Pre-/post-functionalization in dipyrrin metal complexes-antitumor and antibacterial activity of their glycosylated derivatives

Article abstract of DOI:10.1039/C8DT03059F

A post-functionalization route to tris(dipyrrinato) metal complexes is presented giving access to a range of new complexes relevant in the context of medicinal inorganic chemistry. A pentafluorophenyl group in the meso-position of the dipyrrin ligand serves as an anchor for the connection with alcohols and thiocarbohydrates. The photochemotherapeutic activity of the complexes has been assessed in cellular assays with tumor cell lines and against the Gram-positive bacterium S. aureus. Finally, it is shown that this post-functionalization is also applicable to other dipyrrinato metal complexes.

Full text of DOI:10.1039/C8DT03059F

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Joseph T. Hupp, Omar K. Farha et al.
Efficient extraction of sulfate from water using
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Pre-/Post-functionalization in Dipyrrin Metal Complexes –
Antitumor and Antibacterial Activity of their Glycosylated
Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Claudia S. Gutsche,a,b,c Susanna Gräfe,c Burkhard Gitter,c Keith J. Flanagan,d Mathias O. Senge,d Nora Kulaka and Arno
Wiehe*b,c
DOI: 10.1039/x0xx00000x
www.rsc.org/
A post-functionalization route to tris(dipyrrinato) metal complexes is presented giving access to a range of
new complexes relevant in the context of medicinal inorganic chemistry. A pentafluorophenyl group in the
meso-position of the dipyrrin ligand serves as an anchor for the connection with alcohols and
thiocarbohydrates. The photochemotherapeutic activity of the complexes has been assessed in cellular
assays with tumor cell lines and against the Gram-positive bacterium S. aureus. Finally, it is shown that
this post-functionalization is also applicable to other dipyrrinato metal complexes.
hydrophobic and hydrophilic properties of the compounds, as
well as the substitution with moieties facilitating cell uptake
like carbohydrates.10 Usually, functionalized dipyrrinato metal
Introduction
The introduction of metal-based drugs has proven to be useful
for diverse therapeutic and diagnostic purposes.1 Hence,
medicinal inorganic chemistry allows for the development of
drugs with new mechanisms of action.1c,2 The most prominent
metal complex is cisplatin, which has initiated the field of
medicinal inorganic chemistry.1e,3 Despite its widespread
clinical use as a chemotherapeutic agent there is a need for
the development of new and improved anticancer drugs due
to several drawbacks of cisplatin.3e,h Metal complexes
containing ruthenium1f,4 and gallium1f,4a,5 have shown
promising properties in this respect.
complexes are synthesized by preparing the functionalized
ligand and then forming the metal complex in the final step.11
However, labile functional groups are sometimes incompatible
with this strategy. Hence, methods for introducing
substituents into the assembled complex are of specific
interest.11b
Herein, a post-functionalization route to tris(dipyrrinato) metal
complexes of iron, indium, and gallium is presented. The
synthesis makes use of the nucleophilic substitution (SNAr) on
the meso-pentafluorophenyl (PFP) moieties of the dipyrrin
ligands. This nucleophilic substitution in the para-position of
the PFP substituents has already proven to be a valuable tool
for the functionalization of diverse porphyrinoids.10e,12
Alternatively, the application of pre-functionalized dipyrrins as
ligands for the synthesis of these tris(dipyrrinato) complexes is
exemplified. The phototoxicity of selected complexes was
evaluated in cellular assays with several tumor cell lines and
against the Gram-positive bacterium S. aureus.
Dipyrrins,6 also known as dipyrromethenes, can serve as
ligands
complexes.6,7a,b,8 Dipyrrins become more stable when
substituted with electron-withdrawing groups and
in
bis(dipyrrinato)6,7
or
tris(dipyrrinato)
conformationally more flexible when unsubstituted in the α-
position.6,7b,c Complexes with dipyrrin ligands have, up to now,
found mostly applications in material sciences.8e,f,g,9 An
application in the biomedical arena requires the balance of
Furthermore, it is shown that this post-functionalization
approach is also applicable to other metal complexes by
transferring the reaction conditions to the reaction of PFP-
substituted (dipyrrinato)bis(bipyridyl) ruthenium(II) complexes
with nucleophiles.
a.Institut für Chemie und Biochemie, Freie Universität Berlin, Fabeckstr. 34/36,
14195 Berlin, Germany.
b.Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195
Berlin, Germany.
c. biolitec research GmbH, Otto-Schott-Str. 15, 07745 Jena, Germany, e-mail:
arno.wiehe@biolitec.de.
Additionally, in this publication the structures of five new
tris(dipyrrinato) metal(III) complexes, with either indium(III),
gallium(III), or iron(III) centers, are described. The structural
elucidation of tris(dipyrrinato)metal complexes was first
reported in 1997 by Brückner et al. and over the following
decades, several such structures have been deposited to the
Cambridge Crystallographic Data Center (CCDC) database.8i
d.Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for
Health Sciences, Trinity College Dublin, The University of Dublin, St. James's
Hospital,Dublin 8, Ireland..
