Assembling Pentatopic Terpyridine Ligands with Three Types of Coordination Moieties into a Giant Supramolecular Hexagonal Prism: Synthesis, Self-Assembly, Characterization, and Antimicrobial Study

Article abstract of DOI:10.1021/jacs.9b08484

Three dimensional (3D) supramolecules with giant cavities are attractive due to their wide range of applications. Herein, we used pentatopic terpyridine ligands with three types of coordination moieties to assemble two giant supramolecular hexagonal prism

Full text of DOI:10.1021/jacs.9b08484

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Article
Assembling Pentatopic Terpyridine Ligand with Three Types of
Coordination Moieties into Giant Supramolecular Hexagonal Prism:
Synthesis, Self-Assembly, Characterization, and Antimicrobial Study
Heng Wang, Chung-Hao Liu, Kun Wang, Minghui Wang, Hao Yu, Sneha
Kandapal, Robert Brzozowski, Bingqian Xu, Ming Wang, Shuai Lu, Xin-
Qi Hao, Prahathees Eswara, Mu-Ping Nieh, Jianfeng Cai, and Xiaopeng Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08484 • Publication Date (Web): 11 Sep 2019
Downloaded from pubs.acs.org on September 11, 2019
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Journal of the American Chemical Society
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Assembling Pentatopic Terpyridine Ligand with Three Types of
Coordination Moieties into Giant Supramolecular Hexagonal Prism:
Synthesis, Self-Assembly, Characterization, and Antimicrobial Study
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Heng Wang,†,┴ Chung-Hao Liu, Kun Wang, Minghui Wang, Hao Yu, Sneha Kandapal, Robert
‡,┴
¶,§
†
∥
§
∇
§
∥
†,#
#
∇
Brzozowski, Bingqian Xu, Ming Wang, Shuai Lu, Xin-Qi Hao, Prahathees Eswara, Mu-Ping
,‡
,†
,†
Nieh,* Jianfeng Cai,* Xiaopeng Li*
†Department of Chemistry, University of South Florida, Tampa, Florida 33620, United States
‡Polymer Program, Institute Materials Science, Department of Chemical & Biomolecular Engineering, University of
Connecticut, Storrs, Connecticut 06269, United States
¶Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
§Single Molecule Study Laboratory, College of Engineering and Nanoscale Science and Engineering Center, University
of Georgia, Athens, Georgia 30602, United States
∥
State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun,
Jilin 130012, China
∇Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620,
United States
#College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan 450001, China
KEYWORDS pyrylium salts, pyridinium salts, self-assembly, terpyridine, antimicrobial activity
ABSTRACT: Three dimensional (3D) supramolecules with giant cavities are attractive due to their wide range of applications.
Herein, we used pentatopic terpyridine ligands with three types of coordination moieties to assemble two giant
supramolecular hexagonal prisms with molecular weight up to 42,608 and 43,569 Da, respectively. Within the prisms, two
double-rimmed Kandinsky Circles serve as the base surfaces as well as the templates for assisting the precise self-sorting
during the self-assembly. Additionally, hierarchical self-assembly of these supramolecular prisms into tubular-like
nanostructures has been discovered and fully studied by scanning tunneling microscopy (STM) and small angle X-ray
scattering (SAXS). Finally, these supramolecular prisms show good antimicrobial activities against Gram-positive pathogen
methicillin-resistant Staphylococcus aureus (MRSA) and Bacillus subtilus (B. subtilus).
Introduction
base building blocks, and metal vertices;5b, 5c, 10, 11 (iii) multi-
component self-assembly with the assistance of template
molecules; (iv) subcomponent self-assembly with linear
Self-assembly as an “order-out-of-chaos” strategy is
widely utilized by nature to efficiently assemble biological
structures with sophisticated functionalities.
12
7a, 13
ligands as the edges of both base and lateral face.
