Illuminating metal-ion sensors: Benzimidazolesulfonamide metal complexes

Article abstract of DOI:10.1021/ic101700t

The synthesis, structure, and solution spectroscopy of several (2-sulfonamidophenyl)benzimidazole metal complexes are reported. These ligands, which have been reported as selective molecular sensors for Zn²⁺, readily form complexes with Co

Full text of DOI:10.1021/ic101700t

10226 Inorg. Chem. 2010, 49, 10226–10228
DOI: 10.1021/ic101700t
Illuminating Metal-Ion Sensors: Benzimidazolesulfonamide Metal Complexes
David Martin, Matthieu Rouffet, and Seth M. Cohen*
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla,
California 92093, United States
Received August 20, 2010
Chart 1. Compounds Used as Stains and Sensors for Zn2þ
The synthesis, structure, and solution spectroscopy of several
(2-sulfonamidophenyl)benzimidazole metal complexes are reported.
These ligands, which have been reported as selective molecular
sensors for Zn2þ, readily form complexes with Co2þ, Ni2þ, Cu2þ
,
and Zn2þ. Surprisingly, the ligand adopts different binding modes
depending on the metal ion. The work here provides insight into the
coordination chemistry of these ligands, which may allow for the
development of improved metal-ion sensors and metalloprotein
inhibitors.
ratiometric response, which allows for quantitative analysis
of Zn2þ 5
.
In addition to Zn2þ-specific fluorescent probes, our labo-
ratory has recently described the use of these zinc-binding
motifs in the design of matrix metalloproteinase (MMP)
inhibitors.6 It was found that several 8-sulfonamidoquinoline
and (2-sulfonamidophenyl)benzimidazole fragments showed
good activity and selectivity against several MMP isoforms.
Despite the importance of metal binding in the activity of
these compounds, there is essentially no information on the
coordination chemistry of (2-sulfonamidophenyl)benzimida-
zole ligands to any metal ion. In this study, several benzimi-
dazolesulfonamide metal complexes are reported, and their
binding modes are directly compared to the well-documented
8-sulfonamidoquinoline analogues.
The TPBI ligand readily forms a variety of metal com-
plexes under mild conditions. Co2þ, Ni2þ, and Zn2þ com-
plexes were obtained by combining methanolic solutions of
TPBI and a metal salt at room temperature. In the prepara-
tion of Ni2þ and Zn2þ complexes, the metal acetate salts were
used and precipitation of the complexes was observed im-
mediately. In the case of Co2þ, the nitrate salt was used,
necessitating the addition of a base (Et3N) for complex
formation. To synthesize the Cu2þ complex, a methanolic
Despite much effort in trying to unravel the role of metal
ions in biology, much remains to be learned about how metal
cations are trafficked and stored prior to their incorporation
into different metalloproteins.1 Of particular interest is zinc,
which is the second most abundant d-block metal ion in
humans.2 Historically, Zn2þ wasdetected using dithizoneasa
histochemical stain (Chart 1),1 which revealed much about
the spatial distribution of Zn2þ in various tissues. Today,
fluorescent probes have attracted considerable attention for
the direct visualization of biological Zn2þ at the molecular
level. One of the first probes to be used was 8-hydroxyquino-
line, which was further developed into Zinquin3,4 (Chart 1), a
compound containing an 8-sulfonamidoquinoline core. The
metal-binding properties and coordination chemistry of the
8-sulfonamidoquinoline motif have been well describedin the
literature. These compounds were found to show a strong
increase in fluorescence upon binding Zn2þ. Later, Fahrni
et al. developed Zn2þ-selective fluorescent sensors based on
2-(20-tosylaminophenyl)benzimidazole (TPBI; Chart 1).5
These molecules absorb at ∼300-340 nm and emit at ∼400
nm (upon Zn2þ coordination), which may limit their use in
vivo; however, they are attractive because they provide a
TPBI solution was added to a yellow solution of CuCl2
3
2H2O in acetonitrile. Upon the addition of aqueous NaOH,
the solution turned dark red, indicating formation of the
complex. This Cu2þ complex did not precipitate out of the
reaction mixture, so the solvents were removed under va-
cuum and the resulting residue was dissolved in acetone/
CH2Cl2. The product was crystallized by vapor diffusion with
diethyl ether as the precipitant.
*To whom correspondence should be addressed. E-mail: scohen@ucsd.edu.
(1) McRae, R.; Bagchi, P.; Sumalekshmy, S.; Fahrni, C. J. Chem. Rev.
2009, 109, 4780–4827.
(2) Nolan, E. M.; Lippard, S. J. Acc. Chem. Res. 2008, 42, 193–203.
(3) Nasir, M. S.; Fahrni, C. J.; Suhy, D. A.; Kolodsick, K. J.; Singer, C. P.;
O’Halloran, T. V. J. Biol. Inorg. Chem. 1999, 4, 775–783.
(4) Fahrni, C. J.; O’Halloran, T. V. J. Am. Chem. Soc. 1999, 121, 11448–
11458.
UV-vis absorption spectra for the complexes are shown in
Figure 1. In the UV region, Zn(TPBI)2 has absorbance
(5) Henary, M. M.; Wu, Y.; Fahrni, C. J. Chem.—Eur. J. 2004, 10, 3015–
3025.
(6) Rouffet, M.; de Oliveira, C. A. F.; Udi, Y.; Agrawal, A.; Sagi, I.;
McCammon, J. A.; Cohen, S. M. J. Am. Chem. Soc. 2010, 132, 8232–8233.
r
pubs.acs.org/IC
Published on Web 10/13/2010
2010 American Chemical Society