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
CCDC 1841032–1841036 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
This journal is © The Royal Society of Chemistry 20xx
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These compounds have found a variety of uses over the years As can be seen, the absorption spectra of the three
with one of the main features being its incorporation into tris(dipyrrinato) metal complexes (Figure 1) show two
metal–organic frameworks and non-covalent networks.13 This pronounced absorption bands at ~450 and ~515 nm. This
is due to their characteristic octahedral shape that the differs significantly from the single broad absorption band of
tris(dipyrrinato) motifs form around their metal(III) centers, dipyrrin ligand. The absorption spectra of the gallium(III) and
the planar conformation of the dipyrrin ligand, and a variety of indium(III) complex are very similar whereas the spectrum of
short contacts that can be achieved due to various substitutes the iron(III) complex is considerably broadened.
on the dipyrrin ligand. These features typically generate an Crystals suitable for X-ray structural characterization were
appealing packing pattern for metal–organic frameworks or obtained for compounds
2 and 3 (Figures 2 and 3). Their
host–guest complexes. For the compounds studied herein, structures are the first of examples of tris(dipyrrinato)metal
these characteristics will be the focus of the discussion, as well complexes bearing a pentafluorophenyl (PFP) unit on the
as how the presentation of fluorine atoms on the aromatic meso-position. These two structures have two separate
rings adds a unique element to the packing pattern of packing patterns, however, both structures feature several
tris(dipyrrinato)metal complexes, which to date, has not been F∙∙∙H contacts, which appear to be directional within each
studied.
respective structure. The packing of compound 2 and 3 is likely
to be influenced by the metal(III) center due to N–M bond
lengths, adding to the distinction of their packing patterns.
Results and discussion
The reaction of purified and isolated PFP-dipyrrin7c
Both compounds
2 and 3 crystallized with one complete
1
with molecule in the asymmetric unit. For simplicity, the dipyrrin
InCl3, GaCl3, or FeCl3∙6H2O, respectively, in the presence of a units surrounding the metal(III) centers in the structures have
base (DIPEA), gave complexes
2
-
4
(Scheme 1). Complex
4
has been labelled A, B, and C following the atom label, as seen in
Figures 2 and 3.
previously been described in the literature.7b
The structure of compound
2 has a bifurcated interaction
centered on the proton of C1B. These are C1B–H1B∙∙∙F2B
[2.615(1) Å, 117.2(1)°] and C1B–H1B∙∙∙F4A [2.615(1) Å,
114.3(1)°], which forms a head-to-head H∙∙∙F network of
interactions. Additionally, there is a H∙∙∙F interaction between
C3A–H3A∙∙∙F3B [2.519(1) Å, 162.9(1)°], which forms a zig-zag
network within the crystal structure. Other interactions of
note are C2A–H2A∙∙∙F3A [2.525(1) Å, 147.3(1)°] and the
reciprocal dimer interaction of F1B∙∙∙F2B [2.837(2) Å]. This
forms the rather complex packing pattern seen in Figure S 1.
There is an almost octahedral orientation of ligands around
the metal(III) center with an N–In–N angle range of 84.6(5)–
95.2(5)° and an N–In bond length range of 2.188(1)–2.243(1)
Å. Additionally, there is an In∙∙∙In distance of 8.402(1)–9.347(1)
F
F
InCl3 or GaCl3
THF, DIPEA
reflux, 6 h
F
F
F
F
44% (In)
48% (Ga)
N
F
F
F
F
F
F
F
N
N
N
M
FeCl3 6H2O
MeOH, DIPEA
50 °C, 30 min
F
N
F
N
NH
N
F
1
61%
F
2
M = In(III)
3 M = Ga(III)
4 M = Fe(III)
F
F
F
Scheme 1 Synthesis of tris(dipyrrinato) metal complexes 2-4.
Å
to the nearest neighboring molecule. Interestingly, it
In Figure 1 the absorption spectra of dipyrrin
1
and the
appears that the C-subunit in this structure forms no apparent
interactions or short contacts.
complexes 2-4 are shown.
In compound
3, the F∙∙∙H interactions observed are much
simpler than those of
2. The F∙∙∙H contacts of C7A–H7A∙∙∙F1A
[2.458(2) Å, 173.0(2)°] and C7B–H7B∙∙∙F5B [2.435(2) Å,
141.9(2)°] are repeated between all units, holding the
structure at a Ga∙∙∙Ga distance of 8.837(1)–8.904(1) Å to the
nearest neighboring molecule. This is clearly represented in
the moiety packing of compound
3 (Figure S 2). Additionally,
the N–Ga–N angle range of 88.3(1)–92.6(1)° and an N–Ga bond
length range of 2.046(3)–2.084(3) Å forms an octahedral
complex around the Ga(III) metal center.
There are only minor differences between compounds
2
and
3
2
due to the metal(III) centers, which results in compound
having a longer N–M bond length between the ligand and
metal(III) center and a larger N–M–N angle. Aside from this,
both structures result in an octahedral complex. This
difference appears to impact the potential F∙∙∙H networks
Figure 1. Absorption spectra (normalized) of dipyrrin
complexes 2-4 in DCM.
1
and tris(dipyrriato) metal
formed in both samples, with compound
2 containing many
more short contacts compared to compound
3.
2 | J. Name., 2012, 00, 1-3
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functionalized complexes
2
-4. This is not unexpected as the
phenyl ring carrying the substituent is twisted to the plane of
the dipyrrin (see below and above the X-ray structures of
complexes
compound
2
and
3) by 90–100° for compound 2 and 73–94° for
3
. Therefore, the substituent has only a very limited
influence on the electronic structure of the dipyrrin unit.
Figure 2. View of the molecular structure of complex
2 in the crystal. Hydrogen
atoms and labels for carbon atoms have been omitted. Thermal ellipsoids give
50% probability.
Figure 4. Absorption spectra (normalized) of tris(dipyrriato) gallium complex
3
and the alkoxy-substituted gallium complexes 5a,b in DCM.