1
In
However, most of the ligands were designed with high
symmetry to afford all the metal binding sites with the same
chemical environment. It remains a challenge to introduce
different coordination environments into the same ligand to
further enhance the complexity of prisms.
supramolecular chemistry field, coordination-driven self-
assembly plays an important role in constructing a wide
variety of metallo-supramolecules in a well-controlled
2
manner.
Particularly,
three
dimensional
(3D)
3
supramolecules with cavities are very attractive due to
their applications in catalysis, stabilization of (air/water)-
sensitive molecules, drug delivery, and artificial
transmembrane channels. Among these 3D structures,
supramolecular prisms have been assembled mainly
through the following four strategies: (i) two-component
self-assembly with multitopic subunits at the lateral/base
faces hinged by ditopic motifs as the vertices or pillars; 8,9
In supramolecular chemistry, pyridinium salts have been
extensively utilized as building blocks to assemble cages
with good solubility in water and tunable host-guest
interactions on the basis of their multiple positive charges.
Consequently, a wide range of 3D structures, e.g., triangular
4
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7
1
4
15
16
17
prism,
molecular dice,
bowl sharp cage,
and
18
octahedron, have been constructed with pyridinium
moieties. In most of these cases, pyridinium groups were
introduced into the backbone via pendent linkers. Without
(
ii) multi-component self-assembly with lateral face motifs,
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sufficient rigidity and directionality, the so-formed the anchored TPY a freely rotating axle as well as the rigid
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pyridinium ligands, however, were unable to assemble
large 3D supramolecules with higher complexity through
backbone with a proper intrinsic angle for adapting a
vertical conformation to the hexagonal base surface during
the self-assembly. Accordingly, a new pentatopic TPY
ligand, L1, was designed as shown in Scheme 1, and
efficiently synthesized by utilizing the pyrylium-pyridinium
2
b
directional bonding approach. Pyrylium salt−aryl primary
amine condensation is an alternative synthetic approach to
introduce pyridinium group into supramolecular
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architectures with rigid backbone. Benefiting from the
efficient condensation reaction as well as the modularized
synthetic strategy, a series of giant 2D Kandinsky Circles
salts chemistry. During the synthesis, the key precursor
diketone 5 was prepared via a 3-fold Suzuki coupling
reaction based on the tribromo-pyrylium salt 3. Note that
the reaction time (6 hours) was one of the most crucial
parameters to achieve a good yield (65%), owing to the
instability of 5 under basic condition. Another ligand, L2,
with a longer alkyl chain was prepared via the similar
procedure.
(
KCs) with concentric hexagon rings was obtained in our
previous study, in which pyridinium groups were acting as
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bridges connecting different rims. In addition, these 2D
KCs showed potent antimicrobial activity against Gram-
positive pathogen methicillin-resistant Staphylococcus
aureus (MRSA) through forming transmembrane
With the ligands in hand, another crucial requirement of
forming desired prism is precisely narcissistic self-sorting
2
0a
channels.
a
Beyond 2D concentric hexagons, we herein designed and
assembled hexagonal prisms based on pyrylium salts and
pyridinium salts chemistry. We prepared two pentatopic
2,2′:6′,2″-terpyridine (TPY) ligands, in which the metal-TPY
coordinations are settled in three different environments
of the three distinct types of TPY groups to form <TPY -
a
b
b
c
c
Cd(II)-TPY >, <TPY -Cd(II)-TPY >, and <TPY -Cd(II)-TPY >
coordination sites during the self-assembly. Without fully
excluding the possibilities of undesired coordination,
polymeric complex instead of discrete structure could be
formed during the assembly. To address the above
concerns, self-assembly of the pentatopic ligands with
a~c
(Scheme 1, TPY ). After assembly, giant and discrete 3D
structures, i.e., supramolecular hexagonal prisms, were
constructed with two Kandinsky Circles as the bases and the
tail-anchored <TPY-Cd-TPY> linkages as the lateral edges,
respectively. The obtained hexagonal prisms have high
tendency to further hierarchically assemble into 1D
nanostructures by base-to-base stacking in solution. In
addition, these hexagonal prisms display antimicrobial
activity against Gram-positive bacteria, including MRSA and
Bacillus subtilus (B. subtilus).
