Formation of gels in the presence of metal ions

Article abstract of DOI:10.1007/s00726-011-0908-0

A small library of stereoisomeric pseudopeptides able to make gels in different solvents has been prepared and their attitude to make gels in the presence of several metal ions was evaluated. Four benzyl esters and four carboxylic acids, all containing a moiety of azelaic acid (a long chain dicarboxylic acid) coupled with four different pseudopeptide moieties sharing the same skeleton (a phenyl group one atom apart from the oxazolidin-2-one carboxylic group), were synthesized in solution, by standard coupling reaction. The tendency of these pseudopeptides to form gels was evaluated using the inversion test of 10 mM solutions of pure compounds and of stoichiometric mixtures of pseudopeptides and metal ions. To obtain additional information on the molecular association, the gel samples were left dry in the air to form xerogels that were further analyzed using SEM and XRD. The formation of gel containing Zn(II) or Cu(II) ions gave good results in term of incorporation of the metal ions, while the presence of Cu(I), Al(III) and Mg(II) gave less satisfactory results. This outcome is a first insight in the formation of stable LMWGs formed by stoichiometric mixtures of pseudopeptides and metal ions. Further studies will be carried out to develop similar compounds of pharmacological interest.

Full text of DOI:10.1007/s00726-011-0908-0

Amino Acids (2011) 41:609–620
DOI 10.1007/s00726-011-0908-0
ORIGINAL ARTICLE
Formation of gels in the presence of metal ions
•
Nicola Castellucci Giuseppe Falini
•
•
Gaetano Angelici Claudia Tomasini
Received: 13 December 2010 / Accepted: 30 March 2011 / Published online: 13 April 2011
Ó Springer-Verlag 2011
Abstract A small library of stereoisomeric pseudopep-
tides able to make gels in different solvents has been pre-
pared and their attitude to make gels in the presence of
several metal ions was evaluated. Four benzyl esters and
four carboxylic acids, all containing a moiety of azelaic
acid (a long chain dicarboxylic acid) coupled with four
different pseudopeptide moieties sharing the same skeleton
(a phenyl group one atom apart from the oxazolidin-2-one
carboxylic group), were synthesized in solution, by stan-
dard coupling reaction. The tendency of these pseudopep-
tides to form gels was evaluated using the inversion test of
10 mM solutions of pure compounds and of stoichiometric
mixtures of pseudopeptides and metal ions. To obtain
additional information on the molecular association, the gel
samples were left dry in the air to form xerogels that were
further analyzed using SEM and XRD. The formation of
gel containing Zn(II) or Cu(II) ions gave good results in
term of incorporation of the metal ions, while the presence
of Cu(I), Al(III) and Mg(II) gave less satisfactory results.
This outcome is a first insight in the formation of stable
LMWGs formed by stoichiometric mixtures of pseudo-
peptides and metal ions. Further studies will be carried out
to develop similar compounds of pharmacological interest.
Keywords Low molecular weight gelators Á
Pseudopeptides Á Metal ions Á Azelaic acid Á
Pseudoprolines
Abbreviations
D-Oxd
LMWG
L-Phe
(4R,5S)-4-Carboxy-5-methyl oxazolidin-2-one
Low molecular-weight gelator
L-Phenylalanine
SEM
Scanning electron microscopy
X-ray powder diffraction
Dichloromethane
XRD
CH2Cl2
AcOEt
MeOH
Ethyl acetate
Methanol
aMe-Phg b3-Homophenylglycine
b3-hPhg
OBn
D-Pro
a-Methyl-phenylglycine
O-Benzyl
D-Proline
Introduction
The term gel was coined in the 1860s (Graham 1861) to
mean a wide variety of materials, easily identified by the
simple ‘‘inversion test’’ (Raghavan and Cipriano 2005),
where a test tube is inverted to ascertain whether the
sample will flow under its own weight. A gel is assumed to
be a sample that has a yield stress preventing it from
flowing down the tube, while a sol is taken to be a sample
that flows down the tube. The ability of compounds to
gelate solvents relies on the balance between their tendency
for self aggregation and their affinity for solvent molecules
(Estroff and Hamilton 2004; Sangeetha and Maitra 2005;
van Bommel et al. 2003; Yang and Xu 2007).
N. Castellucci Á G. Falini (&) Á C. Tomasini (&)
Dipartimento di Chimica ‘‘G. Ciamician’’,
`
Alma Mater Studiorum Universita di Bologna,
Via Selmi 2, 40126 Bologna, Italy
e-mail: claudia.tomasini@unibo.it
G. Angelici
Department of Chemistry, University of Basel,
St. Johanns-Ring 19, 4056 Basel, Switzerland
123

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N. Castellucci et al.
To understand the mechanism of gel formation, a gel can
be broken down into a primary, secondary, and tertiary
structure, much like a protein (Simmons et al. 2001; Aggeli
et al. 2001). The primary structure (angstrom to nanometer
scale) is determined by events at the molecular level that
promote anisotropic aggregation in one or two dimensions
of gelator molecules. To achieve gelation, there must be a
balance between the tendency of the molecules to dissolve
or to aggregate, and an intermolecular interaction of suit-
able strength is required for the formation of a gel (Zhu
et al. 2010; Suzuki et al. 2010). Hydrogen bonding and p–p
stacking interactions are the principle interactions involved
in the aggregation of these molecules (Ajayaghosh and
Praveen 2007; Ajayaghosh et al. 2008).
differentiation, and organization. Furthermore, organogels
formed from N-stearoyl-L-alanine methyl ester in refined
safflower oil can be used for the controlled delivery of
rivastigmine, which is used to treat Alzheimer’s disease
(Vintiloiu et al. 2008).
Self-assembled gels are now showing significant prom-
ise in the field of localized drug delivery, as gels can easily
fit into any shape that is required. For example, drugs
mixed within a solution of LMWG, which forms a self-
assembled gel on contact with bodily fluids such as blood
(e.g., due to the resulting pH changes), could be delivered
topically or by injection after tumor resection. On gelation,
the gel theoretically would then be held in the cavity,
thereby allowing the drugs to act locally (Ellis-Behnke
et al. 2006).
