aim of preparing bioconjugated
compounds by means of a coupling reaction with an amine
group of a biomolecule. In the first stage, we studied the
reaction between 2 and the methyl esters of the amino acids
glycine and β-alanine as a test for the application of this
26
arylpiperazine moiety are useful for binding to 5-HT1A
serotonergic receptors in the central nervous system and
radiopharmaceuticals with this fragment27 are highly relevant
for the study of neuropsychiatric diseases. Furthermore, since
this compound is a piperazine derivative, it is useful for testing
if the ability of 2 to react with amines can be extended to
secondary amines. Experimental results confirmed this
hypothesis, and the functionalized zinc dithiocarbamate 5 was
prepared by following a method as simple as that used for the
synthesis of the model compounds 3 and 4; as was noted for
those compounds, 5 was also obtained pure in good yield
(71%).
The last compound of this family was prepared by reaction
between 2 and D-(+)-glucosamine to yield the bioconjugate
dithiocarbamate 6. This reagent was chosen because obtaining
99mTc-glucose derivatives is a subject of prime interest, due to
the notion that these compounds could be a more readily
available and less expensive alternative to 18F-2-deoxy-2-fluoro-
D-glucopyranose (FDG), which is currently employed for
tumor imaging.28 As in previous complexes, 6 was also obtained
as a pure compound by a similarly simple procedure with minor
differences due to the different solubilities of glucose
derivatives.
All synthesized compounds were characterized by the usual
spectroscopic and spectrometric techniques. NMR signals
corresponding to the isonipecotic fragment were observed in
all compounds in positions similar to those found for 2, the
most shifted signal being the resonance in 1H NMR assigned to
the hydrogen at position 4 of the piperidine ring, which is
consistent with the substitution of the succinimidyl ester
located in the same position by the amide group in 3−6. In
addition, the expected signals of all amide fragments were
1
observed in H and 13C NMR spectroscopy, as well as the
molecular ion peak (M + Na+) for the functionalized zinc
dithiocarbamates 3−6.
E
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Rhenium Carbonyl Compounds Prepared by Trans-
metalation Reactions (7−10). The transmetalation reaction
between the functionalized zinc complexes 3−6 and rhenium
was studied with the carbonyl [ReBr3(CO)3]2−, as shown in
Scheme 6.
This reaction was carried out in methanol, although the
solubility of zinc complexes 3−6 is very low in this medium.
Thus, the fast conversion of suspensions of zinc complexes 3−6
in methanol into clear solutions after the addition of rhenium
carbonyl is indicative of the driving force of the transmetalation
reaction. 13C NMR spectroscopy confirms the nearly
quantitative character of this reaction, since NMR analysis of
the reaction mixture shows the complete absence of the signal
assigned to the carbon atom of a dithiocarbamate group linked
to zinc (∼204 ppm) and it displays a downfield-shifted peak
(∼210 ppm) assigned to the dithiocarbamate bonded to
rhenium.
Carbonyl complexes 7−10 were characterized by the usual
spectroscopic and spectrometric techniques. The NMR
chemical shifts of groups coordinated to rhenium metal are
consistent with reported data for other [Re(CO)3(SS)(P)]
complexes,29 showing the resonances of coordinated phosphine
(31P) and the carbon atom of the dithiocarbamate group linked
to rhenium. The signals of the characteristic set of fac-
{Re(CO)3} fragments are displayed in the IR spectra, and the
molecular peaks (M + Na+) are observed for complexes 7−10
in ESI-MS spectrometry. Spectroscopic data of functional
groups linked to dithiocarbamate are similar to those of
complexes 3−6, showing that the substitution of zinc metal by
rhenium has very little influence on the biomolecular fragment.
The crystal structure of complex 8 confirms the proposed
structure for rhenium complexes, showing an arrangement very
similar to those previously reported for other [Re(CO)3(SS)-
(P)] complexes29,30 (Figure 4). The coordination around
temperature and shows the coalescence of the two signals at
temperatures of nearly 50 °C. This result is consistent with the
existence of two isomers differing in the position of the
biomolecular fragment linked to the C4 atom of the piperidine
ring (axial or equatorial). The position of this group can be
interconverted at low temperatures via different mechanisms,
such as a rotation around the C−N bond of dithiocarbamate.31
No separation between the two isomers was possible by HPLC
analysis of 7−10, and a single peak was always observed. These
results support the hypothesis of a fast conversion between the
two isomers that makes their separation unviable.