2
0a
Cd(II) ion was carried owing to its higher reversibility.
The self-assembly was performed in DMSO (10 mg/mL of
o
L1 or L2) at 80 C for 12 hours with the stoichiometric ratio
of ligand/metal = 2/5 (Figure 1a).
Figure 1. (a) Self-assembly of hexagonal prisms HP1 and
HP2; (b) side view and (c) top view of the representative
energy-minimized structures from molecular modeling of
HP1/2; alkyl chains were omitted for clarity
Scheme 1. Synthesis of ligands L1 and L2. (i) BF
3
•Et
O, toluene, tert-
(35% aqueous solution),
, 12 hours; (iv) 4 Å molecular sieve, DMSO, 120
2
O,
o
1
00 C, 2 hours; (ii) Pd(PPh
3
)
4
, NaHCO
butanol, 80 C, 6 hours; (iii) HBF
MeOH, CHCl
3 2
, H
o
4
3
o
Characterization of Supramolecules. Electrospray
ionization-mass spectrometry (ESI-MS) was first utilized to
C, 24 hours.
Results and Discussion
characterize the obtained complexes (the anions were
−
exchanged to PF
6
), as shown in Figure 2. Figure 2a (HP1)
Synthesis of the ligands and self-assembly of the
complexes. In order to incorporate 2D KCs into 3D
hexagonal prisms, additional TPY group is necessary to
serve as the lateral edges, which act a distinct structural role
compared to the base edges. As such, 1,3-substituted phenyl
group was introduced to the ligand as a spacer, providing
shows one dominant set of peaks with continuous charge
states ranging from 16+ to 32+, due to successive loss of the
counterions, PF . A very similar spectrum of HP2 is
6
observed (Figure 2c) with slight shifts of the peaks towards
higher m/z region. After deconvolution, the average molar
−
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masses of HP1 and HP2 are 42,608 and 43,569 Da,
respectively, matching well with their expected chemical
compositions [(C164 72] (HP1) and
12Cd30(PF (HP2), ruling out the
NMR spectroscopy was further employed to identify the
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structural information of the complexes by comparing with
1
H
139
N
16
O
4
)
12Cd30(PF
6
)
their corresponding ligands. Figure 3 displays the H-NMR
[(C170
H
151
16
N O
4
)
6
)
72
]
spectra of HP1 and L1. L1 exhibits three different sets of
possibilities of forming other undesired complexes. These
two supramolecules are among the largest metallo-
TPY protons with integration ratio as 1/2/2 (Figure 3a),
a
corresponding to the TPY groups in the tail (TPY ), the outer
2
1
b
c
supramolecules ever reported.
mobility-mass spectrum (TWIM-MS)
b) displays a series of bands with narrowly distributed
Traveling wave ion
rim (TPY ), and the inner rim (TPY ) of the ligand,
respectively. After coordination, characteristic up-field
2
0a, 22
of HP1 (Figure
6
,6’’
2
shifts of all TPY-H signals are observed with Δδ = 0.8 – 1.0
ppm (Figure 3b), which is attributed to the electron
shielding effect of the <TPY-Cd(II)-TPY> coordination
environments. Also, much broader spectrum is displayed
after coordination, due to the lower tumbling motion of the
drifting time at each charge state, indicating no other
isomers or conformers exist. HP2 also displays similar
TWIM-MS spectrum shown in Figure 2d.
