Acyclic cucurbit[n]uril-type molecular containers: Influence of aromatic walls on their function as solubilizing excipients for insoluble drugs

Article abstract of DOI:10.1021/jm501276u

We studied the influence of the aromatic sidewalls on the ability of acyclic CB[n]-type molecular containers (1a-1e) to act as solubilizing agents for 19 insoluble drugs including the developmental anticancer agent PBS-1086. All five containers exhibit go

Full text of DOI:10.1021/jm501276u

Article
pubs.acs.org/jmc
Acyclic Cucurbit[n]uril-type Molecular Containers: Influence of
Aromatic Walls on their Function as Solubilizing Excipients for
Insoluble Drugs
Ben Zhang and Lyle Isaacs*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
*
S Supporting Information
ABSTRACT: We studied the influence of the aromatic sidewalls on the
ability of acyclic CB[n]-type molecular containers (1a−1e) to act as
solubilizing agents for 19 insoluble drugs including the developmental
anticancer agent PBS-1086. All five containers exhibit good water
−
1
solubility and weak self-association (K ≤ 624 M ). We constructed
s
phase solubility diagrams to extract K and K values for the container·
drug complexes. The acyclic CB[n]-type containers generally display
rel
a
significantly higher K values than HP-β-CD toward drugs. Containers
a
1
a−1e bind the steroidal ring system and aromatic moieties of insoluble
drugs. Compound 1b displays highest affinity toward most of the drugs
studied. Containers 1a and 1b are broadly applicable and can be used to formulate a wider variety of insoluble drugs than was
previously possible with cyclodextrin technology. For drugs that are solubilized by both HP-β-CD and 1a−1e, lower
concentrations of 1a−1e are required to achieve identical [drug].
INTRODUCTION
■
Molecular container compounds have been extensively studied
over the years by synthetic, supramolecular, materials, and
medicinal chemists by virtue of their ability to alter the
properties of compounds bound within their interior. Some of
the best-investigated classes of molecular container compounds
include crown ethers, cryptands, carcerands, calixarenes,
cyclophanes, cyclodextrins, and complexes self-assembled by
metal·ligand and H-bonding interactions as well as reversible
1
covalent bonds. For example, encapsulation inside molecular
containers can reduce the reactivity of highly reactive species
like P , reduce the odor of malodorous compounds, promote
4
the reactions of included substrates, provide the basis of stimuli
responsive molecular machines, enhance the photophysical
properties of encapsulated dyes, and even reverse the toxic
1
f,2
effects of certain compounds.
We, and others, have been
studying an alternative class of molecular containers known as
3
cucurbit[n]urils (CB[n], n = 5, 6, 7, 8, 10, Figure 1). CB[n]
compounds are particularly attractive because of the remarkably
high affinity, selectivity, and stimuli responsiveness that they
4
display toward their guests in aqueous solution. For these
Figure 1. Structures of molecular containers used previously as
solubilizing agents for insoluble drugs: HP-β-CD, SBE-β-CD, CB[n],
and acyclic CB[n]-type container 1a.
reasons, CB[n] compounds have been used as key components
in the construction of functional supramolecular systems
including affinity separation phases, supramolecular velcro,
surface enhanced Raman scattering sensing, and for biomem-
5
generation of nanocrystalline solid forms of the drug, salt
brane assays.
7
formation, solid dispersions, and higher solubility prodrugs. Of
An urgent problem facing the pharmaceutical industry is that
a high percentage of new chemical entities with documented
target affinity are so poorly soluble that formulation is
highest relevance to supramolecular chemists, however, is the
6
challenging. A number of techniques and tools have been
Received: August 20, 2014
Published: November 4, 2014
developed to address the drug solubility issue including the
©
2014 American Chemical Society
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Journal of Medicinal Chemistry