Although the reaction between the zinc dithiocarbamates 3−
6 and the rhenium carbonyl [ReBr3(CO)3]2− confirms the
viability of the transmetalation reaction, to take advantage of
this approach in radiopharmacy, the reaction must be feasible in
aqueous medium. With the aim of exploring this possibility, the
reaction of an aqueous solution of [Re(H2O)3(CO)3]+ at a very
low concentration (10 ppm) with the zinc complex 4 was
studied as shown in Scheme 7. Complex 4 and triphenylphos-
phine were successively added as solid compounds to an
aqueous solution of [Re(H2O)3(CO)3]+, yielding a suspension
that was heated and finally centrifuged. The formation of the
rhenium complex 8 was evidenced by the ESI-MS of the clear
water solution, which gave a unique signal with the isotopic
pattern of rhenium. This peak corresponds to the molecular
signal (M + Na+) previously observed for complex 8. It should
be emphasized that this reaction runs in aqueous medium, even
though the solubility of the reactants in water is very low (the
solubility of the zinc complex 4 was measured by inductively
coupled plasma optical emission spectrometry (ICP-OES); it
was as low as 0.66 ppm). Consequently, this approach provides
a simple method for performing high-yield reactions with a low
concentration of the reactants in the reaction medium. The
application of this method to radiopharmacy could provide
radiopharmaceuticals with a very high ratio of labeled to
unlabeled biomolecules (see Figure 1).32
CONCLUSIONS
■
The zinc dithiocarbamate of isonipecotic acid (1) and its
succinimidyl ester (2) are new complexes that have been
synthesized using simple preparation procedures which allow
obtaining the desired complex in high yield and purity for use
in subsequent reactions. The X-ray diffraction analyses of these
complexes have shown very similar dinuclear structures for
both, confirming that there are no relevant interactions
between the succinimidyl fragment and the metal atom in 2.
All these results indicate that compound 2 can be an excellent
starting material for the conjugation of biomolecules to zinc.
Hence, we established the versatility of complex 2 to act as a
synthon for linking the zinc dithiocarbamate fragment to
molecules that contain a primary or secondary amine by a
coupling reaction with the succinimidyl ester group. This
reaction has been performed with glycine, β-alanine, 1-(2-
methoxyphenyl)piperazine, and D-(+)-glucosamine, yielding
the zinc complexes 3−6. The low solubility of these complexes,
in conjunction with the high yield of the coupling reaction,
permits obtaining pure 3−6 by simple addition of an alcohol or
alcohol/water mixture to the reaction medium.
Figure 4. Perspective view of complex 8. Hydrogen atoms have been
omitted for clarity.
rhenium metal can be described as a slightly distorted
octahedron, in which the main distortion comes from the
chelated dithiocarbamate, which forces the S−Re−S angle to be
near 70°.
A remarkable detail of complexes 7−10 is that two signals of
different intensity and with similar chemical shifts (separated by
0.4−0.6 ppm) are observed in the 31P NMR spectra and an
analogous situation is detected for some 1H NMR signals. This
phenomenon was not observed in previous studies with other
[Re(CO)3(SS)(P)] complexes, and it suggests the presence of
two isomers in solution. The shape of this signal evolves with
The study of the transmetalation reaction between the
rhenium carbonyl [ReBr3(CO)3]2− and the zinc dithiocarba-
mates 3−6 has led to the rhenium dithiocarbamates 7−10, in
accord with the higher stability of complexes with an element of
the third transition series with a d6 configuration with respect to
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Scheme 7
(COO−), 52.5 (S2CNCH2), 43.8 (S2CNCH2CH2CH), 29,4
(S2CNCH2CH2). ESI MS (negative mode, m/z): 493 (M − Na+).