Communication
Inorganic Chemistry, Vol. 49, No. 22, 2010 10227
Figure 1. Top: Representative UV absorbance spectra of TPBI and its
complexes. Bottom: Visible absorbance spectra ofNi(TPBI)2, Co(TPBI)2,
and Cu(TPBI)Cl. All spectra were recorded in dimethyl sulfoxide.
maxima at 296 nm (ε = 29000 M-1 cm-1), 304 nm (ε =
34000 M-1 cm-1), and 334 nm (ε = 35 000 M-1 cm-1). The
Co2þ and Ni2þ complexes also show maxima at 296 and 304
nm [Co(TPBI)2, ε = 32 000 and 37 000 M-1 cm-1; Ni-
(TPBI)2, ε = 30 000 and 32 000 M-1 cm-1]. In addition,
Co(TPBI)2 displays a transition at 338 nm and Ni(TPBI)2 at
352 nm (ε = ∼29 000 M-1 cm-1 in both cases). Cu(TPBI)Cl
shows only one transition at 296 nm (ε = 19 000 M-1 cm-1).
The complexes are relatively weakly colored, as shown by
their absorbance in the visible region of the spectrum. The red
Co(TPBI)2 complex is the most intensely colored, with
maxima at 532 and 550 nm and extinction coeffiecients of
237 and 231 M-1 cm-1, respectively. Co(TPBI)2 also has a
weak, broad absorbance centered at 790 nm (ε = 37 M-1
cm-1). Cu(TPBI)Cl is also red, having an absorbance max-
imum at 510 nm (ε = 161 M-1 cm-1) and a very broad
absorbance centered at 840 nm (ε = 95 M-1 cm-1) that trails
into the visible region. The green Ni(TPBI)2 complex has the
faintest color, with absorbance maxima at 448 and 690 nm
(ε = 109 and 55 M-1 cm-1, respectively). The fluorescence of
the complexes was checked using a hand-held UV lamp (254
and 365 nm), and only Zn(TPBI)2 emitted. Zn(TPBI)2 was a
strong emitter in aqueous solution at ∼415 nm when excited
at 305 nm (data not shown).5
Figure 2. X-ray structural representations of Zn- (top), Co- (middle), and
Ni(TPBI)2 (bottom), with solvent molecules and H atoms (except for the
imidazole N-H) removed for clarity. Only one complete TPBI ligand is
shown for clarity. Thermal ellipsoids are shown at 50% probability.
Zn2þ ion with bond lengths of 2.005(2) and 1.978(2) A, re-
spectively (Figure 2). The complex cocrystallized with
one CHCl3 solvent molecule in the asymmetric unit.
Extension of the inversion symmetry reveals a heavily
distorted tetrahedral ZnN4 coordination sphere, with
N-Zn-N angles ranging from 92.05(7)° to 133.2(1)°. A
long interaction between the Zn2þ ion and one of the
sulfonamide O atoms may contribute to this distortion
(Zn-O ∼ 2.70 A).
Red and green blocks of Co(TPBI)2 2DMF and Ni(TPBI)2
3
3
2DMF also crystallized in the space group C2/c with an
asymmetric unit similar to that of Zn(TPBI)2 but with the
CHCl3 solvent replaced by a N,N-dimethylformamide (DMF)
molecule. The TPBI ligand adopts a binding mode similar to
that in the Zn2þ complex (Figure 2). In Co(TPBI)2, the
Co-N distances are 1.981(3) and 1.992(3) A for the sulfon-
amide and imidazole N atoms, respectively. The tetrahedral
CoN4 coordination is more distorted than that in the Zn2þ
complex, with N-Co-N angles ranging from 91.5(1)° to
138.5(2)°. This increase in distortion is accompanied by a
closer interaction between the Co atom and sulfonamide O
atoms, with a Co-O bond length of 2.62 A (Figure 2). The
Ni-N bonds in Ni(TPBI)2 are somewhat shorter at 1.962(2)
and 1.981(2) A for the sulfonamide and imidazole N atoms,
respectively. The NiN4 tetrahedron is even more distorted,
having angles between 91.13(9)° and143.68(14)° and a strong
Single crystals of M(TPBI)2 (M = Zn2þ, Co2þ, Ni2þ
)
and Cu(TPBI)Cl were obtained, and their structures were
determined by X-ray diffraction. Colorless blocks of Zn-
(TPBI)2 2CHCl3 crystallize in the monoclinic space group
3
C2/c. The asymmetric unit consists of a deprotonated TPBI
ligand bound by the imidazole and sulfonamide N atoms to a