Article
Scheme 1. Structures of Known Acyclic CB[n] Solubilizing Excipients 1b and 1c and Synthesis of 1d and 1e
Figure 2. Chemical structures of drugs used in this study.
use of the cyclodextrin derivatives hydroxypropyl-β-cyclo-
dextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-
β-CD, Figure 1) to improve the solubility of insoluble drugs by
cationic species, (2) terminal aromatic walls to promote π−π
interactions between container and insoluble drug, and (3)
11
solubilizing sulfonate arms that result in high solubility.
8
encapsulation inside the molecular containers. A number of
Compound 1a is not toxic in in vitro and in vivo assays, and
drugs are formulated for administration to humans by
encapsulation inside HP-β-CD and SBE-β-CD. Accordingly,
researchers in the CB[n] area are exploring their use in this
class of applications. For example, CB[n] have been used to
increase the solubility of a number of insoluble drugs (e.g.,
albendazole, chlorambucil, camptothecin), to retard degrada-
paclitaxel (8) formulated as 1a·paclitaxel maintains its ability to
11c
efficiently kill HeLa cells.
We also showed that acyclic
CB[n]-type container 1b and relatives are capable of in vivo
reversal (in rats) of the biological effects of rocuronium which
is a neuromuscular blocking agent commonly used by
11d
9
anesthesiologists during surgery. Previously, we studied the
tion reactions, and for targeted drug delivery.
−
influence of the nature of the solubilizing groups (e.g., SO vs
3
The Isaacs group has been interested in understanding the
mechanism of CB[n] formation and using that information to
prepare CB[n]-type receptors with new structural features and
+
3
OH vs NH ) on the ability of acyclic CB[n] type containers to
act as solubilizing agents for insoluble drugs and found that
sulfonate groups are particularly well-suited for this application
because they impart high solubility in water and do not
10
recognition properties. In 2012, we reported the synthesis of
acyclic CB[n]-type receptor 1a and its use as a solubilizing
excipient for insoluble drugs. Compound 1a and relatives have
three main structural features: (1) a central glycoluril oligomer
to impart curvature and the ability to bind to hydrophobic and
+
12
promote self-folding and complexation (e.g., as NH
does).
3
In this Article we explore the influence of the nature of the
aromatic sidewalls on the ability of the acyclic CB[n]-type
9
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containers (1a−1e, Scheme 1) to act as solubilizing agents for
Self-Association Properties of Acyclic CB[n]-type
Containers 1a−1e. Previously, we have investigated the
self-association of 1a and 1b by dilution experiments monitored
by H NMR spectroscopy. We found that the observed changes
in chemical shift for each container fit well to a 2-fold self-
insoluble drugs.
1
RESULTS AND DISCUSSION
■
This Results and Discussion section is organized as follows.
First, we describe the synthesis and solubility of two new acyclic
CB[n]-type receptors 1d and 1e. Next, we investigate the self-
association properties of 1a−1e. Subsequently, we create phase
solubility diagrams (PSDs) for 1a−1e toward a range of well-
known poorly soluble pharmaceutical agents (Figure 2) and
analyze trends in the solubilization data.
association model and extracted the corresponding self-
−1
association constants (1a, K = 47 M ; 1b, K = 624
M ).
s
s
−1 11c,15
Because 1a and 1b have a low propensity to self-
associate, they are well-suited to act as solubilizing excipients
1
for insoluble drugs. In a similar manner, we performed the H
NMR dilution experiment (15−0.1 mM) for 1d and measured
−1
the corresponding value of K for 1d as 130 M . When we
s
Design and Synthesis of Acyclic CB[n]-type Contain-
ers 1a−1e. Previously, we reported the synthesis and
application of acyclic CB[n] type containers 1a−1c by the
double electrophilic aromatic substitution reaction of glycoluril
tetramer bis(cyclic ether) building block 2 with the
corresponding dialkoxyaromatic sidewalls 3 in hot