Traditional gel chemistry is dominated by polymers, but
recently current interest is growing rapidly in ‘‘supramo-
lecular’’ gels, composed of LMWGs and their complexes
with metal ions and small anions (Piepenbrock et al. 2010;
Terech and Weiss 1997). Self-assembled gels (also known
as supramolecular or physical gels) comprised of LMWGs
would theoretically be better suited to the field of bioma-
terials relative to polymer biomaterials because their
scaffold of nanofiber networks are on the same order of
magnitude as found in the extracellular matrix (ECM),
thereby providing a pseudo in vivo environment for cell
migration, growth, and differentiation. Furthermore, many
LMWGs, being derived from biocompatible components
and held together by noncovalent forces, degrade more-
easily than the more prevalent polymer gels.
A topic of great interest is nowadays the delivery of
platinum(II)-based anticancer agents, as cisplatin, carbo-
platin and oxaliplatin, that are widely utilized in the clinic,
although with numerous disadvantages, due to toxicity to
‘‘normal’’ tissues.
With the aim of circumventing unwanted side-effects, a
great deal of research is being conducted in the areas of
cancer-specific targeting, drug administration and drug
delivery (Harper et al. 2010), that includes such technolo-
gies as liposomes, dendrimers, polymers and nanotubes,
with all showing promise for the delivery of platinum
compounds. The delivery of platinum(II)-based anticancer
agents by means of self-assembled gels, made of stoichi-
ometric amounts of LMWG and platinum(II) derivatives,
could be a innovative answer against the high toxicity
towards ‘‘normal’’ tissues.
An extraordinary diverse range of compounds can act as
LMWGs, but usually they have a long aliphatic chain, such
as (R)-12-hydroxystearic acid (Huanga and Weiss 2007;
Shibata et al. 2010) connected with a polar head, such as
cholesteric acids (Hu et al. 2009; Bot et al. 2009). The
tendency of the head to get organized into a three dimen-
sional network enhances the probability to have the for-
mation of a gel, that can be used in the chelation and
delivery of metals for several applications, for instance in
medicinal chemistry (Iwanaga et al. 2010; Morales et al.
2009) or in material sciences (Chatterjee et al. 2010; Li
et al. 2010; Wicklein et al. 2009).
The aim of this work is a first insight in the application
of biocompatible gelators, derived from natural proteino-
genic amino acids and fatty acids and able to chelate a
series of metal ions. These compounds could be used in
future to form self-assembled gels including platinum(II)-
based anticancer agents or other compounds of pharma-
cological interest.
Results and discussion
Several examples have been reported recently (Truong
et al. 2011). Peptide amphiphiles (PAs) composed of a
hydrophilic peptide head and a hydrophobic tail have
evolved as biofunctional molecules that self-assemble into
highly ordered nanostructures, leading to the formation of
nanofibers, which can then undergo physical crosslinking
to form three-dimensional networks to provide gel struc-
tures (Kim et al. 2009; Segers and Lee 2007). The self-
assembled PA nanofiber gels have been extensively studied
as potential biomaterials for tissue engineering scaffolds
because of their ability to mimic the important properties
of the natural ECM such as cell adhesion, proliferation,
A small library of stereoisomeric compounds, all contain-
ing a moiety of azelaic acid (a long chain dicarboxylic
acid) coupled with different pseudopeptides was prepared.
Azelaic acid was chosen after a screening among some
long chain mono- and di-carboxylic acids: pseudopeptides
derived from long chain mono-carboxylic acids (such as
C5H11COOH and C11H23COOH) do not form gels in any
case. All these compounds contain the L-Phe-D-Oxd moi-
ety. This skeleton is the minimal framework of a class
of pseudopeptides, having the ability to self-organize
(Angelici et al. 2008, 2009).
123

Formation of gels in the presence of metal ions
611
Scheme 1 Reagents and
conditions (i) H2, Pd/C MeOH,
r,t. 2 h; (ii) a- or b-amino acid
(1 equiv.), HBTU (1 equiv.),
Et3N (3 equiv.) dry CH3CN,
40 min; (iii) TFA (18 equiv.),
dry CH2Cl2, r. t., 4 h; (iv)
azelaic acid (0.5 equiv.), HBTU
(1 equiv.), Et3N (3 equiv.) dry
CH3CN, 40 min
Scheme 1 reports the general formula of the eight
compounds: they are four benzyl esters and four carboxylic
acids. These compounds were synthesized in solution, by
standard coupling reaction. Starting from Boc-L-Phe-D-
Oxd-OBn (Angelici et al. 2008), we prepared the four
derivatives 1a–d by replacing the OBn moiety with four
unusual amino acids: the two enantiomers of b3-hPhg
(Angelici et al. 2010) and the two enantiomers of aMe-Phg.
Then we replaced the N-protection Boc moiety with azelaic
acid to prepare derivatives 2a–d. The four compounds were
then deprotected by hydrogenolysis to give the free car-
boxy termini 3a–d.
first checked for compounds 2a and 2b, in several solvents
or mixtures of solvents. The best outcome was obtained
with a 1:1 mixture of dichloromethane/ethyl acetate for 2a
and 2b and with a 1:1 mixture of water and methanol for 3a
and 3b. These mixtures of solvents were used to check if
the more expensive compounds containing the aMe-Phg
moiety (2c, 2d, 3c and 3d) would form a gel. Unfortunately
no gel formation was obtained in any case.
The gel–sol transition temperature (Tgel) gives important
information on the thermal stability of the gels prepared in
different ways (Takahashi et al. 1980; Yamanaka and Fujii
2009) and was measured by the ball-dropping method (see
‘‘Experimental’’). Reversible gels, that reform after cooling
down, are reported in entries 1, 5, 13 and 18.
The tendency of these compounds to form gels was
checked with the inversion test. To prepare gels, 6 mg of
compounds 2a–d or 5 mg of compounds 3a–d were
weighted out exactly in a test tube (8 mm wide), and then
dissolved in the solvents reported in Table 1 (500 ll) to
afford a 10 mM solution. As ultrasounds influence the
aggregation properties of the molecules in the solvents
(Choi et al. 2008, 2009; Isozaki et al. 2007), the tube was
shaken for a few minutes by hand and then sonicated for
15 min at room temperature, then it was left standing still
overnight before checking the gel formation.