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21
protons in the large complex. Notably, four sets of distinct
3’,5’
TPY-H
signals clearly display in the spectrum of HP1
instead of three sets in the case of L1. The additional set of
a3’,5’
signals is caused by the splitting of TPY-H
after the
formation of the <TPY-Cd(II)-TPY> lateral edges. One
possible reason for the splitting is probably ascribed to the
steric hindrance of the lateral faces, which blocks the free
rotation of the TPY group and further slows down the
a3’,5’
tumbling motion of TPY-H . As a result, much broader
a3’,5’
1
b,c3’,5’
TPY-H
signals are observed, compared with TPY-H
signals. H-NMR spectrum of HP2 shows exactly the same
set of signals in the aromatic region (Figure S41).
1
Figure 3. H NMR spectra (600 MHz, 300 K) of (a) L1 in
,
3
CDCl , * represents the solvent residue of CHCl
3
and (b) HP1
in d -DMSO.
6
A 2D diffusion-ordered NMR spectroscopy (2D-DOSY)
analysis of HP1 in d -DMSO reveals a single band at logD ≈
10.5 (Figure S47); HP2 also displays one dominant signal
6
−
band with the same logD value (Figure S48). After
conducting calculation by using the modified Stocks-
Einstein equation based on the column model (detailed
calculating procedure is summarized in the Supporting
Figure 2. (a, c) ESI-MS and (b, d) TWIM-MS plots (m/z vs
drift time) of HP1 and HP2, respectively.
2
4
Information), the experimental diameter of the base is
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found to be 7.0 nm, and the height of prism is 2.5 nm. Such S50). Worm-like nanostructures with uniform diameters at
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sizes are comparable to the predicted results (8.0 nm in
base diameter, and 2.7 nm in height) from the molecular
modeling of these hexagonal prisms (Figure 1b-c). The
other NMR spectroscopic results are summarized in Figures.
S1-28, 35-46, including 2D COSY, 2D NOESY, C NMR
spectra (see SI).
ca. 8 nm were observed, and most of them further
interacted with each other to form bigger aggregation
without well-defined pattern.
In order to obtain more detailed information of the
nanostructures, scanning tunneling microscopy (STM) was
utilized to image the samples on highly oriented pyrolytic
graphite (HOPG) surface. Acetonitrile instead of ethyl
acetate was used as the aggregation solvent, due to its
better solubility of the supramolecules, in order to get well-
dispersed nanostructures on surface (detailed sample
preparation procedure was summarized in SI). Tubular-like
nanostructure was observed as shown in Figure 5a with a
uniform diameter around 8 nm, corresponding to the
diameter of the KC base surface. Breakages on the nanowire
were clearly observed owing to the spacing between
prisms. The periodic distribution of the bright areas and the
gaps observed on the nanowires suggest the base-to-base
packing of the prisms in the 1D nanostructure. The
measured thickness of each repeating sub-structure in the
nanostructure (marked distance in Figure 5b) was around
2.5 nm, which was well consistent with the predicted height
of each supramolecular prism (Figure 1b). And more STM
images of the nanostructures were included in Figures. S51.
1
3
In order to obtain more shape and size information,
atomic force microscopy (AFM) and transmission electron
microscopy (TEM) were applied to image individual
hexagonal prism. AFM images were first collected on fresh
mica surface by drop casting diluted DMF solution (3.5 ×
0
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6
1
0
mol/L) of HP1 for a short time (1 min) and then
washing and drying, to avoid aggregation. Particles with
ring like structures were clearly observed under AFM with
uniform diameters (Figure 4a-b, Figure S49) by utilizing
ultra-sharp cantilever tip (1~2 nm) to reduce the
broadening effect. Detailed analysis of the size and shape of
one selected particle (Figure 4c) reveals a hexagonal ring
with an outer rim diameter at ca. 9 nm and an inner rim
diameter as 4.7 nm, comparable to modeling size (Figure
1b-c). The average height of these particles is around 2.5 nm,
corresponding to the height of one prism molecule. In
addition, individual dots with uniform diameters were also
observed under TEM, as shown in Figure 4d. The zoomed-
in TEM image (Figure 4d inset) shows a ring-like structure,
which can also be assigned to the base of HP1 with a
comparable size (ca. 8 nm in diameter).