1
performed similar H NMR dilution experiments for 1c, we
unexpectedly observed two sets of resonances that were in slow
exchange on the chemical shift time scale. We measured the
diffusion coefficients for these two species by diffusion ordered
−10
2
NMR spectroscopy (D = 2.058 and 1.751 × 10
m /s,
Supporting Information) which allows us to conclude that the
two species correspond to monomer 1c and dimer (1c)2.
Accordingly, we integrated the resonances for the two species at
11c,e,12
CF CO H.
Compounds 1a−1e differ in the nature of
3
2
their aromatic sidewalls (e.g., benzene, naphthalene, tetrahy-
dronaphthalene). These structural differences impact the
conformation of the uncomplexed container (e.g., smaller,
larger, taller cavity) and the type and balance of noncovalent
interactions (e.g., π−π versus dispersion interactions) that form
in the container·drug complexes. For example, the X-ray crystal
structures of 1a show that the tips of the substituted benzene
several different concentrations and determined the value of K
s
−1
16
(
372 M ) in the usual manner. Finally, we performed a
dilution experiment for 1e (35−0.2 mM) and observed both
1
broadening and changes in H NMR chemical shifts.
Unfortunately, the changes in chemical shift could not be
fitted to the standard 2-fold self-association model, and we
believe that 1e undergoes more complex higher order
aggregation. The generally weak self-association observed for
11c
sidewalls are in close contact with one another. Therefore, to
accommodate the longer naphthalene sidewalls of 1b, the
glycoluril tetramer backbone of 1b flexes which results in a
larger cavity that is defined in larger part by the aromatic
1
a−1e is advantageous toward their use as solubilizing
excipients for insoluble drugs because the container is free to
associate with drug without having to overcome strong self-
assocation.
11c
naphthalene sidewalls. Compound 1c is an isomer of 1b; in
this case the sidewalls are shorter and deeper by virtue of the
11e
attachment at the naphthalene 1,8 positions. To prepare new
acyclic CB[n] type receptors 1d and 1e which possess alkyl
substituted sidewalls we needed to prepare compounds 3d and
Theoretical Treatment of Phase Solubility Diagrams.
PSDs are plots of [Drug] as a function of [Container] that are
commonly used to study the ability of molecular containers to
1
5,17
3e. Accordingly, we reacted 2,3-dimethylhydroquinone with
increase the solubility of insoluble drugs.
These PSDs can
1
,3-propane sultone (4) under basic conditions (NaOH) in
assume a variety of shapes, but linear PSDs (A -type) are most
L
dioxane at room temperature to give 3d in 73% yield (Scheme
a). Sidewall 3e was prepared by a multistep procedure
Scheme 1b). First, we performed the Diels−Alder reaction
between benzoquinone and 1,3-butadiene in toluene to give 5
common and occur when container and guest form soluble
1
(
well-defined 1:1 container·guest complexes. Such PSDs behave
according to eq 1 where S is the solubility of drug alone and Ka
0
is the binding constant for the container·drug complex. The
1
3
in 92% yield. Next, we aromatized 5 by treatment with HBr
slope of an A -type PSD simply reflects the ratio of the increase
L
13
to give 6 in 82% yield. Subsequently, we reduced the double
in concentration of drug obtained relative to the concentration
of container used. Container·drug systems that display larger
PSD slopes (e.g., slope ≥0.5) are advantageous because larger
concentrations of drug can be obtained with smaller
concentrations of container. Figure 3 shows the results of
two simulations that were performed on a hypothetical
container·drug system that obeys eq 1 to stimulate the
discussion and analysis of the experimental PSDs created for
containers 1a−1e and HP-β-CD with drugs 8−26 shown in
Figure 2. Figure 3a shows the calculated PSDs for five different
14
bond of 6 under standard conditions to give 7 in 85% yield.
Finally, 7 was reacted with 4 under basic conditions to give the
required aromatic wall 3e in 60% yield. The reaction of