The work was then continued only with compounds 2a,
2b, 3a and 3b to test their ability to generate a gelling status
in the presence of several metal ions: Mg(II), Al(III), Zn(II),
Cu(I) or Cu(II). The selection among the metal ion species
was carried out trying to discriminate among two parame-
ters: coordination chemistry and charge density. Mg(II) and
˚
Cu(II) have similar ionic radius (0.78 and 0.72 A, respec-
tively), but the former forms mainly octahedral coordination
compounds, while the latter gives distorted octahedral
coordination compounds that usually reorganize in tetrahe-
dral or square planar geometries. Cu(I) ions and zinc ions
The results of gelation tests of 2a–d and 3a–d are
reported in Table 1. The tendency to form gels has been
123

612
N. Castellucci et al.
Table 1 Gelling status of the
molecules 2a–d and 3a–d
Entry
Solvent
Compound
After sonication
After 2 h
M. p. (°C)
1
CH2Cl2/AcOEt 1:1
CHCl3/AcOEt 1:1
AcOEt
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3c
3d
SP
PG
G
G
58a
2
PG
G
–
3
76b
41b
80a
–
4
Acetonitrile
CH2Cl2/AcOEt 1:1
CHCl3/AcOEt 1:1
AcOEt
G
G
5
SP
SP
PG
PG
SP
SP
PG
SP
S
G
6
SP
PG
PG
SP
SP
PG
SP
G
7
–
8
Acetonitrile
CH2Cl2/AcOEt 1:1
CH2Cl2/AcOEt 1:1
CH2Cl2
–
9
–
10
11
12
13
14
15
16
17
18
19
20
21
22
–
–
H2O
–
82a
MeOH/H2O 1:1
i-PrOH/H2O 1:1
i-PrOH
SP
P
PG
P
–
–
CH2Cl2
P
P
–
H2O
P
P
–
75a
MeOH/H2O 1:1
i-PrOH/H2O 1:1
i-PrOH
S
G
PG
PG
S
PG
G
–
SP suspension, G gel, PG partial
gel, S solution, P precipitate
80b
–
MeOH/H2O 1:1
MeOH/H2O 1:1
S
a
Reversible gel
S
S
–
b
Non reversible gel
Table 2 Gelling status of the molecules 2a, 2b, 3a and 3b in the presence of metal ions
a
–
Molecule (solvent)
CuBr
CuBr2
ZnBr2
AlCl3
MgBr2
2a (CH2Cl2/AcOEt, 1:1)
2b (CH2Cl2/AcOEt, 1:1)
3a (MeOH/H2O, 1:1)
3b (MeOH/H2O, 1:1)
G (58)
G (80)
G (82)
G (75)
PG
PG
S
G (62)
G (60)
G (68)
SP
G (50)
G (50)
G (92)
G (59)
G (75)
PG
SP
PG
PG
S
PG
SP
G (42)
The gel–sol transition temperature (Tgel) expressed in °C is reported in parenthesis. The gels that increase their Tgel (and consequently their
thermal stability) in the presence of metal ions are in bold
SP suspension, G gel, PG partial gel, S solution
a
Metal ions free gel
˚
have different ionic radius (0.95 and 0.69 A, respectively),
but both preferentially form tetrahedral coordination com-
pounds, however, Zn(II) have also a strong tendency to give
sonication (see experimental). After 16 h, an homogeneous
gel was formed. In the case of copper salts, the gel was pale
green while in the other cases the gel was colorless. In the
case of gels formed with 3a (or 3b) and the inorganic salt in
methanol/water mixture, an homogeneous mixture was
immediately formed and became a colorless gel after 16 h.
The results of the gelation experiments of molecules 2a,
2b, 3a or 3b in the presence of metal ions are reported in
Table 2.
˚
octahedral geometries. Al(III) (ionic radius 0.45 A) can give
coordination compounds having tetrahedral and octahedral
geometries, being the latter more common in the presence of
charged ligands (Cotton et al. 1999). These metal ions have
also different charge density: Al(III) [ Zn(II) [ Cu(II) *
Mg(II) [ Cu(I). The choice among the biological friendly
chloride or bromide as counter anion was carried out in the
view to give the gel a potential use of the gels to control the
release of metal ions. As consequence, we paid a price in
term of solubility in organic solvents.
While all these molecules formed gels in the reported
conditions, they behave differently, in the presence of these
five metal ions.
In the presence of Zn(II), they all formed gels, however,
the strength of the gel was reduced, except for 3a. On the
contrary, Cu(I) prevents the formation of gels in any case,
Gels were prepared by suspension of an equimolecular
amount of 2a (or 2b) and the inorganic salt, followed by
123

Formation of gels in the presence of metal ions
613
as its presence in 2a, 2b and 3b gave partial gels, while 3a
gave a suspension. A very different result was obtained
with Cu(II): 2a, 2b and 3a formed gels, while 3b associated
in a suspension. In the presence of Al(III) or Mg(II), the
four compounds afforded very different results, as reported
in Table 2. Only 2a and 3b form a gel in the presence of
Al(III) and Mg(II), respectively. The former was stronger,
and the latter weaker with respect to the corresponding
metal ions free gels. In conclusion, among the tested
molecules 2b is the best gelator in the presence of metal
ions, it always associates in a gel-like form, either gel or
partial gel. 2a failed to be in a gel-like form in the presence
of Mg(II) only.
diffraction peaks) and that this status is not affected by the
presence of metal ions, indeed the main diffraction peaks
associated with the molecular structure do not change in
relative intensity and angular position. This outcome indi-
cates that metal ions do not influence the crystallinity and
aggregation of the 2a xerogels, therefore we can infer that
the functional groups involved in the inter-molecular
interactions responsible for the formation of the gel scaffold
are not involved in the metal binding. In the XRD patterns
from 2a_Cu(II) and 2a_Al xerogels, additional diffraction
peaks associable to metal ion salts are detectable. Copper
bromide is present in the 2a_Cu(II) xerogel, while in the
2a_Al xerogel the Al(III) compound(s) generating the dif-
fraction peaks has not been identified. While Al(III) parti-
cles form aggregates that are SEM visible, copper bromide
particles are not, suggesting that are finely dispersed in the
xerogel structure (Fig. 2 2a_Al, 2a_Cu(II)). In contrast, in
the 2a_Zn xerogel XRD pattern only diffraction peaks due
to 2a appear, and no additional diffraction peaks were
observed. Interestingly, the presence in the gel of metal ions
compound crystalline particles (Cu(II) and Al(III)) increa-
ses its thermal stability (Table 2). Only the Zn(II) do not re-
precipitate in the form of an inorganic crystalline material
suggesting that they have a higher capability of interaction
with the gel molecules or that form amorphous compounds.