Figure 5. (a) STM images of tubular-like nanostructure on
a HOPG surface, (b) cross-section of the line marked on the
nanostructure shown in (a). (c) The hollow cylinder model
of the aggregated tubular-like nanostructure is
hierarchically self-assembled by hexagonal prism unimer.
−
4
(d) 1-D SAXS of HP1 in acetonitrile solution (2.5 × 10
mol/L). “□” represents the experimental data. The solid
black line represents the best fit result.
Figure 4. AFM images of (a) individual HP1 on mica surface
(
b) a selected single HP1 molecule and its 3D image (right
bottom inset), (c) cross-section of the molecule shown in
b); (d) TEM images of individual HP1, zoomed-in image in
One dimensional small angle X-ray scattering (1D-SAXS)
was further used to study the aggregation of HP1 in
(
−
4
acetonitrile solution (2.5 × 10 mol/L), and the results are
inset.
-1
summarized in Figure 5d. As expected, a q decay was
observed stemming from the low-q region beyond the
probing range (Figure 5d, region I), suggesting the existence
of long cylindrical objects with the average length over
Investigation of the hierarchical self-assembly
behavior. In our previous report, we found that KCs were
able to hierarchically self-assemble into tubular-like
nanostructures through the face-to-face packing.20a With
the similar KCs structure acting as the bases, we speculated
HP1 could similarly pack into nanostructures through base-
to-base packing, which might provide us additional
structural information of the prism. Gels were obtained by
slow diffusion of ethyl acetate (the poor solvent) into the
DMSO solution of HP1, then investigated by TEM (Figures
1
000 Å, consistent with the nanostructures observed in
STM images. Apparently, the HP1 aggregates in acetonitrile
with the base-to-base configuration prior to the incubation
process on HOPG surface for STM imaging. Apart from the
tubular-like structure, scattering signals corresponding to
individual HP1 unimer were also observed at higher q
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region (Figure 5d, region II) with three quasi-Bragg peaks
located between 0.15 and 0.5 Å corresponding to the high
order harmonics (q*, 2q* and 3q*), likely originating from
the well-defined repeating spacing, D of the hexagonal
prisms in the cylindrical aggregate. As a result, the best
fitting model contains the contributions from discoidal
shells, hollow cylinders and three Gaussian peaks (Figure
deconvolution, the averaged molar mass of the signals at
lower m/z region was 20,094 Da, which exactly fits the
chemical composition of [(L1) 30]. In addition, the
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-1
6 6
Cd12(PF )
isotope pattern of each charge state (12+ – 22+) agrees well
with the corresponding simulated one (Figure 6 inset and
Figure S52). Such a chemical composition is assigned to a
double-rimmed KC with 6 tailed anchored free TPY groups
(Scheme 2). It can be viewed as an intermediate prior to the
formation of our desired prism structure (HP1). The peaks
at higher m/z region are assigned to HP1 with 18+ to 23+
charge. The coexistence of KC intermediates with HP1 was
further confirmed by the TWIM-MS spectrum (Figure 6b)
with two sets of signals. The signal bands at the lower m/z
region with relative shorter drifting time are attributed to
the intermediates, while the well splitted signal bands at
higher m/z region correspond to the hexagonal prism
5
c). As shown in Figure 5d, the best fit agrees well with the
experimental data and the fitting parameters are listed in
Table S1. And the best fitting prism height, outer rim and
inner rim diameters are (2.5 ± 0.2), (6.8 ± 1.1) and (4.0 ±
0
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.2) nm, respectively, which are consistent with the
molecular modeling results (Figure 1b-c). Moreover, the
cylindrical aggregates share the same inner rim and outer
rim diameter with those of the unimer, except for an ultra-
2
휋
long length. The uniform D derived from q* as 퐷 = 푞
≈ 4.2
∗
structure with longer drift time. Between [(L1)
6
Cd12(PF
such as
6 30
) ]
nm is also consistent with the STM result (Figure 5b).