10228 Inorganic Chemistry, Vol. 49, No. 22, 2010
Martin et al.
complexes compared to 150° for TPBI). Angling of the
sulfonamide group toward the metal allows one of the O
atoms to act as a weak donor, which is a feature not found in
the structures of analogous quinoline-based complexes.3,7-23
Many homoleptic complexes of quinolinesulfonamide li-
gands with Zn2þ and Cu2þ have been previously reported.
The Zn2þ complexesdo notdiffer significantly fromtheTPBI
complex reported here, aside from thosedifferences described
above.3,8,11,12,14,15,23 In the case of Cu2þ, the ability of the
TPBI ligand to supply a third donor deters the formation of a
homoleptic complex, as found in previously reported struc-
tures with 8-sulfonamidoquinoline ligands.9,10,13,16-20 The
metal adopts the favored square-planar geometry and avoids
steric clashes between ligands by retaining a chloride ligand
as its fourth donor. The more electron-deficient Co2þ and
Ni2þ have complexes reported with two quinolinesulfona-
mide ligands, but the metals also ligate two solvent molecules
(water or methanol) in order to adopt an octahedral geo-
metry.7,21 Homoleptic complexes have only been reported by
using bulkier 2,4-dimethylquinoline-22 and dimethylaminon-
apthalenesulfonamide24 ligands in order to deter the ligation
of solvent molecules. In contrast, the TPBI ligand readily
makes homoleptic complexes with these metals with dona-
tion from sulfonamide O atoms and the somewhat bulkier
ligand framework. 2-(2,2-Sulfonamidophenyl)benzimidazole
derivatives are promising fluorescence-based sensors for
Zn2þ as well as potent leads for metalloproteinase inhibitors.
The detailed coordination chemistry provided here will be
essential to the development of the next generation of sensors
and inhibitors based on these scaffolds.
Figure 3. Asymmetric unit of Cu(TPBI)Cl, with H atoms (except for the
imidazole N-H) removed for clarity. Thermal ellipsoids are shown at
50% probability.
interaction with the sulfonamide O atoms with a Ni-O dis-
tance of 2.57 A.
Red blocks of Cu(TPBI)Cl crystallize in the triclinic space
group P1, with an asymmetric unitconsisting of one Cu2þ ion
bound by a single deprotonated TPBI ligand and a chloride
ion (Figure 3). The Cu2þ ion adopts a distorted square-planar
geometry consisting of the chloride ion, imidazole and sul-
fonamide N atoms, and, unlike the previous structures, a
fully coordinated sulfonamide O atom. The Cu-N distances
are muchshorter than the M-N bonds in the other structures
at 1.956(3) and 1.908(3) A for the imidazole and sulfonamide
N atoms, respectively. The Cu-O distance is 2.235(2) A, and
the Cu-Cl distance is 2.214(1) A. The Cu2þ ion is coplanar
with the Cl and N donors, with the O donor 17.6° out of the
plane, as measured by the N-N-Cl-O torsion angle. Attempts
to make a homoleptic Cu(TPBI)2 complex with other metal
sources such as nitrate, acetate, sulfate, and acetylacetonate
were unsuccessful.
The primary structural difference between TPBI and the
well-studied quinolinesulfonamide ligands (of the type used
in Zinquin; Chart 1) is that, upon metal binding, TPBI forms
a six-membered chelate, as opposed to a five-membered ring
for the quinoline-based ligands. This causes the bite distance
(Nbenz-Namide) to be ∼0.2 A larger, yielding Nbenz-M-
Namide bond angles that are roughly 10° wider than those in
the 8-sulfonamidoquinoline complexes. The other conse-
quence of the six-membered chelate is the closer positioning
of the sulfonamide functionality to the metal, as observed by
the Nbenz/quin-Namide-S angle (∼170° for quinoline-based
Acknowledgment. We thank Dr. Y. Su for performing
the mass spectrometry experiments. This work was sup-
ported by the NIH (Grant R21HL094571-01).
Supporting Information Available: X-ray crystallographic
files in CIF format, synthetic and crystallographic details, and
Table S1. This material is available free of charge via the Internet
at http://pubs.acs.org. The atomic coordinates (CCDC refer-
ence numbers 789121-789124) for these structures have also
been deposited with the Cambridge Crystallographic Data
Centre. The coordinates can be obtained, upon request, from
the Director, Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, U.K.
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