These observations suggest that the metal ions, although are
not able to alter 2a and 2b molecular crystalline assembly
(same XRD patterns), may affect the interactions among
supra-molecular scaffold units, since the morphology of the
xerogel is changed by their presence.
To obtain additional information on the molecular
association, the gel samples were left to dry in the air to
form xerogels that were further analyzed using SEM and
XRD. The results of the SEM observations and of the XRD
analyses are reported in Figs. 1, 2, 3.
The molecular assembly of 2a in the xerogel is strongly
affected by the presence of metal ions (Fig. 1). The metal
ions free xerogel picture shows the presence of locally
oriented long strips that cross on the large scale (Fig. 1 2a).
Sometimes these strips merge laterally forming layers in
which holes are present. The scenario of the xerogel
changes in the presence of the metal ions: in the presence
Cu(II) and Zn(II) the 2a molecules form rope-like assem-
blies highly twisted (Fig. 1 2_Zn(Cu)), while in the pres-
ence of Al(III) 2a mainly assembles forming a holed
layered structure (Fig. 1 2_Al) that in some extent resem-
bles what observed in the absence of metal ions. The XDR
data (Fig. 1 right) show that 2a is present in a crystalline
form in the xerogel (as proved by the presence of several
The SEM morphologies and the XRD patterns of the 2b
xerogels are reported in Fig. 2. 2b associates forming a
Fig. 1 The SEM images of the xerogels formed by the molecule 2a:
in the absence of metal ions (2a); the presence Cu(II) (2a_Cu(II)); in
the presence of Zn(II) (2a_Zn) or in the presence of Al(III) (2a_Al)
are shown on the left. The arrow in (2a_Al) indicates a crystalline
aggregate made of an aluminium salt. On the right side, the
corresponding X-ray powder diffraction patterns are reported. Bars
indicate the diffraction peaks which could be associated with
crystalline regions of 2a. Hash symbols indicate the diffraction peaks
that can be associated with crystalline CuBr2, according to the powder
diffraction file PDF 98-005-5875 (Simon and Oeckler 2000),
Asterisks indicate the diffraction peaks associated with an Al
containing compound that could not be identified (crystals from this
unidentified compound are shown by the arrow in 2a_Al)
123

614
N. Castellucci et al.
Fig. 2 The SEM images of the xerogels formed by: the molecule 2b
(2b) in the absence of metal ions; the molecule 2b in the presence
Cu(II) (2b_Cu(II)) or in the presence of Zn(II) (2b_Zn), are shown
on the left. On the right side, the corresponding X-ray powder
diffraction patterns are reported. Bars indicate the diffraction peaks
which could be associated to crystalline regions of 2b. Hash symbols
indicate the diffraction peaks that can be associated to crystalline
CuBr2 according the powder diffraction file PDF 98-005-5875 (Simon
and Oeckler 2000)
xerogel containing bundles of fibers that are branched,
forming a complex web in which many holes are present.
The presence of Cu(II) or Zn(II) changes the aggregation of
2b, favouring the formation of highly twisted long rope-
like aggregates, as previously observed for the 2a xerogels
obtained in similar conditions. This effect is not surprising,
considering that the skeleton of 2a and 2b are very similar.
The presence of Zn(II) seems to favour the merging of the
rope-like structure giving a more compact material. The
2b_Cu(II) xerogel hosts particles of crystalline copper
bromide while the 2b_Zn xerogel contains any Zn(II)
crystalline compound. The crystallinity of 2b in the xerogel
increases in the presence of Cu(II), as revealed by the
presence in the XRD pattern of more and more defined
diffraction peaks.
observable only in the XRD pattern from the 3a_Cu(II)
xerogel.
In the xerogel status, 3b associates in porous structures
similar to those formed by 3a, also in the presence of
Mg(II) or Zn(II). The 3b_Zn xerogel is morphological
similar to that of 3b and makes entangled filaments that
form a porous structure in which crystalline particles are
embedded. On the contrary, the XRD pattern from 3b
xerogel is characterized by the presence of several dif-
fraction peaks indicating a crystalline molecular aggrega-
tion, that are reduced by the presence of Zn(II). Finally, the
XRD pattern from the 3b xerogel hosting Mg(II) shows any
diffraction peaks typical of the molecular packing, but
shows only diffraction peaks due to unidentified mineral
crystalline phases. In Table 3 a summary of the result of
morphological and structural characterizations is reported.
The analysis of the results of the gelling experiments
and the characterization of the xerogels can give some hints
on the influence of the metal ions in the gelation process.
Copper(I) ion has a negative effect on gel formation. This
implies a weakening of the inter-molecular interactions
making the gel. It may be related to its properties to give
almost only complexes with tetrahedral coordination or to a
strong change of the solvent features. Magnesium ions
have also a negative role on the gelation capability of the
molecules, as gel formation is inhibited except for 3b, in
which the gel thermal stability is reduced with respect to
the metal free one. This may suggest a weakening of the
interactions among the 3b molecules due to Mg(II). These
ions could interact with the molecules reducing their ability
to form intermolecular bonds. Indeed, the periodic inter-
molecular interactions (i.e. the crystallinity) in the 3b
Similar analyses were carried out on the xerogels
obtained from 3a and 3b (Fig. 3). These compounds are
very polar, as they contain a carboxylic group, and can
form gels with mixtures of water and methanol. Besides its
ability to form gels as a pure compound, 3a retains its
ability to form gel in the presence of Cu(II) and Zn(II)
only. In the xerogel status, 3a associates forming a porous
structure in which no well defined structural motifs are
observable. In the presence of Zn(II), 3a_Zn xerogel
structure makes a more compact material, as could be
foreseen considering the high thermal stability of the
3a_Zn gel (see Table 2). Also in this case we could sup-
pose that the metal ions affects the way in which the
molecular scaffolds make the gel. All the XRD patterns
from 3a xerogels show only one diffraction peak, indicat-
ing that the molecules are associated in a poor ordered way.