Crystals suitable for X-ray structural characterization were
obtained for compound 5a (Figure 5). The structure of 5a
solved with only a 1/3 of the molecule present in the
asymmetric unit. This structure differs from compound
3 due
to the now substituted 4-position, which contains a butyloxy
group. This alternate substitution has quite an impact on the
F∙∙∙H networks formed and results in an artistic kaleidoscope–
type pattern of packing in the unit cell (Figure 6). The structure
of 5a shows two major F∙∙∙H contacts, C17–H17A∙∙∙F3 [2.405(1)
Å, 158.2(1)°] and C6–H6∙∙∙F1 [2.406(1) Å, 157.8(1)°]. However,
due to the high symmetry within this structure, these
interactions are repeated three times in one unit creating an
elaborate F∙∙∙H network within the structure. This results in a
Figure 3. View of the molecular structure of complex
3 in the crystal. Hydrogen
atoms and labels for carbon atoms have been omitted. Thermal ellipsoids give
50% probability.
As a test reaction, complex
3 was reacted with selected
alcohols under reaction conditions typical for nucleophilic
substitution on the PFP moiety (alcohol in excess, solid,
powdered KOH, Scheme 2).[10e,14] In all cases, the substituted
shorter Ga∙∙∙Ga distance of 7.595(1)
neighboring molecule, as compared to compound
Ga–N angle range of 88.3(1)–90.6(1)° and an N–Ga bond
length range of 2.052(1)–2.055(1) Å is similar to compound
Å
to the nearest
3. The N–
complexes 5a
-c
were obtained in moderate yields.
3.
While viewed along the c-axis, the structure of compound 5a
appears to be rotated by ~90° to the next layer, resulting in the
aforementioned kaleidoscope–type pattern.
RO
F
F
F
F
F
F
F
F
ROH, KOH
N
F
Overall, the structure of 5a forms a tight packing pattern with
shorter distances between the metal(III) centers of
neighboring molecules in comparison to its PFP counterpart
N
N
THF
F
F
F
F
F
F
N
N
N
N
rt, 16 h
Ga
N
Ga
OR
F
N
N
N
F
F
N
compound 3. The main in this compound is the participation of
F
F
5a R =
50%
25%
the substituted 4-position (butyloxy) with interactions to
fluorine atoms rather than the pyrrole rings as seen in
F
F
F
F
5b
R =
3
RO
F
F
F
5c R =
54%
compound 3. This results in more space around the fluorinated
phenyl rings, causing the metal(III) centers to be closer
together, forming an attractive highly symmetric packing
pattern.
Scheme 2 Substitution reaction of
3 with alcohols.
The absorption spectra of these complexes 5a-c (Figure 4)
show no pronounced differences compared to the non-
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Journal Name
R
F
F
F
F
R
N
F
F
F
F
InCl3, GaCl3 or
FeCl3 (H2O)6
F
F
F
N
N
N
M
N
R
THF, DIPEA
reflux, 16-24 h
or
MeOH, 50 °C
30 min - 3 d
N
F
NH
N
F
10a,11a,12a,13a
5a, 5b, 10b,11b M = Ga(III)
10c,11c,12c,13c M = Fe(III)
M = In(III)
F
6-9
F
R
F
6, 10a-c
R =
N
H
5a, 8, 12a,c
R =
O
5a
12a
12c
= 30%
10a
10b
10c
= 24%
= 30%
= 6%
= 0%
7, 11a-c
= 97%
R =
11b
5b, 9, 13a,c R =
N
H
O
11a
11c
= 66%
= 79%
= 75%
5b
13a
13c
= 56% = 65%
= 57%
Scheme
3 Synthesis of tris(dipyrrinato) metal complexes via reaction of
functionalized dipyrrins with the corresponding metal salts.
Figure 5. View of the molecular structure of complex 5a in the crystal. Hydrogen
atoms and labels for carbon atoms have been omitted. Thermal ellipsoids give
50% probability.
Two of the complexes, 12c and 13a, were characterized by
single crystal X-ray crystallography (Figures 7-10). 12c and 13a
were both solved with 1/3 of the molecule present in the
asymmetric unit similar to that of 5a. The structures of 12c and
13a show a similar F∙∙∙H network as seen in compound 5a. 12c
and 13a have a similar artistic packing pattern as seen in
compound 5a while viewed along the c-axis with layers rotated
by ~90° to each other, resulting in a kaleidoscope–type
pattern, Figure 8, and Figure 10. The inclusion of an allyloxy
(
13a) group or a butyloxy (12c) group alters the F∙∙∙H networks
formed in comparison to the PFP compounds of 2 and
3.
The structure of 12c contains two major F∙∙∙H contacts, C17–
H17A∙∙∙F2 (2.380(2) Å, 157.2(3)°), C2–H2∙∙∙F4 (2.410(2) Å,
154.3(2)°). Just as in compound 5a above the interactions are
reciprocated and repeated three times over symmetry
resulting in an extensive F∙∙∙H network. The overall geometry
of compound 12c is an octahedral orientation of the ligands
around the metal(III) center. There is a N–Fe–N angle range of
86.2(1)–91.8(1)° and a N–Fe bond length range of 1.964(3)–
1.970(3) Å. Additionally, there is a Fe∙∙∙Fe distance of 7.522(2)
Å to the nearest neighboring molecule.
Figure 6. View of the crystal packing of complex 5a along the c-axis. Hydrogens
atoms and atom labels have been omitted for clarity.