Anal. Calcd for C14H18N2Na2O4S4Zn·2H2O: C, 30.35; H, 4.00; N,
5.06. Found: C, 30.39; H, 3.91; N, 4.97.
the zinc (d10). The crystal structure analysis of 8 was solved,
showing a coordination set around the rhenium metal similar to
that of other [Re(CO)3(SS)(P)] complexes. The study of the
transmetalation between a very dilute solution of [Re-
(H2O)3(CO)3]+ (10 ppm) and complex 4 has evidenced that
this reaction is so favorable that it takes place at very low metal
concentration, although the water solubility of the zinc complex
4 is as low as 0.66 ppm. This result highlights the potential
application of this approach to the preparation of radiophar-
maceuticals, since it can improve the ratio of labeled to
unlabeled biomolecules because the concentration of the zinc
labeling reagent in the reaction media is limited by its low
solubility. If it is true that the radionuclide concentration under
labeling conditions is still below the solubility of 4, it should be
noted that complex 4 is just a model compound (β-alanine
methyl ester derivative) and it is reasonable to think that zinc
complexes bioconjugated to larger biomolecules may show
lower solubility.
Synthesis of Complex 2. N,N,N′,N′-Tetramethyl-O-(N-
succinimidyl)uronium tetrafluoroborate (TSTU; 256 mg, 0.85
mmol) was added to a solution of complex 1 (200 mg, 0.36 mmol)
and N,N-diisopropylethylamine (DIPEA; 13 μL, 0.07 mmol) in dry
dimethylformamide (DMF; 1 mL). The heterogeneous mixture was
stirred for 16 h, and then 140 mL of a H2O/EtOH mixture (1/1, v/v)
was added. The crude precipitate was centrifuged and washed with
EtOH and Et2O to give a white solid (239 mg, 99% yield) that can be
recrystallized from hot acetonitrile. IR (KBr, cm−1): 1736 (CO,
1
succinimidyl), 1634 (CO, ester), 1493 (C−N, S2CN). H NMR
(DMSO-d6, δ in ppm): 4.73 (d, J = 13.4 Hz, 2H, S2CNCH2,eq), 3.53 (t,
J = 12.4 Hz, 2H, S2CNCH2,ax), 3.22 (m, 1; H, S2CNCH2CH2CH),
2.83 (s, 4H, succinimidyl), 2.10 (m, 2H, S2CNCH2CH2,eq), 1.70 (m,
2H, S2CNCH2CH2,ax). 13C NMR (DMSO-d6, δ in ppm): 203.4
(S2CN), 170.1 (CO, succinimidyl), 169.8 (CO, ester), 49.9
(S2CNCH2), 36.3 (S2CNCH2CH2CH), 27.4 (CH2, succinimidyl),
25.5 (S2CNCH2CH2). ESI MS (positive mode, m/z): 688.9 (M +
Na+). Anal. Calcd for C22H26N4O8S4Zn: C, 39.55; H, 3.92; N, 8.39.
Found: C, 39.82; H, 3.83; N, 8.61.
EXPERIMENTAL SECTION
All reactions were performed under nitrogen using standard Schlenk
tube techniques. Infrared spectra were recorded with a Perkin-Elmer
2000 FT spectrometer. The NMR spectra were recorded in the Servei
■
Synthesis of Complexes 3−5. Complex 2 (1.0 g, 1.5 mmol) was
dissolved in dry DMF (10 mL). The appropriate amine (3.8 mmol)
and DIPEA (7.5 mmol) was added to the solution, and the reaction
mixture was stirred overnight. A mixture of water and EtOH (1/1, v/
v) (100 mL) was added, and the crude product was centrifuged and
washed with the same mixture to eliminate the excess of the amine and
DIPEA. The product was dried under vacuum.
de Ressonan
̀ ̀ ̀
cia Magnetica Nuclear de la Universitat Autonoma de
Barcelona on Bruker DPX-250, DPX-360, and AV400 instruments.