glycoluril tetramer 2 with sidewall 3d (4 equiv) in a 1:1 (v:v)
mixture of TFA:Ac O at 70 °C gave acyclic CB[n] type
2
container 1d in 43% yield. Similarly, the reaction of 2 with 3e
(
4 equiv) gave container 1e in 30% yield.
Solubility Properties of the Acyclic CB[n]-type
Containers 1a−1e. An important property of a container
that is to be used as a solubilizing excipient for insoluble drugs
is the inherent solubility of the container alone. Previously, we
have reported the solubility of 1a and 1b in 20 mM sodium
−6
containers and a single drug with S = 1 × 10 M which form
0
well-defined 1:1 container·drug complexes of high solubility.
The different Ka values for the different container·drug
complexes translate into PSDs with different slopes. For
example, a change in slope from 0.1 to 0.5 and from 0.5 to 0.9
phosphate buffered D O at pD 7.4 as 105 and 14 mM,
2
respectively. We used the methodology reported previous-
1
1c,12
1
ly,
H NMR assay in the presence of 1,3,5-benzene
each corresponds to a 9-fold increase of K . Importantly, a
a
tricarboxylic acid as internal standard of known concentration,
to determine the inherent solubilities of 1c (115 mM), 1d (353
mM), and 1e (145 mM). The high solubilities of 1a, 1c, 1d,
and 1e make them particularly attractive as solubilizing
excipients for insoluble drugs.
precise knowledge of S is not necessary in order to calculate
0
relative K values (K = Ka,C1·D1/Ka,C2·D1) from the PSDs
a
rel
obtained with two different containers (e.g., C1 and C2)
toward a common drug (e.g., D1) because the S values cancel
0
as shown in eq 2. If S is known precisely, then absolute Ka
0
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known concentration of 1,3,5-benzene tricarboxylic acid as a
nonbinding internal standard of known concentration which
allows us to use the ratio of the integrals for drug versus
internal standard to measure drug concentration. We have
measured full PSDs for all 19 drugs with the six containers
(
Supporting Information). In nearly all cases, linear PSDs were
observed at low [container] indicative of well-defined 1:1
complex formation, although some of the PSDs display plateau
regions at higher [container] which indicates that the solubility
of the container·drug complex is lower than that of the
uncomplexed container. Table 1 gives the initial slopes of the
PSDs determined by linear regression for all container−drug
combinations. Table 1 also presents the K values calculated
rel
using eq 2 referenced to the weakest binding host (usually HP-
β-CD with Krel = 1). The uncertainties in Krel are generally
≈
10−20%, although larger uncertainties are noted for PSDs
with slope greater than 0.8. Figure 4 presents the PSDs
measured for three drugs [estradiol (18), developmental
anticancer agent 17, camptothecin (14)] with the 6 different
containers. In the sections below, we analyze the data presented
in Table 1 to ascertain key features of the use of acyclic CB[n]-
type containers as solubilizing excipients for insoluble drugs.
Container 1b Is the Most Potent Solubilizing Agent. Of the
Figure 3. Simulations of the phase solubility behavior of hypothetical
container·drug 1:1 systems that obey eq 1. (a) Plot of [Drug] versus
[
(
Container] for a system with S = 1 μM and five different K values.
0
a
−1
B) Plot of slope of the PSD versus K (M ) for five different values
a
of S (1 mM, 100 μM, 10 μM, 1 μM, 100 nM).
0
1
9 drugs tested, compound 1b is the most efficient solubilizing
agent (e.g., largest slope, highest K ) for 12 drugs, and is nearly
the best for one additional drug [slopes for ziprasidone (26):
values can be calculated using eq 1. Figure 3b shows a plot of
rel
the slope of the PSD as a function of the K for the container·
a
1b = 0.432 versus 1e = 0.458]. For five drugs [melphalan (10),
drug complex for five different values of S (1 mM, 100 μM, 10
0
amiodarone (13), camptothecin (14), 17α-ethynylestradiol
μM, 1 μM, 0.1 μM). Clearly, the lower the inherent solubility of
the drug (S ), the higher the value of K needed to result in a