The structure of 13a contains one major F∙∙∙H contacts, C17–
H17B∙∙∙F4 (2.319(1) Å, 134.1(1)°), which, just like 5a and 12c
above, is reciprocated and repeated three times due to
symmetry. This results in the allyloxy chains being tethered to
the fluorine groups of the phenyl ring through a F∙∙∙H network.
Additionally, the presence of a F∙∙∙F short contact, F2∙∙∙F4
(2.765(2) Å) results in an aggregation of phenyl rings within the
unit cell. The overall geometry of compound 13a is an
octahedral orientation of the ligands around the metal(III)
center. There is an N–In–N angle range of 83.6(1)–95.2(1)° and
a N–In bond length range of 2.218(2)–2.221(2) Å. Additionally,
there is an In∙∙∙In distance of 7.564(2) Å to the nearest
neighboring molecule.
Similar test reactions of 2 and 3 with hexylamine under the
conditions described for the reaction of amines with PFP
substituents10e did not yield the desired amino-substituted
complexes (see SI for details). There was either no reaction (3) or
only partial reaction (2), i.e. a mixture of mono-, bis-, and tris-
substituted complexes was obtained. A chromatographic separation
of this mixture proved not to be possible.
However, the target complexes 10b,c, 11a-c were accessed by the
reaction of the corresponding amino-functionalized dipyrrin ligands
6, 7 with the metal chlorides (Scheme 3). In a similar manner the
alkoxy-substituted complexes 5a,b, 12a,c, and 13a,c could also be
obtained via the pre-functionalized dipyrrins 8 or 9. These pre-
functionalized dipyrrins were obtained by DDQ oxidation of the
corresponding substituted dipyrranes.12,14 Such pre-functionalized
dipyrrins and dipyrranes have already been successfully employed
for the synthesis of BODIPYs and other porphyrinoids.12,14
Overall, the structures of 12c and 13a form a tight packing
pattern. In comparison to PFP counterpart (2), compound 13a
displays a shorter distance between the metal(III) centers of
neighboring molecules. The main difference between packing
of compound 13a and 12c with the PFP complexes
2 and 3, is
the participation of the substituted 4-position (13a: allyloxy,
4 | J. Name., 2012, 00, 1-3
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12c: butlyloxy) with interactions to fluorine groups rather than Figure 9. View of the molecular structure of complex 13a in the crystal.
the pyrrole rings. As with compound 5a, this results in more Hydrogen atoms and labels for carbon atoms have been omitted. Thermal
space around the fluorinated phenyl rings and causes the ellipsoids give 50% probability.
metal(III) centers to be closer together, forming an attractive
high symmetric packing pattern.
Figure 7. View of the molecular structure of complex 12c in the crystal. Hydrogen
Figure 10 View of the crystal packing of complex 13a along the c-axis. Hydrogen
atoms and labels for carbon atoms have been omitted. Thermal ellipsoids give
atoms have been omitted for clarity.
50% probability.
Glycosylation is a valuable tool to increase the uptake of active
moieties by cells and bacteria.10,15 Glycosylation of
porphyrinoids has extensively been applied to increase the
bioavailability and efficacy of these compounds in the
photodynamic therapy of tumors.10a,e In this respect,
thiocarbohydrates have proven to be useful nucleophiles to
achieve glycosylation of diverse substrates.10a,e Gallium(III) has
garnered considerable interest as a chemotherapeutic agent
i.a. based on its role as an antimetabolite to iron(III);16 hence,
complexes
3
and
4
were chosen for glycosylation experiments.
and with the thiocarbohydrates
The reaction of complexes
3
4
1-thio-β-D-glucose sodium salt or 1-thio-β-D-galactose sodium
salt, respectively, yielded the desired glycosylated dipyrinato-
complexes, 14a,b and 15a,b in all cases (Scheme 4). It is
important to note that it would be difficult to obtain such
glycosylated complexes via pre-functionalized ligands due to
the sensitivity of the thiol linkage to oxidation. Under the
strong oxidative conditions used for the preparation of the
Figure 8. View of the crystal packing of complex 12c along the c-axis. Hydrogen
atoms have been omitted for clarity.
dipyrrin (DDQ), the thiol would be oxidized to the sulfone.17
A
possible nucleophilic substitution with thiocarbohydrates at
the stage of the dipyrrin, on the other hand, would be
impaired by the competing reactivity of alpha- and para-
phenyl-position towards nucleophiles.18 Moreover, the final
assembly of the iron(III) complex would again require the
strong oxidant FeCl3∙6H2O.
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F
F
F
F
complexes. Hence, their (photo)cytotoxicity was tested on several
tumor cell lines and against the bacterium S. aureus.
F
F
F
F
F
NaSR, DMF
rt
40 min - 1.5 h
The toxicity of 14a,b and 15a,b in the absence and presence of light
was evaluated in cellular assays in human epidermoid carcinoma
A253, human epithelial carcinoma A431, human oral
adenosquamous carcinoma CAL27, and colorectal adenocarcinoma
HT29 cells (see Figures 12 and 13). In addition, the mouse fibroblast
cell line L929 was tested as a non-tumorous cell line. The assays
were carried out after incubation for 24 h, with the complexes in
medium containing 10% fetal calf serum (FCS). Both, the
cytotoxicity and the photocytotoxicity were determined at two
different complex concentrations (2 and 10 μM). A white light
source at a dose rate of approx. 50 J/cm2 was used for irradiation.