and
HP1,
Cd13(PF
other
intermediates
6 6 4
and [(L1) Cd14(PF )30(OH) ]
[(L1)
6
6
)
30(OH)
2
]
(
Scheme 2) were also detected by isotope analysis of mass
spectra (Figures S53-S54). Every two of these KCs
intermediates together with proper amount of Cd(II) finally
formed HP1 via forming the lateral edges as the scaffold of
the 3D structure. Such a step-wise assembly mechanism
leads to the precise self-sorting of the three types of TPY
groups into three distinct coordination environments
(
Scheme 2). As a result, the KC rings plays dual roles during
the formation of the supramolecular hexagonal prisms
through acting as the structural base surface, and the
template to guide the formation of the lateral edges.
Scheme 2. Proposed self-assembly mechanism of L1
coordinating with Cd(II) to form HP1.
Figure 6. (a) ESI-MS and (b) TWIM-MS (m/z vs drift time)
of the self-assembly of L1 with Cd(II) under a milder
condition. Both intermediates (A series of signals) and HP1
Table 1. The antimicrobial activity and selectivity of the
ligands and supramolecules
(
B series of signals) were observed, right inset of (a):
theoretical and experimental isotope patterns of A19+.
HP1
HP2
L1
L2
3 2
Cd(NO )
Mechanism study of the self-assembly. After
characterization of the desired supramolecular hexagonal
prisms, we further studied the self-assembly mechanism of
these prism structures. Briefly, the self-assembly of L1 with
Cd(II) (molar ratio: 2/5) was performed under a milder
MRSA (IC50
μg/mL)
,
1
1
3
3
> 25
3
B. subtilus (IC50
,
3
2
-
-
μg/mL)
o
Hemolysis (HC50,
condition (i.e.,2 mg/mL of L1 in DMSO, 50 C for 3 hours) in
>250
>250
>250
>250
>250
μg/mL)
order to determine the intermediate state of the assembling
procedure. ESI-MS spectrum (the anions were transferred
Selectivity
−
to PF
6
) shows two dominant sets of sharp peaks (Figure
HC /IC
50
>250
>250
>80
>80
>10
5
0
6
a), locating at lower m/z (700 – 1500 Da) and higher m/z
(MASA)
(
1500 2300 Da) regions, respectively. After
–
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deconvolution fluorescence microscopy,
Page 6 of 20
3
D
a
Selectivity
HC50/IC50
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combination of optical and computational techniques to
maximize the observed resolution and signal from a
>80
>120
-
-
>80
(B. subtilus)
2
8
biological specimen, was further employed to monitor the
location of HP1/2 during their inhibiting the growth of
MRSA and B. subtilus. Benefiting from the strong
fluorescence (FL) nature of these two supramolecules (the
FL spectra of HP1/2 are recorded in Figure S55-56), no
external dye is needed to visualize the cell membrane. As
shown in Figure 7, strong fluorescence was observed on the
surface of both S. aureus and B. Subtilus after being treated
with HP1/2. In addition, in both cases, no free fluorescent
material was observed outside of the cells. These results
indicate the high selectivity and binding affinity of the
antimicrobial materials for the bacteria, which confirm that
these supramolecular prisms strongly interact with these
Gram-positive bacteria and then inhibit the growth of MASA
and B. subtilus.
Antimicrobial activity. It is expected that these 3D
prisms might show antimicrobial activity against Gram-
positive bacteria for the following reasons: (i) the high
density of positive charges on these supramolecules
provides high affinity with the negative charged cell
envelop of the Gram-positive bacteria;25 (ii) pyridinium
containing agents are widely applied in antimicrobial
2
6
fields; (iii) the prisms may act as transmembrane channels
0
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to disrupt the bacterial membrane.20a As a result, the
antibacterial activities of HP1/2 were evaluated with two
Gram-positive bacteria, i.e., MRSA and B. subtilus, (Table 1).