(
19), voriconazole (24)], 1b forms such tight complexes
slope ≈1) that it is not possible to calculate a K value using
0
a
(
PSD of comparable slope. As a special case of eq 1, consider the
rel
eq 1. Acyclic CB[n]-type containers including 1a and 1b are
situation when (K )(S ) = 1; under this constraint, then slope =
a
0
11f,19
known to be relatively flexible
and often exhibit an out-of-
0
.5 (Figure 3b). From a practical point of view this means that
to efficiently solubilize an insoluble drug (e.g., slope of PSD =
.5) with an inherent solubility of 10 μM (100 nM) requires a
plane distortion (e.g., helical twist) as they wrap around their
guests. Accordingly, each container·drug complex will exhibit a
different geometry based on the size, shape, and functionality of
the drug. However, we offer some rationale for the observed
superior performance of 1b. Figure 5 shows the previously
0
5
−1
7
−1
K value of 10 M (10 M ). In theory, the high values of K
a
a
that are typically observed for CB[n]-type receptors promise to
enable the solubilization of drugs whose solubilities are too low
to be solubilized by lower affinity hosts (e.g., cyclodextrins).
reported X-ray structures of 1a and 1b as their CF CO H
3 2
11c
solvates. First, the size of the cavity of 1b is larger than that
of 1a as measured by the distance between the opposing
quaternary C atoms (1a, 10.93 and 11.44 Å; 1b, 11.99 and
slope
K =
a
S0(1 − slope)
(1)
1
1
2.90 Å) of the dimethylglycoluril units. The increased size of
b is caused by its longer naphthalene sidewalls (relative to 1a)
slope
C1·D1
K
S0,D1(1 − slopeC1·D1)
a,C1·D1
a,C2·D1
Krel = K
=
which would clash sterically in a more compact geometry.
Second, the naphthalene walls of 1b engage in edge-to-face
π−π interactions with one another that creates a large
hydrophobic π-surface that should allow it to simultaneously
engage in edge-to-face and offset face-to-face π−π interactions
with insoluble aromatic drugs. Containers 1d and 1e which
feature Me and cyclohexyl substituted o-xylylene sidewalls
should possess larger cavities than 1a; however, the alkyl
substitution reduces the available π-surface area which should
decrease their affinity toward insoluble aromatic compounds.
For container 1c, the isomeric naphthalene sidewalls are of
comparable length to 1a and result in a narrow and deep cavity.
Accordingly, we surmise that the length of the naphthalene
walls of 1b and their ability to define a hydrophobic box of large
π-surface area makes 1b a superior solubilizing agent relative to
containers 1a and 1c−1e.
slope
C2·D1
S0,D1(1 − slopeC2·D1
)
(
slopeC1·D1)(1 − slopeC2·D1)
slopeC2·D1)(1 − slopeC1·D1
=
(
)
(2)
Use of 1a−1e as Solubilizing Agents for Insoluble
Drugs. In order to more fully understand the correlation
between container structure (e.g., 1a−1e), drug structure and
properties, and the ability of the containers to solubilize
insoluble drugs, we created PSDs for containers 1a−1e and
HP-β-CD with the 19 insoluble drugs (8−26) shown in Figure
. Of these, 18 are drugs currently used in practice along with
PBS-1086 (17) which is a developmental compound with
documented anticancer activity. To create these PSDs we stir
an excess of insoluble drug with a known concentration of
container until equilibrium is achieved, then remove remaining
insoluble drug by filtration or centrifugation, and measure the
2
18
Solubilization of Steroids. The test panel of insoluble drugs
contained three steroids [estradiol (18), 17-α-ethynylestradiol
(19), and fulvestrant (25)]. Steroids can often be solubilized
with HP-β-CD, which allows a head-to-head comparison with
1
concentration of drug in the supernatant by H NMR
spectroscopy. Our H NMR assay relies on the addition of a
1
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Table 1. Inherent Solubility (S , μM) of Selected Drugs and Values of Slope Calculated from the Linear Region of the PSDs for
0
a
Containers 1a−1e and HP-β-CD with Drugs 8−26
1
a
1b
1c
Krel
Ka
Krel
Ka
Krel
Ka
S0 (μM)
slope
slope
slope
8
9
n.d.
n.l.