́
Microanalyses were performed by the Servei d’Anal
̀
isi Quımica del
́
Departament de Quımica de la Universitat Auton
̀
oma de Barcelona. Mass
spectra and exact mass measurements were respectively obtained on an
Esquire 3000 with electrospray ionization and a Bruker Daltonics ion
trap and on a Bruker Apollo microTOFQ with electrospray ionization
Complex 3. Yield: 678 mg, 74%. IR (KBr, cm−1): 3294 (N−H,
amide), 1753 (CO, amide), 1646 (CO, ester), 1492 (C−N,
S2CN). 1H NMR (DMSO-d6, δ in ppm): 8.4 (t, J = 5.96 Hz, 1H, NH),
4.8 (d, J = 12.86 Hz, 2H, S2CNCH2,eq), 3.8 (d, J = 5.96 Hz, 2H,
NCH2CO), 3.62 (s, 3H, OCH3), 3.31 (m, 2H, S2CNCH2,ax), 2.53 (m,
1H, S2CNCH2CH2CH), 1.82 (m, 2H, S2CNCH2CH2,eq), 1.58 (m, 2H,
S2CNCH2CH2,ax). 13C NMR (DMSO-d6, δ in ppm): 202.7 (S2CN),
174.6 (CO, amide), 170.6 (NCH2CO), 51.7 (OCH3), 50.6
(S2CNCH2), 39.9 (S2CNCH2CH2CH), 28.2 (S2CNCH2CH2). ESI
MS (positive mode, m/z): 637.0 (M + Na+). Anal. Calcd for
C20H30N4O6S4Zn: C, 38.99; H, 4.91; N, 9.09. Found: C, 38.71; H,
4.91; N, 8.92.
́ ́
̀
isi Quımica del Departament de Quımica de la
by the Servei d’Anal
Universitat Autonoma de Barcelona. The zinc concentration in water
̀
solutions was measured by inductively coupled plasma optical
emission spectrometry (ICP-OES) on a Polyscan 61E (Thermo Jarrell
́
Ash) spectrometer by Servei d’Anal
̀
isi Quımica del Departament de
́
Quımica de la Universitat Auton
̀
oma de Barcelona.
Synthesis of Complex 1. A solution of NaOH (2.8 g, 70 mmol)
in water (70 mL) was added to a solution of isonipecotic acid (4.5 g,
35 mmol) in methanol (MeOH, 140 mL), and the resulting solution
was cooled to 0 °C. Carbon disulfide (2.45 mL, 40.9 mmol) was slowly
added to this cold solution, and the mixture was stirred at this
temperature for 1 h. Next, the cooling bath was removed and the
mixture was stirred overnight at room temperature. After this time, a
solution of zinc acetate (3.8 g, 17.5 mmol) in water (35 mL) was
added dropwise with vigorous stirring to the previous mixture for a
period of 4 h. The resulting solution was cooled to 4 °C, and colorless
crystals precipitated after 12−24 h. This solid was filtered off, washed
with MeOH and Et2O, and dried under vacuum, giving a white powder
(8.1 g, 84% yield). IR (KBr, cm−1): 1553 (COO−), 1493 (CN, S2CN).
1H NMR (D2O, δ in ppm): 4.97 (d, J = 12.9 Hz, 2H, S2CNCH2,eq),
3.32 (dt, J = 12.7 Hz, J = 2.7 Hz, 2H, S2CNCH2,ax), 2.30 (m, 1H,
S2CNCH2CH2CH), 1.95 (dd, J = 13.7 Hz, J = 3.3 Hz, 2H,
S2CNCH2CH2,eq), 1.65 (dq, J = 13.2 Hz, J = 3.7 Hz, 2H,
S2CNCH2CH2,ax). 13C NMR (D2O, δ in ppm): 201.8 (S2CN), 184.1
Complex 4. Yield: 580 mg, 58%. IR (KBr, cm−1): 3271 (N−H,
amide), 1746 (CO, amide), 1640 (CO, ester), 1492 (C−N,
S2CN). 1H NMR (DMSO-d6, δ in ppm): 8.0 (t, J = 5.41 Hz, 1H, NH),
4.8 (d, J = 12.6 Hz, 2H, S2CNCH2,eq), 3.60 (s, 3H, OCH3), 3.27 (m,
4H, S2CNCHax, NCH2CH2CO), 2.45 (m, 3H, S2CNCH2CH2CH,
NCH2CH2CO), 1.76 (m, 2H, S2CNCH2CH2,eq), 1.57 (m, 2H,
S2CNCH2CH2,ax). 13C NMR (DMSO-d6, δ in ppm): 202.7 (S2CN),
174.0 (CO, amide), 172.2 (NHCH2CH2CO), 51.8 (OCH3), 51.1
(S2CNCH2), 40.6 (S2CNCH2CH2CH), 35.1 (NHCH2CH2CO), 34.0
(NHCH2CH2CO), 28.7 (S2CNCH2CH2). ESI MS (positive mode, m/
z): 665.1 (M + Na+). Anal. Calcd for C22H34N4O6S4Zn·H2O: C,
39.90;; H, 5.48; N, 8.46. Found: C, 39.96; H, 5.37; N, 8.41.