Both HP1/2 showed antimicrobial activity on MRSA with
IC50s as 1 μg/mL (ca. 22 nmol/L), which was lower than the
IC50s of the corresponding ligands (3 μg/mL, 1200 nmol/L)
and the control group, Cd(NO
3
)
2
•4H
2
O, (IC50 > 25 μg/mL, 8.1
5
×
10 nmol/L). Compared with the previous reported 2D
Conclusions
2
0a
KCs,
HP1/2 displayed lower antibacterial activity,
probably due to their low solubilities and high aggregation
tendency proved by TEM/STM/SAXS studies. These
features caused the precipitation or aggregation of HP1/2
in contact with the growth medium before their effective
interaction with MRSA cells. As a result, supramolecular
prisms with better water-solubility are expected to possess
enhanced antimicrobial activity.
In this study, we were able to construct giant metallo-
supramolecular hexagonal prisms with pentatopic
terpyridine ligands, which displayed three different
coordination environments during the self-assembly. Such
a design fully takes advantage of the rigid scaffold of the
pyridinium-aryl group and its facile synthesis. In addition,
the detailed study of the self-assembly process reveals that
the double-rimmed KCs are the key intermediate species to
form a hexagonal prism architecture. The assembled
supramolecular hexagonal prisms had a strong tendency to
form tubular-like nanostructure in solution as evidenced by
STM imaging and SAXS study. Furthermore, the pyridinium
salt contained supramolecular prisms showed potent
antimicrobial activities against two Gram-positive bacteria,
possibly due to their high binding affinity on the membrane
of these bacteria. Overall, through deep understanding of
the design and self-assembly process, this study may shed
more lights for designing more sophisticated 3D
supramolecular architectures with desired functions.
In addition, to expand the antimicrobial spectrum of this
type of supramolecule, B. subtilus was used to evaluate the
new agents. HP1/2 showed obvious antimicrobial activity
against B. subtilus, while L1/2 did not exhibit any toxicity
(
Table 1). Note that the weight-based IC50 value of Cd(II)
control was comparable to the values of HP1/2. However,
considering the much lower weight percentage of Cd(II) in
HP1 (8.0%) and HP2 (7.8%) than in Cd(NO ) •4H O (37%),
3 2 2
as well as the strong chelation of Cd(II) with the pentatopic
TPY ligands in HP1/2, the antibacterial potency of the
supramolecules should be mainly derived from the
ensembles rather than individual component.
The red-blood-cell hemolysis studies of HP1/2 show
negligible hemolytic toxicity (HC50 higher than 250 μg/mL),
leading to their good antimicrobial selectivity toward MRSA
and B. subtilus. We speculated that such a good selectivity
should be based on the stronger electrostatic interaction of
cationic HP1/2 with the negative charged surfaces of the
ASSOCIATED CONTENT
Supporting Information. Synthetic details, molecular
modeling, ligand and complex characterization, including
1
13
H NMR, C NMR, 2D COSY, 2D NOESY, 2D DOSY, ESI-MS,
UV-Vis, emission spectra and additional STM images are
included in supporting information. This material is
available free of charge via the Internet at
http://pubs.acs.org.
2
5
Gram-positive bacteria,
than with the zwitterionic
2
7
surfaces of the mammalian cells.
AUTHOR INFORMATION
Corresponding Author
*
*
*
mu-ping.nieh@uconn.edu
jianfengcai@usf.edu
xiaopengli1@usf.edu
Author Contributions
┴These authors contributed equally.
Figure 7. 3D deconvolution fluorescence microscopy
images of bacteria cells with and without treatment of
HP1/HP2 (4 μmol/L, DMSO as the control agent). Scale bar:
1 μm.