Weak diffraction peaks due to copper(II) bromide are
123

Formation of gels in the presence of metal ions
615
Fig. 3 The SEM images of the xerogels formed by: the molecule 3a
(3a) and the molecule 3b (3b) in the absence of metal ions; the
molecule 3a in the presence Cu(II) ions (3a_Cu(II)) or in the
presence of Zn ions (3a_Zn); the molecule 3b in the presence of Mg
ions (3b_Mg) or in the presence of Zn ions (3b_Zn), are shown on the
left. The arrow in (3b_Mg) indicates a crystalline aggregate made of a
magnesium salt. On the right side, the corresponding X-ray powder
diffraction patterns are reported. Bars indicate the diffraction peaks
which could be associated to crystalline regions of 3a or 3b. Hash
symbols indicate the diffraction peaks that can be associated to
crystalline CuBr2 according the powder diffraction file PDF 98-005-
5875 (Simon and Oeckler 2000). Asterisks indicates diffraction peaks
that can not be univocally associated to specific crystalline forms
Table 3 Morphological and structural characterization of xerogels obtained from gels hosting metal ions
a
Molecule
CuBr CuBr2
ZnBr2
AlCl3
MgBr2
b
b
2a
Morph.c polym.
()d min. ph. ()e
Strips
phase 1
Rope like phase 1 (=) Rope like
salt (no)
Holed strips phase 1 (=)
dif. salts (yes)
phase (=)
–
b
b
b
b
b
b
b
b
2b
3a
3b
Morph. polym. () Filaments
min. ph. () phase 1
Morph. polym. () Spongy
min. ph. () phase 1
Morph. polym. () Spongy
min. ph. () phase 1
Rope like phase 1
(?) salt (no)
Rope like
phase 1 (=)
Spongy phase 1 (-) Spongy phase
salt (no)
1 (=)
b
Spongy phase
1 (--)
Spongy amorphous
dif. salts (yes)
–
In parenthesis, the presence (yes), or absence (no), of SEM observable mineral particles is indicated. In parenthesis is reported, the relative
degree of crystallinity, evaluated from the intensity of the diffraction peaks, relative to the xerogel metal ions free: equal (=), higher (?), lower
(-) or much lower (--)
a
Control experiment, xerogel obtained from metal free gel
b
Gel did not form in the presence of the metal ions
c
Morphological description of the xerogel
d
Polymorphic phase of the peptide formed in the xerogel
e
Observed mineral phase associated to the xerogel. Salt indicates the re-precipitation of the same salt dissolved in the gel
xerogel is reduced by the presence of magnesium ions.
Al(III) inhibits the gel formation, except for the molecule
2a. The 2a_Al gel increases its thermal stability with
respect to pure 2a gel. This observation may suggest that
Al(III) should strengthen the intermolecular interactions in
the gel, although the crystallinity of the xerogel is not
123

616
N. Castellucci et al.
affected. Al(III) being present as salt particles may act also
as filler, improving the mechanical properties of the gel.
Al(III) can form tetrahedral compounds other than octa-
hedral ones, as Mg(II) does; this coordination flexibility
may be involved in the alteration of the gel properties. The
high charge density of Mg(II) may also have a role in
destabilizing the gel structure.
Experimental
The melting point of the compounds under investigation
were determined in open capillaries and are uncorrected.
High quality infrared spectra (64 scans) were obtained at
2 cm-1 resolution using a 1 mm NaCl solution cell and a
FT-infrared spectrometer. All spectra were obtained in
3 mM solutions in dry CH2Cl2 at 297 K or as 1% solid
mixture with dry KBr. All compounds were dried in vacuo
and all the sample preparations were performed in a
nitrogen atmosphere. Routine NMR spectra were recorded
with spectrometers at 600, 400 or 300 MHz (1H NMR) and
at 150, 100 or 75 MHz (13C NMR). The measurements
were carried out in CDCl3 and in DMSO-d6. The proton
signals were assigned by gCOSY spectra. Chemical shifts
are reported in d values relative to the solvent (CDCl3 or
DMSO-d6) peak.
Zn(II) does not inhibit the capability of the molecules to
form gels. This means that the key molecular interaction
forming the gel structure are not affected by the presence of
Zn(II). These gels have thermal stability lower than the co-
respective metal ion free 2a, 2b and 3b gels. Only 3a forms
a gel with higher thermal stability in the presence of Zn(II).
Interestingly, the xerogels obtained in the presence of
Zn(II) do not contain any crystalline salt particles; this may
be due to Zn(II)-molecules interactions that prevent the salt
precipitation or the re-precipitation of Zn(II) salts in an
amorphous form. These interactions, or the presence of
small amorphous particles, may strengthen molecular
entanglements, as occurs for 3a, or weaken them, as occurs
for 2a, 2b and 3b.
General method for the preparation of compounds 1a–d
Similar considerations may be applied to explain the
effect of Cu(II) in the gel formation. However, in this case
the xerogels obtained from the parent gels bearing Cu(II)
always show the presence of particles of copper(II) bro-
mide. Thus, it can be supposed that the interaction between
copper(II) ions and the molecules is minimal or that is lost
in the xerogel formation, although they are still trapped in
the xerogel network.
A solution of Boc-L-Phe-D-Oxd-OH (Angelici et al. 2009)
(0.27 mmol, 0.10 g) and HBTU (0.3 mmol, 0.12 g) in dry
acetonitrile (25 mL) was stirred under inert atmosphere for
10 min at room temperature. Then a mixture of the
required a- or b- amino acid benzyl esterÁTFA (see Fig. 1)
(0.27 mmol, 0.10 g) and Et3N (0.81 mmol, 0.12 mL) in
dry acetonitrile (10 mL) was added at room temperature.
The solution was stirred for 40 min under inert atmosphere,
then acetonitrile was removed under reduced pressure and
replaced with ethyl acetate. The mixture was washed with
brine, 1 N aqueous HCl (3 9 30 mL) and with 5% aqueous
NaHCO3 (1 9 30 mL), dried over sodium sulphate and
concentrated in vacuo. The product was obtained pure after
silica gel chromatography (cyclohexane/ethyl acetate 8:2
as eluant) in 80–85% yield.
Conclusions
In conclusion, a small library of LMWGs has been syn-
thesized by coupling some pseudopeptides with azelaic
acid, a long chain dicarboxylic acid. The ability to form
gels in the presence of several solvents and of five metal
ions, differing for their coordination chemistry and charge
density has been analyzed.
Boc-L-Phe-D-Oxd-(R)-b3-hPhg-OBn 1a (Angelici et al.