0

0

1.8 ± 0.23
1.0(±0.18) × 10
34 ± 19
2.7 ± 0.34
0.12 ± 0.0041
9.4 ± 0.45
.1(±0.67) × 104
TL
0.48 ± 0.076
62 ± 13
0.026 ± 0.0032
4
5
3
3.4(±0.85) × 105
10
n.d.
1.2 ± 0.0080
0.040 ± 0.0031
1.1 ± 0.072
0.10 ± 0.0071
TL
0.81 ± 0.10
0.46 ± 0.010
1
1
1
1
1
1
1
1
1
1
12 ± 1.9
1.5 ± 0.15
.5(±0.62) × 103
3.9 ± 0.39
9.4(±1.6) × 103
30 ± 2.2
4
7.2(±1.2) × 10

2
2
3
4
5
6
7
8
9
14 ± 1.7
66 ± 2.7
54 ± 3.9
5.7 ± 1.1
1.9 ± 0.41
4.5 ± 0.90
8.8 ± 0.42
24 ± 2.4
0.59 ± 0.0095
0.080 ± 0.0074
0.14 ± 0.0070
0.024 ± 0.0017
0.043 ± 0.0037
0.71 ± 0.027
0.35 ± 0.019
0.35 ± 0.016
6.3(±0.30) × 10
0

0
1
1
2
4
2
.0(±0.14) × 105
0.89 ± 0.11


1.03 ± 0.15
1.1 ± 0.059
0.47 ± 0.037
0.54 ± 0.017
0.89 ± 0.0043
0.92 ± 0.053
1.1 ± 0.0045
TL
0.14 ± 0.0074
0.26 ± 0.019
0.022 ± 0.0022
0.052 ± 0.0023
0.14 ± 0.013
0.38 ± 0.015
0.41 ± 0.071
1.6 ± 0.18
2.4(±0.16) × 10
2.2 ± 0.20
6.3(±0.67) × 10
1.69 ± 0.17
4.0(±0.87) × 10
7.0 ± 1.4
.3(±0.13) × 103
1.0 ± 0.073
TL
TL
3
3
3
4
4
4
4
.9(±0.26) × 103
1.8 ± 0.14
TL
67 ± 7.3
1.6(±0.35) × 105
1.5(±0.30) × 10
6.3(±1.4) × 105
50 ± 5.0
1.9(±0.38) × 106
51 ± 33
1.3(±0.86) × 106
.4(±0.90) × 103
5.8 ± 1.2
2
.4(±0.55) × 104
15 ± 2.0
2.9(±0.63) × 10
1.0
5
.5(±1.2) × 105
2.4 ± 0.15
.2(±0.48) × 104
1.0
3.7(±0.82) × 10
2.7 ± 0.14
7.0(±0.46) × 10
1.25 ± 0.27
2.8(±0.65) × 10
8.6 ± 1.8
6
2
TL
.2(±0.24) × 104

TL
2
0
1
n.d.
0
0

0.12 ± 0.0098
0.034 ± 0.0020
2
23 ± 3.1
0.066 ± 0.0034
2.0 ± 0.16
.1(±0.45) × 103

0.31 ± 0.027
13 ± 1.4
1.0
3
3
2
2.0(±0.32) × 104
1.5(±0.23) × 10

22
23
24
n.d.
n.d.
0
n.l.
0

0
0.079 ± 0.0092
0.50 ± 0.047
1.0

0

38 ± 1.6
3.4 ± 0.54
.6(±0.36) × 104

1.0 ± 0.026
TL
0.40 ± 0.037
2.3 ± 0.32
1.7(±0.20) × 10

4
TL
2
5
6
n.d.
0
0.10 ± 0.0055
0.43 ± 0.052
1.0
0
2
63 ± 3.5
1.1 ± 0.19
TL
29 ± 5.0
.2(±0.2) × 104
0.18 ± 0.018
8.2 ± 1.1
3
1
3.4(±0.40) × 10
1
d
1e
HP-β-CD
Krel
Ka
Krel
Ka
Krel
Ka
S0 (μM)
slope
slope
slope
8
n.d.
0

0
0


0

9
2.7 ± 0.34
0.10 ± 0.0057
8.0 ± 0.51
0.015 ± 0.0005
1.0
3
4
.3(±0.60) × 104
32 ± 12