As seen in Figures 12 and 13 all compounds showed no or only very
limited toxic effects in the absence of light. There is, however, a
striking difference in the phototoxicity between the glycosylated
gallium(III) and iron(III) complexes. Whereas the iron(III) complexes
(14a, 15a) show no or only very limited phototoxicity (15a, HT29
cell line), both gallium(III) complexes (14b, 15b) exhibit a very high
phototoxicity, even at lower concentration (2 µM). With the
exception of the results with the HT29 cell line (15b), there seems
to be no difference in the sensitivity of the four tumor cell lines to
the phototoxic action of these gallium(III) complexes. This
phototoxicity is also observed for the non-tumorous L929 fibroblast
cell line, suggesting that the phototoxic activity is not related to
some tumor-cell specific interaction. As a control experiment, the
allyloxy-substituted gallium(III) complex 5b (Figure 13, bottom) was
also tested against the five cell lines and gave only very low
phototoxicity (see Figure 13 below). This illustrates that the
phototoxic activity is not simply due to the central metal ion but
rather to the combination of metal ion and carbohydrate
substitution. The literature on comparable metal complexes may
suggest a phototoxicity via type I or type II photoreactions.19a-c
However, the exact mechanism of this phototoxicity remains to be
elucidated. For ruthenium(II) complexes other mechanisms like a
photodissociation of ligands have been proposed.19d-f In addition,
further investigations e.g. by ICP-MS or LA-ICP-MS20 will be
necessary to directly measure the uptake of complexes. At present,
it cannot be ruled out that the different efficacy of the gallium and
iron complexes may also be influenced by a different uptake
behavior.
N
N
F
F
F
F
F
F
F
N
N
N
N
N
N
M
N
M
N
SR
F
N
N
F
F
F
F
F
F
F
14a,b,15a,b
3-4
RS
F
F
F
M = Ga(III), Fe(III)
OH
OH
O
HO
O
R =
HO
HO
R =
HO
OH
OH
14a
14b
M = Fe(III) = 21%
M = Ga(III) = 49%
15a
15b
M = Fe(III) = 32%
M = Ga(III) = 88%
Scheme 4 Synthesis of glycosylated tris(dipyrrinato) complexes 14a
,b
and 15a,b.
Figure 11 shows the absorption spectra of the glucosylated
gallium(III) complex 14b in comparison with the butyloxy-
substituted analogue 5a and the parent complex 3. Again there are
only marginal differences between in the absorption spectra
corresponding to the limited influence of the para-phenyl
substituent on the basic chromophore.
Figure 11. Absorption spectra (normalized) of complexes 3, 5a and 14b in DCM (3,5a)
and MeOH (14b).
As mentioned above there is increasing interest in ruthenium(II)
and gallium(III) complexes as potential anti-tumor compounds.4d,5c
Apart from their cytotoxic effects in the absence of light, their
photoactivation has also come into focus.19 Therefore it seemed
reasonable to assess the photobiological properties of the new
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Figure 12. Phototoxicity of 14a,b (glucose-substituted complexes) in cellular assays with the L929, A431, A253, HT29 and CAL27 cell lines. P values for the tests are
given in the SI. * indicates significance values with p < 5 x 10-3
.
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Figure 13. Phototoxicity of 15a,b (galactose-substituted complexes) and 5b (allyloxy-substituted gallium(III) complex) in cellular assays with the L929, A431, A253, HT29 and CAL27
cell lines. P values for the tests are given in the SI. * indicates significance values with p < 5 x 10-3
.
Another field of application for photoactive substances is the High phototoxicity of the glycosylated gallium(III) complexes (14b,
photodynamic inactivation of bacteria.21 Thus, complexes 5b, 14a,b 15b) but no activity of the glycosylated iron(III) complexes (14a,
and 15a,b were tested against S. aureus, a common standard in the 15a) and the allyloxy-substituted gallium(III) complex (5b). For both
investigation of antibacterial activity and a typical Gram-positive gallium(III) complexes – even at the lowest concentration of 1 µM –
member of the microflora of infected wounds.22 Cultures of S. after white light irradiation, a complete inactivation of S. aureus
aureus were incubated with the complexes for 30 min in three was observed corresponding to a six log reduction of the bacteria.
different concentrations (1, 10, and 100 μM). A white light source at
a dose rate of approx. 100 J/cm2 was used for irradiation (see SI for
details). The activity pattern of the complexes against S. aureus was
very similar to that found in the tumor cells (Figures 14 and 15);
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Figure 14. Photoinactivation of S. aureus by 14a,b (glucose-substituted complexes) in phosphate-buffered saline (PBS) (30 min incubation, irradiation with white
light), MC = metal complex, given is the logarithm of the number of colony-forming units, lg (CFU/ml). For 14b under light irradiation for all three concentrations, a
complete inactivation of the bacteria is observed.
Figure 15. Photoinactivation of S. aureus by 15a,b (galactose-substituted complexes) and 5b (allyloxy-substituted gallium(III) complex) in phosphate-buffered saline
(PBS) (30 min incubation, irradiation with white light), MC = metal complex, given is the logarithm of the number of colony-forming units, lg (CFU/ml). For 15b under
light irradiation for all three concentrations, a complete inactivation of the bacteria is observed.