2010) Boc-L-Phe-D-Oxd-(S)-b3-hPhg-OBn 1b (Angelici
et al. 2010) Boc-L-Phe-D-Oxd-(R)-aMe-Phg-OBn 1c
M.p. = 128°C; [a]D20 = ?88.9 (c = 1.1, CH2Cl2); IR
(CH2Cl2, 3 mM): m 3,437, 3,389, 3,336, 1,788, 1,737, 1,701,
1,678 cm-1; IR (1% in dry KBr): m 3,390, 3,324, 1,783,
Very good results have been obtained with Zn(II) and
Cu(II) ions, that form gels in several conditions, while the
formation of gels in the presence of Cu(I), Al(III) and
Mg(II) affords less satisfactory results.
1
1,748, 1,716, 1,689 cm-1; H NMR (400 MHz, CDCl3): d
This outcome is a first insight in the formation of stable
LMWGs obtained with stoichiometric mixtures of metal
ions and pseudopeptides containing a moiety formed by
phenyl group one atom apart from the oxazolidin-2-one
carboxylic group. Further studies will be carried out to
develop similar compounds of pharmacological interest.
For instance self-assembled gels containing platinum(II)-
based anticancer agents could furnish a innovative answer
to the problem of delivery of these compounds, reducing
their high toxicity towards ‘‘normal’’ tissues.
1.25 (d, 6H, J = 6.3 Hz), 1.55 (s, 9H), 1.97 (s, 3H), 2.84
(dd, 1H, J = 8.0, 13.2 Hz), 3.07 (dd, 1H, J = 6.0,
13.2 Hz), 4.29 (d, 1H J = 3.6 Hz), 4.43 (m, 1H), 4.91
(d, 1H, J = 5.2 Hz), 5.05 (AB, 2H, J = 12.4 Hz), 5.69
(m, 1H), 7.12–7.16 (m, 2H), 7.22–7.34 (m, 11H), 7.44–7.49
(m, 2H), 7.61 (s, 1H); 13C NMR (75 MHz, CDCl3): d 21.4,
21.9, 28.4, 30.2, 38.0, 53.9, 62.7, 63.6, 67.8, 75.0, 80.1,
126.3, 127.7, 128.2, 128.5, 128.7, 128.9, 129.1, 129.7,
135.5, 136.2, 151.9, 173.3. Anal. calcd. for C35H39N3O8: C,
66.76; H, 6.24; N, 6.67; Found: C, 66.81; H, 6.20; N, 6.64.
123

Formation of gels in the presence of metal ions
617
Boc-L-Phe-D-Oxd-(S)-aMe-Phg-OBn
1d
M.p. =
CH2(C3H6CO-L-Phe-D-Oxd-(S)-b3-hPhg-OBn)2
2b
196°C; [a]2D0 = ?17.3 (c = 0.25, CH2Cl2); IR (CH2Cl2,
M.p. = 129°C; [a]D20 = ?32.0 (c = 1.0, CH2Cl2); IR
(CH2Cl2, 3 mM): m 3,435, 3,319, 1,788, 1,735, 1,675,
1,655 cm-1; IR (1% in KBr): m 3,411, 3,309, 3,088, 1,772,
3 mM): m 3,434, 3,385, 1,789, 1,737, 1,720, 1,703 cm-1
;
IR (1% in dry KBr): m 3,389, 3,309, 1,768, 1,742, 1,718,
1,701, 1,687 cm-1; NMR (400 MHz, CDCl3): d 1.26
(d, 6H, J = 6.6 Hz), 1.55 (s, 9H), 1.98 (s, 3H), 2.89
(m, 1H), 3.11 (m, 1H), 4.30 (m, 1H), 4.56 (m, 1H), 5.12
(AB, 2H, J = 12.4 Hz), 5.16 (bs, 1H), 5.71 (q, 1H,
J = 6.8 Hz), 7.16–7.42 (m, 16H); 13C NMR (75 MHz,
CDCl3): d 21. 3, 28.5, 30.2, 54.3, 63.2, 68.0, 74.5, 126.4,
127.6, 128.3, 128.6, 128.8, 129.0, 129.8, 136.4, 151.8,
166.4, 173.8, 183.2. Anal. calcd. for C35H39N3O8: C,
66.76; H, 6.24; N, 6.67; Found: C, 66.73; H, 6.19; N, 6.70.
1,732, 1,715, 1,650, 1,556, 1,531 cm-1
;
1H NMR
(400 MHz, CDCl3): d 1.08–1.52 (m, 16H), 1.92–2.15
(m, 4H), 2.81–2.99 (m, 6H), 3.18 (m, 2H), 4.12 (m, 2H),
4.39 (m, 1H), 4.58 (m, 1H), 5.05 (m, 2H), 5.13 (m 1H),
5.15 (s, 2H), 5.52 (m, 1H), 5.75 (m, 1H), 6.03 (m, 1H),
7.15–7.38 (m, 30H), 7.41 (d, 1H, J = 6 Hz), 7.85 (d, 1H,
J = 6.4 Hz); 13C NMR (50 MHz, CDCl3): d 21.0, 24.8,
28.5, 29.7, 35.3, 36.4, 40.8, 50.3, 53.2, 56.9, 62.5, 66.5,
75.2, 126.8, 127.5, 127.6, 128.2, 128.4, 128.7, 128.9,
129.2, 135.0, 135.7, 140.6, 151.0, 166.4, 170.1, 175.5,
174.3. Anal. calcd. for C69H74N6O14: C, 68.41; H, 6.16; N,
6.94. Found: C, 68.44; H, 6.17; N, 6.92.
General method for the preparation of compounds 2a–d
CH2(C3H6CO-L-Phe-D-Oxd-(R)-aMe-Phg-OBn)2 2c
M.p. = 76°C; [a]D20 = ?22.0 (c = 1.0, CHCl3); IR
(CH2Cl2, 3 mM): m 3,343, 3,374, 3,366, 3,335, 1,787,
1,771, 1,738, 1,732, 1,683, 1,674 cm-1; IR (1% in dry
KBr): m 3,392, 3,370, 1,734, 1,701, 1,653 cm-1; NMR
(400 MHz, CDCl3): d 0.98–1.44 (m, 16H), 1.88–2.05
(m, 4H), 1.96 (s, 6H), 2.92 (m, 2H), 3.17 (m, 2H), 4.24
(m, 2H), 4.41 (m, 2H), 5.12 (AB, 4H, J = 12.4 Hz), 5.28
(m, 2H), 5.78 (bs, 1H), 6.10 (bs, 1H), 7.05–7.37 (m, 29H),
7.44 (m, 2H), 7.81 (m, 1H); 13C NMR (50 MHz, CDCl3): d
21.0, 24.6, 24.7, 28.3, 28.4, 28.5, 35.3, 36.8, 53.0, 62.4,
62.7, 67.5, 74.4, 126.3, 127.3, 127.4, 128.1, 128.2, 128.4,
128.7, 129.3, 135.2, 139.4, 151.6, 166.6, 171.7, 173.0,
173.6. Anal. calcd. for C69H74N6O14: C, 68.41; H, 6.16; N,
6.94. Found: C, 68.37; H, 6.19; N, 6.99.
A solution of fully protected di- or tripeptide (2 mmol) and
TFA (36 mmol, 2.78 mL) in dry methylene chloride
(20 mL) was stirred at room temperature for 4 h, then the
volatiles were removed under reduced pressure and the
corresponding amine salt was obtained pure in quantitative
yield without further purification.