Notes
The authors declare no competing financial interest
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ACKNOWLEDGMENT
Journal of the American Chemical Society
Watson−Crick G·C Base Pair in Water: Aqueous Hydrogen Bonds in
Hydrophobic Cavities. J. Am. Chem. Soc. 2010, 132 (20), 7194-7201.
(a) Samanta, S. K.; Moncelet, D.; Briken, V.; Isaacs, L.,
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We acknowledge the support from NIH (R01GM128037 to
X.L.; 5R01AL110098-05 to B.X), and partial support through
University of South Florida Nexus Initiative (UNI) Award.
The SAXS data were collected with the help of Dr. Lin Yang,
at the 16ID-LiX Beamline, National Synchrotron Light
Source II, Brookhaven National Laboratory (BNL), NY, USA
through a beamtime proposal (BAG-302208). The LiX
beamline is part of the Life Science Biomedical Technology
Research resource, jointly supported by the National
Institutes of Health, National Institute of General Medical
Sciences, under Grant P41 GM111244, and by the
Department of Energy Office of Biological and
Environmental Research under Grant KP1605010, with
additional support from NIH Grant S10 OD012331. NSLS-II
is a U.S. Department of Energy (DOE) Office of Science User
Facility, operated for the DOE Office of Science by
Brookhaven National Laboratory under Contract No. DE-
SC0012704.
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Jiang, X.; Brzozowski, R.; Wang, M.; Gao, X.; Li, Y.; Xu, B.; Eswara, P.;
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o
Scheme 1. Synthesis of ligands L1 and L2. (i) BF •Et O, 100 C, 2 hours; (ii) Pd(PPh ) , NaHCO , H O,
3
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3 4
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toluene, tert-butanol, 80 oC, 6 hours; (iii) HBF4 (35% aqueous solution), MeOH, CHCl , 12 hours; (iv) 4 Å
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molecular sieve, DMSO, 120 oC, 24 hours.
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Figure 1. (a) Self-assembly of hexagonal prisms HP1 and HP2; (b) side view and (c) top view of the
representative energy-minimized structures from molecular modeling of HP1/2; alkyl chains were omitted
for clarity
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Figure 2. (a, c) ESI-MS and (b, d) TWIM-MS plots (m/z vs drift time) of HP1 and HP2, respectively.
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Figure 3. 1H NMR spectra (600 MHz, 300 K) of (a) L1 in CDCl , * represents the solvent residue of CHCl ,
3
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and (b) HP1 in d -DMSO.
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Figure 4. AFM images of (a) individual HP1 on mica surface (b) a selected single HP1 molecule and its 3D
image (right bottom inset), (c) cross-section of the molecule shown in (b); (d) TEM images of individual
HP1, zoomed-in image in inset.
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Figure 5. (a) STM images of tubular-like nanostructure on a HOPG surface, (b) cross-section of the line
marked on the nanostructure shown in (a). (c) The hollow cylinder model of the aggregated tubular-like
nanostructure is hierarchically self-assembled by hexagonal prism unimer. (d) 1-D SAXS of HP1 in
acetonitrile solution (2.5 × 10−4 mol/L). “□” represents the experimental data. The solid black line
represents the best fit result.
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Figure 6. (a) ESI-MS and (b) TWIM-MS (m/z vs drift time) of the self-assembly of L1 with Cd(II) under a
milder condition. Both intermediates (A series of signals) and HP1 (B series of signals) were observed, right
inset of (a): theoretical and experimental isotope patterns of A19+.
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Scheme 2. Proposed self-assembly mechanism of L1 coordinating with Cd(II) to form HP1.
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Figure 7. 3D deconvolution fluorescence microscopy images of bacteria cells with and without treatment of
HP1/HP2 (4 μmol/L, DMSO as the control agent). Scale bar: 1 μm.
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