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The last step was to expand the synthetic concept also to other complexes – in this case 2,2-bipyridyl – does not interfere with the
metal complexes. Due to their medical relevance4d,19c ruthenium(II) nucleophilic functionalization.
complexes were chosen. As starting point the well-known
dichloro(p-cymen)ruthenium(II) dimer23 16 was reacted with PFP-
to obtain the [(η6-p-cymen)ruthenium(Cl)(5-
Cl-
HO
dipyrrin
1
HO
HO
OH
pentafluorophenyl)dipyrrin)] [17].24 Reaction with 2,2’-bipyridine
afforded the new PFP-substituted ruthenium(II) complex 18
(Scheme 5).8d,24,25
O
F
S
-
Cl
F
F
F
F
F
F
F
OH
O
HO
HO
F
F
S-Na+
F
F
F
F
OH
N
N
N
N
Dipyrrin 1
DCM, DIPEA
rt, 24 h
DMF
Cl
Cl
Ru
rt, 10 min
Ru
N
N
Cl
N
N
Ru
Ru
N
N
50%
N
N
N
N
Cl
94%
Ru
Cl
16
18
21
17
Scheme 7 Post-functionalization of a dipyrrinato ruthenium(II) complex with
Cl-
thioglucose.
N
N
N
F
F
F
F
EtOH
24 h, reflux
N
N
N
These examples illustrate the versatility of the current approach to
obtain functionalized metal complexes using the PFP moiety as an
anchor for SNAr reactions with nucleophiles.
Ru
68%
N
F
N
18
Scheme 5. Synthesis of PFP-substituted ruthenium(II) complex 18.
Conclusions
In conclusion, the post-functionalization of tris(dipyrrinato)
complexes of gallium(III), indium(III), and iron(III) carrying
Using the conditions employed above, 18 was functionalized via
SNAr with allyl and propargyl alcohol, as well as allyl amine and
propargyl amine to obtain the alkoxy-substituted ruthenium(II)
complexes 19a,b and the amino-substituted complexes 20a,b in
acceptable yields (Scheme 6).
pentafluorophenyl
moieties
with
alcohols
and
thiocarbohydrates has been achieved. Using this synthetic
route, metal complexes with sensitive functional groups are
available in a facile manner and good yields. For the less
sensitive alkoxy-groups, the complexes can also be prepared
with the corresponding pre-functionalized dipyrrins. It is
shown that this synthetic approach is also applicable to other
metal complexes giving access to functionalized ruthenium(II)
complexes. Selected complexes were tested for their
(photo)cytotoxicity in cellular assays against tumor cell lines
and against the bacterium S. aureus. Phototoxic activity
against tumor cells as well as against S. aureus was
predominantly observed with the glycosylated gallium(III)
complexes. The phototoxic activity appears to be dependent
on the metal as well as on the carbohydrate unit present. The
specific mechanism of phototoxic action, as well as the post-
functionalization with other (thio)carbohydrates and
biomolecules, will be elucidated in future studies.
ROH
THF, KOH
rt, 2-5 h
Cl-
N
F
F
F
F
N
N
N
or
18
R
Ru
N
N
RNH2
DMSO
80 °C, 1-48 h
19,20
H
N
O
O
20a R =
20b R =
43%
41%
19a
80%
62%
R =
H
19b R =
N
Scheme 6. Substitution of complex 18 with nucleophiles.
Finally, also the thioglycosylation proved to be transferable to
ruthenium(II) complexes, the thioglycosylated complex 21 being
isolated in 50% yield after just 10 min reaction time (Scheme 7). As
can be seen the presence of different ligands in the ruthenium(II)
Acknowledgement
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The authors thank D. Steen and R. Wiehe for helpful InCl3 or GaCl3 and DIPEA (14 eq) were added and the reaction
discussions during the preparation of the manuscript. This mixture was refluxed for 6 h. After cooling to rt the solvent was
project has received funding from the European Union’s evaporated, purified by column chromatography (silica gel, DCM)
Horizon 2020 research and innovation programme under the and recrystallization (DCM/n-hexane) to obtain the product as
1
Marie Skłodowska-Curie Grant Agreement No. 764837 and was orange crystals. The products were analyzed by H, 13C, 19F NMR
supported by a grant from Science Foundation Ireland (IvP spectroscopy, HRMS, melting point, elemental analysis, and UV/Vis
13/IA/1894) (M.O.S.). The biolitec research GmbH gratefully spectroscopy.
acknowledges
financial
support
by
the
German
Bundesministerium für Bildung und Forschung (BMBF) (project Synthesis of tris(5-pentafluorophenyl-dipyrrinato)iron(III) [4]:
“Response-FV9”, FKZ 03ZZ0914I).
Experimental Section
General
Under argon atmosphere PFP-dipyrrin 1 (100 mg, 0.32 mmol, 3.1
eq) was dissolved in dry MeOH (10 mL), FeCl3∙6 H2O (27 mg, 0.10
mmol) and DIPEA (0.24 mL, 186 mg, 1.44 mmol, 14 eq) were added
and the mixture was stirred for 30 min at 50 °C. The mixture was
diluted with DCM and washed several times with water. The organic
layer was dried with sodium sulfate, filtered and evaporated to
dryness. The crude product was purified by column
chromatography (silica gel, DCM) and washed with pentane to
obtain the product as a black solid (60 mg, 61%). The data are in
accordance with the literature.7b
The nomenclature and numbering (13C and 19F NMR spectra) are in
accordance with IUPAC recommendations. THF and DMF used as
solvents for the reactions were stored over molecular sieves. All
liquid reagents were added through syringes. Purchased reagents
were used as received without further purification. All reactions
were monitored by TLC analysis. The preparative purification of
mixtures by column chromatography was conducted on silica gel
(60 M, 40-63 μm). The yields refer to analytically pure compounds.