Complex 5. Yield: 870 mg, 71%. IR (KBr, cm−1): 1639 (CO,
amide), 1436 (C−N, S2CN). 1H NMR (DMSO-d6, δ in ppm): 6.96−
G
dx.doi.org/10.1021/om300394v | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
6.89 (m, 4H, ArH), 4.87 (d, J = 12.26 Hz, 2H, S2CNCH2,eq), 3.79 (s,
3H, OCH3), 3.68 (s, 2 H, piperazine ring), 3.60 (s, 2H, piperazine
ring), 3.40 (m, 2H, S2CNCH2,ax), 3.05 (m, 1H, S2CNCH2CH2CH),
2.97 (s, 2H, piperazine ring), 2.90 (s, 2H, piperazine ring), 1.80 (m,
2H, S2CNCH2CH2,eq), 1.59 (m, 2H, S2CNCH2CH2,ax). 13C NMR
(DMSO-d6, δ in ppm): 202.6 (S2CN), 172.0 (CO, amide), 152.0−
111.9 (ArH), 55.4 (OCH3), 50.8 (piperazine ring), 50.6 (S2CNCH2),
50.2 (piperazine ring), 45.2 (piperazine ring), 41.4 (piperazine ring),
35.6 (S2CNCH2CH2CH), 28.3 (S2CNCH2CH2). ESI MS (positive
mode, m/z): 843.4 (M + Na+). Anal. Calcd for C36H48N6O4S4Zn: C,
52.57; H, 5.88; N, 10.22. Found: C, 52.24; H, 5.82; N, 9.86.
Synthesis of Complex 6. The complex 2 (1.0 g, 1.5 mmol) was
dissolved in dry DMF (10 mL). Glucosamine chlorhydrate (3.8 mmol)
and DIPEA (3.8 mmol) was added to the solution, which was then
stirred for 3 h. Methanol (100 mL) was added, and the crude mixture
was centrifuged and washed with the same solvent to eliminate the
excess glucosamine and DIPEA. The product was dried under vacuum
(550 mg, 44% yield). IR (KBr, cm−1): 3411 (O−H, alcohols), 1644
(CO, amide), 1492 (C−N, S2CN). 1H NMR (DMSO-d6, δ in
ppm): 7.69 (d, J = 8.31 Hz, 1H, NH), 7.64 (d, J = 7.65 Hz, 1H, NH),
6.47 (d, J = 6.34 Hz, 1H, NHCHCHO), 6.41 (d, J = 4.28 Hz, 1H,
NHCHCHO), 4.90−4.30 (m, 6 H, S2CNCH2,eq, glucosamine ring),
3.60−3.40 (m, 5H, S2CNCH2,ax, glucosamine ring), 3.31−3.00 (m, 2H,
glucosamine ring), 2.56 (m, 1H, S2CNCH2CH2CH), 1.71 (m, 2H,
S2CNCH2CH2,eq), 1.60 (m, 2H, S2CNCH2CH2,ax). 13C NMR
(DMSO-d6, δ in ppm, except glucosamine ring resonances): 192.5
(S2 CN), 163.8 (CO, amide), 51.2 (S2CNCH2 ), 40.8
(S2CNCH2CH2CH), 28.5 (S2CNCH2CH2). ESI MS (positive mode,
m/z): 817.2 (M + Na+); Anal. Calcd for C26H42N4O12S4Zn·2H2O: C,
37.52; H, 5.57; N, 6.73. Found: C, 37.88; H, 5.42; N, 6.69.
(positive mode, m/z): 845.0 (M + Na+). Anal. Calcd for
C32H32N2O6PReS2: C, 46.76; H, 3.92; N, 3.41. Found: C, 46.68; H,
4.00; N, 3.34.