A solution of azelaic acid (0.98 g, 0.52 mmol) and
HBTU (0.4 mg, 1.04 mmol) in dry acetonitrile (22 mL)
was stirred under inert atmosphere for 10 min at room
temperature. Then a mixture of the previously obtained
amine salt (1.04 mmol) and Et3N (3.2 mmol, 0.47 mL)
in dry acetonitrile (15 mL) was added dropwise at room
temperature. The solution was stirred for 40 min under
inert atmosphere, then acetonitrile was removed under
reduced pressure and replaced with ethyl acetate. The
mixture was washed with brine, 1 N aqueous HCl (3 9
30 mL) and with 5% aqueous NaHCO3 (1 9 30 mL),
dried over sodium sulphate and concentrated in vacuo.
The product was obtained pure after silica gel chroma-
tography (DCM 100% ? DCM/acetato di etile 80:20 as
eluant).
CH2(C3H6CO-L-Phe-D-Oxd-(S)-aMe-Phg-OBn)2 2d
M.p. = 150°C; [a]D20 = ?92.0 (c = 1, CHCl3); IR
(CH2Cl2, 3 mM): m 3,433, 3,385, 3,323, 3,304, 1,787,
1,737, 1,714, 1,677 cm-1; IR (1% in KBr): m 3,422, 3,327,
1
3,284, 1,781, 1,749, 1,706, 1,684, 1653, 1642 cm-1; H
NMR (400 MHz, CDCl3):
d 0.88–1.41 (m, 16H),
1.65–2.02 (m, 4H), 1.96 (s, 6H), 2.94 (m, 2H), 3.18 (m,
2H), 4.24 (m, 2H), 4.42 (m, 2H), 5.08 (AB, 4H,
J = 12.0 Hz), 5.28 (m, 2H), 5.71 (bs, 2H), 6.05 (bs, 2H),
7.05–7.35 (m, 30H), 7.40 (bs, 1H), 7.78 (s, 1H); 13C NMR
(100 MHz, CDCl3): d 14.1, 20.8, 21.0, 21.8, 24.5, 28.5,
29.6, 35.2, 36.7, 53.0, 53.4, 60.3, 62.2, 63.0, 67.3, 74.6,
81.4, 126.1, 127.3, 127.9, 128.0, 128.1, 128.3, 128.7,
129.2, 135.4, 151.6, 166.9, 171.6, 173.4. Anal. calcd. for
C69H74N6O14: C, 68.41; H, 6.16; N, 6.94. Found: C, 68.45;
H, 6.20; N, 6.91.
CH2(C3H6CO-L-Phe-D-Oxd-(R)-b3-hPhg-OBn)2
2a
M.p. = 179°C; [a]D20 = ?44.0 (c = 1.1, CHCl3); IR
(CH2Cl2, 3 mM): m 3,433, 3,323, 1,785, 1,735, 1,719,
1,672, 1,658 cm-1; IR (1% in dry KBr): m 3,310, 3,298,
1,773, 1,734, 1,718, 1,653 cm-1 1H NMR (400 MHz,
;
CDCl3): d 1.09–1.58 (m, 16H), 1.85–2.05 (m, 4H),
2.85–3.21 (m, 8H), 4.11 (m, 2H), 4.39 (m, 1H), 4.62 (m,
1H), 5.05 (m, 2H), 5.13 (m 1H), 5.17 (s, 2H), 5.42 (m, 1H),
5.65 (m, 1H), 6.12 (m, 1H), 7.05–7.41 (m, 31H), 7.96 (m,
1H); 13C NMR (50 MHz, CDCl3): d 20.8, 24.7, 28.3, 35.2,
36.5, 40.5, 41.1, 50.6, 53.3, 62.5, 66.5, 75.3, 82.1, 126.4,
127.4, 128.1, 128.5, 128.8, 129.2, 135.1, 135.6, 140.6,
143.5, 151.7, 167.1, 170.5, 172.9, 174.3. Anal. calcd. for
C69H74N6O14: C, 68.41; H, 6.16; N, 6.94. Found: C, 68.47;
H, 6.19; N, 6.91.
General method for the preparation of compounds 3a–d
Compound 1a–e (1 mmol) was dissolved in MeOH
(35 mL) under nitrogen. C/Pd (50 mg, 10% w/w) was
123

618
N. Castellucci et al.
added under nitrogen. A vacuum was created inside the
flask using the vacuum line. The flask was then filled with
hydrogen using a balloon (1 atm). The solution was stirred
for 2 h under a hydrogen atmosphere. The product was
obtained pure after filtration through a Celite pad using
ethyl acetate and concentration in vacuo.
a test tube (8 mm wide). In some cases, the mixture was
sonicated to speed dissolution, by breaking intermolecular
interactions.
The tube was shaken for a few minutes by hand and then
sonicated for 15 min at room temperature, then let stand
for 16 h for the gel formation. The xerogel was obtained,
after solvent evaporation at room temperature.