NMR spectra were recorded on a 400 and 500 MHz instrument,
respectively. Chemical shifts are given in parts per million (ppm)
relative to the resonance of the solvent. As deuterated solvents
chloroform (δ = 7.26, 77.0 ppm) and methanol (δ = 3.31, 49.0 ppm)
were used. Integrals are in accordance to assignments and coupling
constants are given in hertz (Hz). All 13C NMR spectra are proton–
decoupled. The multiplicity is indicated as follows: s (singlet), br s
(broad singlet), d (doublet), t (triplet), m (multiplet), mc (centered
multiplet) dd (doublet of doublets). The ortho- and meta-fluorine
signals in the 19F NMR spectra of the substituted tetrafluorophenyl
moieties exhibit the A,A’B,B’ and A,A’X,X’ coupling pattern typical
for para-substituted aromatic compounds, in the 19F NMR spectra
these signals are denoted as mc. HRMS analyses were performed by
ESI-TOF, the solvent flow rate was adjusted to 4 μL/min and spray
voltage was set to 4 kV. Drying gas flow rate was set to 15 psi (1
bar) and all other parameters were adjusted for a maximum
abundance of the respective [M+H]+. The UV/Vis spectra were
measured with a UV/Visible spectrometer using DCM as solvent and
quartz cuvettes of 1 cm length. Emission spectra were recorded
with a fluorescence spectrometer using quartz cuvettes of 1 cm
length and DCM as a solvent. Melting points are uncorrected.
Compounds 17c, 5-{4-(N-hexylamino)-2,3-5,6-tetrafluorophenyl}-
dipyrrane12, 5-{4-(N-prop-2-ynylamino)-2,3,5,6-tetrafluorophenyl}-
General procedure for the post-functionalization of 3 with
alcohols (complexes 5a-c): Under argon atmosphere complex 3,
freshly powdered KOH (30 eq) and the specific alcohol (20 eq) in dry
THF were stirred at rt for 16 h. The mixture was diluted with DCM,
washed several times with water and the organic layer was dried
with sodium sulfate, filtered and evaporated to dryness. The crude
product was purified by column chromatography (silica gel, DCM/n-
hexane = 1:1) and washed with pentane to obtain the product as an
orange solid. The products were analyzed by 1H, 13C, 19F NMR
spectroscopy, HRMS, melting point, and UV/Vis spectroscopy.
General procedure for the synthesis of para-phenyl-substituted
PFP-dipyrrins 6-9: A mixture of para-phenyl-substituted PFP-
dipyrrane12,14 and DDQ (1.3 eq) in THF was stirred for 20 min at rt.
The mixture was filtered through silica gel and evaporated to
dryness. Further purification was achieved by column
chromatography (silica gel, DCM) to obtain the product as a yellow
1
oil. The products were analyzed by H, 13C, 19F NMR spectroscopy,
HRMS, and UV/Vis spectroscopy.
General procedure for the synthesis of tris(dipyrrinato) complexes
starting from pre-functionalized dipyrrins:
a) Synthesis of indium(III) and gallium(III) complexes 10a, 11a, 12a,
13a, 5a,b 10b and 11b: Under argon atmosphere a mixture of
dipyrrin (3.1 eq), InCl3 (1 eq) or GaCl3 (1 eq) and DIPEA (3.1 eq) were
dissolved in THF and refluxed for the specific time (see SI). After
cooling to rt the mixture was diluted with DCM and washed several
times with water. The organic layer was dried with sodium sulfate,
filtered and evaporated to dryness. The crude product was purified
by column chromatography (see SI for the specific solvent mixture),
washed with pentane to obtain the product as orange crystals. The
dipyrrane12,
dipyrrane14,
5-{4-(prop-2-ynyloxy)-2,3,5,6-Tetrafluorophenyl}-
5-{4-(butyl-1-oxy)-2,3,5,6-tetrafluorophenyl}-
dipyrrane14, and dichloro(p-cymen)ruthenium(II) dimer23 [16] were
prepared according to the literature
.
1
products were analyzed by H, 13C, 19F NMR spectroscopy, melting
Synthetic procedures
point, HRMS, and UV/Vis spectroscopy.
Synthesis of tris(5-pentafluorophenyl-dipyrrinato) indium(III) [2]
and tris(5-pentafluorophenyl-dipyrrinato) gallium(III) [3]: Under
argon atmosphere PFP-dipyrrin 1 (3.1 eq) was dissolved in dry THF,
b) Synthesis of iron(III) complexes 10a-c: Under argon atmosphere
dipyrrin (3.1 eq) was dissolved in dry MeOH; FeCl3∙6 H2O (1 eq) and
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DIPEA (14 eq) were added and the mixture was stirred for 30 min at fibroblast, and colorectal adenocarcinoma HT29 cells were grown in
50 °C. After cooling to rt the mixture was evaporated to dryness, Dulbecco’s modified eagle medium (DMEM) with 10% heat
purified by column chromatography (see SI for the specific solvent inactivated FCS, 1% penicillin (10000 IU) and streptomycin (10000
mixture) and washed with pentane to obtain the product as a green μg mL−1). A stock solution (2 mM) of the metal complex was
1
solid. The products were analyzed by H, 19F NMR spectroscopy, prepared at 4 °C in DMSO and kept in the dark. DMEM (without
melting point, HRMS, and UV/Vis spectroscopy.