Complex 9. Yield: 74 mg, 58%. IR (KBr, cm−1): 2009, 1912, 1905,
1892 (CO), 1723 (CO, amide), 1678 (CO, ester), 1497 (C−
1
N, S2CN). H NMR (CDCl3, δ in ppm): 7.55−6.87 (m, 19H, ArH),
4.31 (d, J = 13.05 Hz, 2H, S2CNCH2,eq), also observed 4.21 (d, J =
13.05 Hz, 2H, S2CNCH2,eq), 3.88 (s, 3H, OCH3), 3.82 s, 2H,
piperazine ring), 3.66 (s, 2H, piperazine ring), 3.10 (s, 4H, piperazine
ring), 2.77 (t, J = 11.51 Hz, 2H, S2CNCH2,ax), also observed 2.53 (t, J
= 11.51 Hz, 2H, S2CNCH2,ax), 2.66 (m, 1H, S2CNCH2CH2CH), 1.65
(m, 2H, S2CNCH2CH2,eq), 1.44 (m, 2H, S2CNCH2CH2,ax). 13C NMR
(CDCl3, δ in ppm, except phenyl resonances): 211.0 (S2CN), 193.4−
190.3 (carbonyls), 172.2 (amide), 55.6 (OCH3), 51.4 (piperazine
ring), 44.5 (S2CNCH2), 37.6 (S2CNCH2CH2CH), 27.4
(S2CNCH2CH2). 31P NMR (CDCl3, δ in ppm): 15.3, also observed
14.7. ESI MS (positive mode, m/z): 912.0 (M + H+). Anal. Calcd for
C39H39N3O4PReS2·H2O: C, 50.42; H, 4.45; N, 4.52. Found: C, 50.55;
H, 4.43; N, 4.52.
Complex 10. Yield: 88 mg, 70%. IR (KBr, cm−1): 2006, 1915, 1906,
1
1892 (CO), 1722 (CO, amide), 1498 (C−N, S2CN) cm−1. H
NMR (acetone-d6, δ in ppm): 7.58−7.46 (m, 15H, ArH), 6.89 (d, J =
8.22 Hz, 1H, NH), 6.86 (d, J = 8.22 Hz, 1H, NH), 5.66 (m, 1H,
NHCHCHO), 5.62 (m, 1H, NHCHCHO), 5.17 (m, 1H,
NHCHCHO), 5.10 (m, 1H, NHCHCHO), 4.31−3.33 (m, 6H,
S2CNCH2,eq, glucosamine ring), 2.83 (alcohols), 2.67 (t, J = 11.04 Hz,
2H, S2CNCH2,ax), 2.55 (m, 1H, S2CNCH2CH2CH), 1.73 (m, 2H,
S2CNCH2CH2,eq), 1.56 (m, 2H, S2CNCH2CH2,ax). 13C NMR
(acetone-d6, δ in ppm, except phenyl resonance): 209.8 (S2CN),
194.2 (CO, amide), 91.4 (NHCHCHO), 76.8 (OCH(OH)CH2OH),
72.2 (NHCHCH(OH)), (NHCHCH(OH)CH(OH)), 61.8
(CH2 OH), 54.7 (NHCH), 45. 4 (S2 CNCH2 ), 42.1
(S2CNCH2CH2CH), 28.3 (S2CNCH2CH2). 31P NMR (acetone-d6, δ
in ppm): 12.0, also observed 11.6. ESI MS (positive mode, m/z):
921.1 (M + Na+). Anal. Calcd for C34H36N2O9PReS2·2H2O: C, 43.72;
H, 4.32; N, 3.00. Found: C, 44.02; H, 4.26; N, 3.02.
Synthesis of Complexes 7−10. The precursor [NEt4]2[Re-
(CO)3Br3] (100 mg, 0.14 mmol) was dissolved in MeOH (10 mL)
and added to a suspension of 3−6 (0.08 mmol) in the same solvent
(30 mL). The mixture was heated to reflux for 1 h. Next,
triphenylphosphine (34 mg, 0.14 mmol) was added and the resulting
suspension was heated to reflux for an additional 1 h. The clear
solution that was obtained was concentrated under vacuum to 5 mL,
and the resulting solution was cooled to 4 °C to crystallize the
complex. The complex was washed with cold MeOH and Et2O to give
a white solid.
Synthesis of Complex 8 in Water Medium. A solution of
[Re(H2O)3(CO)3]+ (10 ppm) was prepared according to a previously
reported method33 and added to a suspension of 4 (1 mg, 2 μmol) in
water (1 mL). The mixture was heated in a boiling water bath for 1 h.
Next, triphenylphosphine (1 mg, 4 μmol) was added and heated in a
boiling water bath for an additional 1 h. The solution was centrifuged
and analyzed by ESI MS. ESI MS (positive ion): 845.0 (M + Na+).