CH2(C3H6CO-L-Phe-D-Oxd-(R)-b3-hPhg-OH)2
3a
M.p. = 140°C; [a]2D0 = ?29.0 (c = 1.0, MeOH); 1H NMR
(CD3OD, 400 MHz): d 0.82–1.59 (m, 16H), 2.03–2.35
(m, 4H), 2.61–2.98(m, 4H), 3.15–3.40(m, 4H), 4.41(M, 2H),
4.48–4.90 (m, 4H), 5.38 (m, 2H), 5.95 (m, 2H), 7.05–7.43
(m, 20H); 13C NMR (CD3OD, 100 MHz): d 19.7, 20.0, 25.4,
28.3, 28.4, 29.1, 35.4, 37.2, 40.3, 46.5, 48.1, 50.7, 63.1, 75.6,
126.1, 128.3, 128.4, 137.8, 142.0, 153.6, 168.2, 172.3, 173.0,
174.4. Anal. calcd. for C55H62N6O14: C, 64.07; H, 6.06; N,
8.15. Found: C, 64.15; H, 6.04; N, 8.14.
Conditions for the gel formation with inorganic salts
Compounds 2a–b (6 mg, 5 lmol) or 3a–b (5 mg, 5 lmol)
and the solvent reported in Table 2 (500 ll) were placed in
a test tube (8 mm wide) together with 1 equivalent of the
inorganic salt. In the case of the organic solvent, the
organic salt remained as a precipitate.
CH2(C3H6CO-L-Phe-D-Oxd-(S)-b3-hPhg-OH)2
3b
The tube was shaken for a few minutes by hand and then
sonicated for 15 min at room temperature, then let stand
for 16 h for the gel formation. When the gel was formed,
no more precipitate was present in the test tube. The
xerogel was obtained, after solvent evaporation at room
temperature.
M.p. = 117°C; [a]2D0 = -31.7 (c = 1.3, MeOH); 1H NMR
(CD3OD, 400 MHz): d 1.05–1.59 (m, 16H), 2.03–2.25
(m, 4H), 2.71–2.94 (m, 4H), 3.10–3.35 (m, 4H), 4.41
(M, 2H), 4.51–4.78 (m, 4H), 5.38 (m, 2H), 5.98 (m, 2H),
7.05–7.43 (m, 20H); 13C NMR (CD3OD, 100 MHz): d
19.6, 25.5, 28.7, 35.3, 37.6, 40.7, 50.4, 53.0, 60.8, 63.1,
65.9, 75.2, 126.4, 126.8, 127.3, 128.2, 128.4, 129.4, 136.7,
143.6, 160.3, 174.8. Anal. calcd. for C55H62N6O14: C,
64.07; H, 6.06; N, 8.15. Found: C, 64.00; H, 6.04; N, 8.19.
Conditions for Tgel determination
CH2(C3H6CO-L-Phe-D-Oxd-(R)-aMe-Phg-OH)2
3c
The gel–sol transition temperature (Tgel) was determined
by heating some test tubes (diameter: 8 mm) containing the
gel and a glass ball (diameter: 5 mm, weight: 165 mg) on
the top of it. When the gel is formed, the ball floats on it.
The Tgel is the temperature at which the gel becomes sol
and, as a consequence, the ball falls down.
1
M.p. = 98°C; [a]2D0 = ?52.0 (c = 0.6, MeOH); H NMR
(CD3OD, 400 MHz): d 0.90–1.61 (m, 16H), 1.92–2.10
(m, 4H), 1.97 (s, 6H), 2.92 (m, 2H), 3.16 (m, 2H), 3.60–3.95
(m, 2H),4.42–4.60 (m, 4H), 5.95 (m, 2H), 7.05–7.60
(m, 20H); 13C NMR (CD3OD, 100 MHz): d 19.4, 19.7, 21.3,
22.3, 25.3, 28.4, 28.6, 30.0, 35.1, 36.9, 52.8, 53.7, 61.7, 62.9,
74.6, 77.0, 125.7, 125.9, 126.5, 127.0, 127.1, 127.7, 127.8,
128.0, 128.7, 129.1, 136.5, 136.8, 152.3, 167.5, 169.5, 172.3,
174.8. Anal. calcd. for C55H62N6O14: C, 64.07; H, 6.06; N,
8.15. Found: C, 64.11; H, 6.01; N, 8.12.
Microscopy
The precipitates were systematically observed by optical
microscopy (OM) and scanning electron microscopy
(SEM). The OM images were collected using an optical
microscope equipped with a CCD camera. Samples SEM
images were collected on glass cover slip after coating with
gold and observed using a scanning electron microscope.
The images were recorded using a CCD digital camera.
CH2(C3H6CO-L-Phe-D-Oxd-(R)-aMe-Phg-OH)2 3d
1
M.p. = 115°C; [a]2D0 = -4.5 (c = 1.2, MeOH); H NMR
(CD3OD, 400 MHz): d 90–1.70 (m, 16H), 1.85 (s, 6H),
1.90–2.25 (m, 4H), 2.88 (m, 2H), 3.95 (m, 1H), 4.20 (m, 1H),
4.48–4.65 (m, 4H), 5.98 (m, 2H), 7.11–7.58 (m, 20H); 13C
NMR (CD3OD, 100 MHz): d 19.4, 19.7, 22.0, 25.4, 28.4,
28.6, 29.3, 35.2, 37.4, 52.8, 62.6, 74.4, 125.9, 126.1, 126.2,
127.2, 127.9, 128.0, 128.2, 128.7, 129.1, 136.6, 140.6, 152.4,
167.7, 168.0, 172.2, 174.4. Anal. calcd. for C55H62N6O14: C,
64.07; H, 6.06; N, 8.15. Found: C, 64.11; H, 6.10; N, 8.12.
X-ray powder diffraction analysis
Powder X-ray diffraction patterns were collected using a
powder diffractometer using Cu Ka radiation generated at
40 kV and 40 mA. The instrument was configured with a
1/16° divergence and 1/16° antiscattering slits. A standard
quartz sample holder 1 mm deep, 20 mm high and 15 mm
wide was used. The diffraction patterns were collected
Conditions for the gel formation
Compounds 2a–d (6 mg, 5 lmol) or 3a–d (5 mg, 5 lmol)
and the solvent reported in Table 1 (500 ll) were placed in
123

Formation of gels in the presence of metal ions
619
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potent organogelator. Soft Matter 5:4971–4974
Huanga X, Weiss RG (2007) Molecular organogels of the sodium salt
of (R)-12-hydroxystearic acid and their templated syntheses of
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`
Acknowledgments CT is grateful to Ministero dell’Universita e
della Ricerca Scientifica (PRIN 2008), Universita di Bologna (Funds
`
for selected topics) and to Fondazione del Monte di Bologna e di
Ravenna for financial support. GF thanks the Consorzio Inter-Uni-
versitario di Ricerca della Chimica dei Metalli nei Sistemi Biologici
for financial support.
Conflict of interest The authors declare that they have no conflict
of interest.
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