phenol red) with 10% FCS was used for further dilution to reach a
concentration of 2 or 10 μM of the metal complex, respectively. In
General procedure for the synthesis of the glycosylated metal microplates 2 × 104 cells per well were seeded in fresh medium
complexes 14a,b and 15a,b: Under argon atmosphere and (DMEM without phenol red) containing 10% FCS with 2 μM or 10
exclusion of light complex 3 or 4 was dissolved in dry DMF, the μM of the metal complex and incubated for 24 h. After an exchange
specific thiocarbohydrate sodium salt (4.5 eq) was added and the of medium (to remove any metal complex not taken up by the
mixture stirred for a specific time (details see in SI) at rt. The cells), the irradiation was performed at RT with a white light source
mixture was evaporated to dryness, purified by column [KL 2500 LCD (Schott)] at a dose rate of app. 50 J cm−2. The cell
chromatography (silica gel, DCM/MeOH = 85:15) and washed with viability of the samples was assessed using the XTT assay26 and the
pentane to obtain the product as a solid. The products were absorbance was measured with a Tecan Infinite 200 microplate
1
analyzed by H, 13C, 19F NMR spectroscopy, melting point, HRMS, reader, at a wavelength of 490 nm.
and UV/Vis spectroscopy.
Bacterial testing
General procedure for the post-functionalization of complex 18 The bacterium S. aureus DSM11729 is a typical Gram-positive
with alcohols: Under argon atmosphere and exclusion of light member of the wound microflora. Cultured bacterial cells were
complex 18 was dissolved in dry THF, freshly powdered KOH suspended in sterile PBS, or sterile PBS supplemented with 10%
(1.3 eq) and the specific alcohol (2 eq) was added and the mixture sterile horse blood serum. The final OD (optical density) at 600 nm
was stirred for a specific time (details see in SI) at rt. The mixture (1 cm cuvette path length) in all cases was 0.015. The bacterial
was diluted with DCM and washed with water several times. The suspensions were placed in sterile black well plates with clear
organic layer was dried with sodium sulfate, filtered and bottoms. Concentrations of metal complexes used in the study
evaporated to dryness. The crude product was purified by column were 100 μM, 10 μM, and 1 μM. After an incubation time of 30 min
chromatography (silica gel, DCM/MeOH
=
85:15) and at rt, the samples were irradiated with a white light source [KL 2500
recrystallization (DCM/n-pentane) to obtain the product as solid. LCD (Schott)] at a dose rate of approximately 100 J cm−2. Control
The products were analyzed by 1H, 13C, 19F NMR spectroscopy, plates containing no metal complex were not exposed to light. The
melting point, HRMS, and UV/Vis spectroscopy.
control samples for dark toxicity were only exposed to metal
complex without any illumination.
General procedure for the post-functionalization of complex 18
with amines: Under argon atmosphere complex 18 was dissolved in Crystallography
dry DMSO, amine (20 eq.) was added and the mixture was stirred Crystals were grown following the protocol developed by Hope by
for a specific time (details see in SI) at 80 °C. The mixture was dissolving the compounds in either DCM or a DCM/MeOH mixture
diluted with DCM, washed with water, dried with sodium sulfate, and allowing for slow evaporate over time and handled as
filtered and evaporated to dryness. The crude product was purified described before.27 Single crystal X-ray diffraction data for all
by column chromatography (silica gel, DCM/MeOH = 85:15) to compounds were collected on a Bruker APEX 2 DUO CCD
1
obtain the product as solid. The products were analyzed by H, 13C, diffractometer by using graphite-monochromated MoKα (λ =
19F NMR spectroscopy, melting point, HRMS, and UV/Vis 0.71073 Å) radiation and Incoatec IμS CuKα (λ = 1.54178 Å)
spectroscopy.
radiation. Crystals were mounted on a MiTeGen MicroMount and
collected at 100(2) K by using an Oxford Cryosystems Cobra low-
Synthesis of glycosylated ruthenium(II) complex 21: Under argon temperature device. Data were collected by using omega and phi
atmosphere and the exclusion of light complex 18 (100 mg, 0.13 scans and were corrected for Lorentz and polarization effects by
mmol) was dissolved in dry DMF (3 mL), 1-thio-β-D-glucose sodium using the APEX software suite.28 Using Olex2, the structure was
salt hydrate (37 mg, 0.17 mmol, 1.3 eq) was added and the mixture solved with the XT structure solution program, using the intrinsic
stirred for 10 min at rt. The mixture was evaporated to dryness and phasing solution method and refined against │F2│ with XL using
purified by column chromatography (DCM/MeOH = 85:15) to least squares minimization.29 Hydrogen atoms were generally
obtain the product as black solid (60 mg, 50%). The product was placed in geometrically calculated positions and refined using a
1
analyzed by H, 13C, 19F NMR spectroscopy, melting point, HRMS, riding model. Details of data refinements can be found in Table S1
and UV/Vis spectroscopy.
Materials and Methods
Cell testing
and S2 and further experimental and refinement detail can be
found in the SI. All images were prepared by using Olex2.29a
CCDC-1841034 (for 2), -1841036 (for 3), -1841035 (for 5a), -
1841033 (for 12c), and -1841032 (for 13a) contains the
supplementary crystallographic data for this paper. These data sets
Human epidermoid carcinoma A253, human epithelial carcinoma can be obtained free of charge from The Cambridge
A431, human oral adenosquamous carcinoma CAL27, L929 mouse
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Nishihara, Inorg. Chem., 2014, 53, 3275–3277; (c) G. Li, L.
Ray, E. N. Glass, K. Kovnir, A. Khoroshutin, S. I. Gorelsky and
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Data
Center
via
http://www.ccdc.cam.ac.uk/data_request/cif.
Conflicts of interest
There are no conflicts to declare.
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