Determination of Solubility of Compounds 3 and 4 in
Water. A suspension in water (10 mL) of the appropriate Zn(II)
compound (3 and 4; 1 mg) was heated to 40 °C for 1 h. Next, the
solution was filtered through a 0.2 μm filter and centrifuged at 13 000
rpm for 20 min. The resulting clear solution was diluted in 1% HNO3
and the Zn content was analyzed by means of inductively coupled
plasma optical emission spectrometry (ICP-OES). Solubility in water:
3.1 ppm for 3 and 0.66 ppm for 4.
Complex 7. Yield: 58 mg, 51%. IR (KBr, cm−1): 2009, 1912, 1905,
1892 (CO), 1723 (CO, amide), 1678 (CO, ester), 1497 (C−
N, S2CN). 1H NMR (CDCl3, δ in ppm): 7.53−7.28 (m, 15 H, ArH),
5.92 (t, J = 5.07 Hz, 1H, NH), 4.31 (d, J = 13.81 Hz, 2H,
S2CNCH2,eq), also observed 4.21 (d, J = 13.81 Hz, 2H, S2CNCH2,eq),
4.05 (d, J = 5.07 Hz, 2H, NCH2CO), 3.81 (s, 3H, OCH3), 2.74 (t, J =
11.96 Hz, 2H, S2CNCH2,ax), also observed 2.50 (t, J = 11.96 Hz, 2 H,
S2CNCH2,ax), 2.28 (m, 1H, S2CNCH2CH2CH), 1.67 (m, 2H,
S2CNCH2CH2,eq), 1.30 (m, 2H, S2CNCH2CH2,ax). 13C NMR
(CDCl3, δ in ppm, except phenyl resonances): 210.1 (S2CN),
193.2−190.4 (carbonyls), 173.7 (amide), 170.5 (ester), 51.6
(OCH3), 43.4 (S2CNCH2CH2CH), 41.3 (S2CNCH2CH2CH), 40.4
(NCH2CO), 26.6 (S2CNCH2CH2CH). 31P NMR (CDCl3, δ in ppm):
14.8, also observed 14.4. ESI MS (positive mode, m/z): 831.0 (M +
Na+); Anal. Calcd for C31H30N2O6PReS2·H2O: C, 45.08; H, 3.91; N,
3.39. Found: C, 45.24; H, 4.08; N, 3.53.
X-ray Crystallography. Data were collected by the Servei de
Difraccio
́
de Raigs X de la UAB using SMART34 software on a Bruker
APEX CCD diffractometer with graphite-monochromated Mo Kα
radiation (λ = 0.710 73 Å) at 100 K for 2 and at room temperature for
1 and 8. Data reductions were performed using the SAINT35 software.
Data were corrected for absorption using SADABS.36 Structures were
solved by direct methods using SHELXS-9737 and refined by full-
matrix least squares on F2 with anisotropic displacement parameters
for the non-H atoms using SHELXL-97.37 The C- and N-hydrogen
atoms were included from calculated positions and refined riding on
their respective carbon or nitrogen atoms with isotropic displacement
parameters.
Complex 8. Yield: 45 mg, 40%. IR (KBr, cm−1): 2009, 1912, 1905,
1892 (CO), 1723 (CO, amide), 1678 (CO, ester), 1497 (C−
N, S2CN). 1H NMR (CDCl3, δ in ppm): 7.53−7.28 (m, 15 H, ArH),
6.10 (m, 1H, NH), 4.31 (d, J = 13.54 Hz, 2H, S2CNCH2,eq), also
observed 4.21 (d, J = 13.54 Hz, 2 H, S2CNCH2,eq), 3.71 (s, 3H,
OCH3), 3.55 (q, J = 5.81 Hz, 2H, NCH2CH2CO), 2.70 (t, J = 13.54
Hz, 2H, S2CNCH2,ax), also observed 2.40 (t, J = 13.54 Hz, 2 H,
S2CNCH2,ax), 2.56 (q, J = 5.81 Hz, 2H, NCH2CH2CO), 2.17 (m, 1H,
S2CNCH2CH2CH), 1.68 (m, 2H, S2CNCH2CH2,eq), 1.26 (m, 2H,
S2CNCH2CH2,ax). 13C NMR (CDCl3, δ in ppm, except phenyl
resonances): 210.9 (S2CN), 193.2−190.4 (carbonyls), 174.2 (amide),
44.5 (S2CNCH2), 34.9 (OCH3), 33.8 (NCH2CH2CO), 33.7
(NCH2CH2CO), 29.8 (S2CNCH2CH2CH), 27.6 (S2CNCH2CH2).
31P NMR (CDCl3, δ in ppm): 15.3, also observed 14.7. ESI MS
In the crystal structure of complex 1 MeOH/water disorder is
present in one site. Fifteen of the eighteen water hydrogen atoms were
located in a difference Fourier map. In the crystal structure of complex
2 MeCN is present, the dimer/MeCN ratio being 1/3. One MeCN
molecule is disordered about an inversion center. In the crystal
structure of complex 8 two molecules with similar conformations are
present in the asymmetric unit.
H
dx.doi.org/10.1021/om300394v | Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Details of the structure solution and refinement are provided as
Supporting Information for complexes 1, 2, and 8.
Katzenellenbogen, J. A. Bioconjugate Chem. 1998, 9, 765−772.
(g) Osella, D.; Pollone, P.; Ravera, M.; Salmain, M.; Jaouen, G
Bioconjugate Chem. 1999, 10, 607−612. (h) Arterburn, J. B.; Rao, K.
V.; Goreham, D. M.; Valenzuela, M. V.; Holguin, M. S.; Hall, K. A.;
Ott, K. C.; Bryan, J. C. Organometallics 2000, 19, 1789−1795.
(16) Lattuada, L.; Barge, A.; Cravotto, G.; Giovenzana, G. B.; Tei, L.
Chem. Soc. Rev. 2011, 40, 3019−3049.
ASSOCIATED CONTENT
* Supporting Information
■
S
Tables of selected bond distances and angles, tables of crystal
data and structure refinement parameters, ellipsoid plots
showing atom numbering, and CIF files giving X-ray crystallo-
graphic data for structure determinations of compounds 1, 2,
and 8. This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Crider, A. M.; Tita, T. T.; Wood, J. D.; Hinko, C. N. J. Pharm.
Sci. 1982, 71, 1214−1219.
(18) Yoshikawa, Y.; Adachi, Y.; Sakurai, H. Life Sci. 2007, 80, 759−
766.
(19) Boyle, E. M.; Kovacich, J. C.; Norbert, F.; Canty, T. O., Jr.;
Morgan, E.; Pohlman, T. H.; Verrier, E. D. Inhibition of NF-κB
mediated tissue injury using dithiocarbamate derivatives. Patent WO
2000/000192, Jan 6, 2000.
AUTHOR INFORMATION
Corresponding Author
*Fax: + 34 935812477. E-mail: Joan.Suades@uab.es.
■
(20) (a) Aravamundan, G.; Brown, D. H.; Venkappayya, D. J. Chem.
Soc. A 1971, 2744−2747. (b) Van Gaal, H. L. M.; Diesveld, J. W.;
Pijpers, F. W.; Van Der Linden, J. G. M. Inorg. Chem. 1979, 18, 3251−
3260. (c) Prakasam, B. A.; Ramalingam, K.; Bocelli, G.; Cantoni, A.
Polyhedron 2007, 26, 4489−4493.
Notes
The authors declare no competing financial interest.
́
(21) Mora, A. J.; Delgado, G.; Ramírez, B. M.; Rincon, L.; Almeida,
ACKNOWLEDGMENTS
This research was supported by the Direccion
■
R.; Cuervo, J.; Bahsas., A. J. Mol. Struct. 2002, 615, 201−208.
(22) (a) Klug, H. P. Acta Crystallogr. 1966, 21, 536−546. (b) Sreehari,
N.; Vaghese, B.; Monoharan, P. T. Inorg. Chem. 1990, 29, 4011−4015.
(c) Motevalli, M.; O’Brien, P.; Walsh, J. R.; Watson, I. M. Polyhedron
1996, 15, 2801−2808. (d) Onwudiwe, D. C.; Ajibade, P. A. Polyhedron
2010, 29, 1431−1436.
́
General de
́
Investigacion
CTQ2007-63913 and BIO2009-12513-C02-02).
́
, Ministerio de Ciencia y Tecnologia (Projects
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