5.4(±0.71) × 10
10
n.d.
0.80 ± 0.071
0.060 ± 0.0046
0.47 ± 0.053
6.9 ± 1.3

0.11 ± 0.012
0.028 ± 0.0019
1.0
1
1
1
1
1
1
1
1
1
1
12 ± 1.9
2.2 ± 0.23
.4(±0.94) × 103

0
1.0
3
2
3
5

2.4(±0.41) × 10
2
3
4
5
6
7
8
9
14 ± 1.7
66 ± 2.7
54 ± 3.9
5.7 ± 1.1
1.9 ± 0.41
4.5 ± 0.90
8.8 ± 0.42
24 ± 2.4
0
0.057 ± 0.0011
0.13 ± 0.0050
0.13 ± 0.0070
0
27 ± 1.1
0.0020 ± 0.000086
0.089 ± 0.0083
0
1.0

4.4(±0.56) × 103
1.6 ± 0.16
1.6(±0.22) × 10
0.13 ± 0.0039
0.50 ± 0.010
0.017 ± 0.0018
0.033 ± 0.0045
0.52 ± 0.023
0.61 ± 0.056
0.38 ± 0.026
1.5 ± 0.14
.2(±0.11) × 103
6.4 ± 0.38
1.0
2
1
3
1
2
1
2
2.3(±0.13) × 103
1.0
1.5(±0.15) × 10

4
3
.9(±0.14) × 10
2.9(±0.26) × 10

1.3 ± 0.14
.0(±0.67) × 103
4.4 ± 1.0

0.013 ± 0.00040
0.0080 ± 0.0015
0
1.0
2.4(±0.46) × 10
1.0
3

0

.9(±0.14) × 104
6.4 ± 0.73

4.1(±1.2) × 10

3
0.16 ± 0.017
0.52 ± 0.064
0.44 ± 0.014
1.1 ± 0.16
4.2(±0.96) × 104
4.7 ± 0.86
1.2(±0.23) × 105
1.4 ± 0.094
3.2(±0.34) × 104
.4(±0.51) × 105
6.8 ± 1.2

0.18 ± 0.0025
0.47 ± 0.048
1.0
.8(±0.31) × 105
1.1 ± 0.11
2.6(±0.13) × 10
1.62 ± 0.24
3.6(±0.61) × 10
4
.5(±0.32) × 104
4
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Article
Table 1. continued
1
d
1e
HP-β-CD
Krel
Ka
Krel
Ka
Krel
Ka
S0 (μM)
slope
slope
slope
2
2
2
2
2
0
1
2
3
4
n.d.
23 ± 3.1
n.d.
0.016 ± 0.0030
1.0
0.021 ± 0.0017
1.3 ±
0




1.0
0

0

0
0


0


0
n.d.
0
0
0
38 ± 1.6
0.83 ± 0.063
17 ± 6.7
.3(±0.51) × 105

0.87 ± 0.054
22 ± 9.3
1.7(±0.70) × 105

0.22 ± 0.018
3
1
7.6(±0.71) × 10
25
6
n.d.
0
0
0

2
63 ± 3.5
0.39 ± 0.013
24 ± 2.3
0.46 ± 0.021
32 ± 3.3
1.4(±0.11) × 104
0.026 ± 0.0022
1.0
2
1
.0(±0.069) × 104
4.2(±0.43) × 10
a
−1
The corresponding K (M ) and K values were calculated using eqs 1 and 2. n.d. = not determined, n.l. = nonlinear PSD; − = could not be
a
rel
determined because PSD is nonlinear or slope = 0; TL = too large to be determined from PSD.
Figure 5. Cross-eyed stereoscopic representations of the X-ray crystal
structures of (a) 1a and (b) 1b. Solvating CF CO H molecules have
3
2
been omitted for clarity. Color code: C, gray; H, white; N, blue; O,
red; S, yellow.
container 1b was capable of solubilizing fulvestrant (25) which
is both highly hydrophobic and fluorinated. Previously, we have
established that 1b binds to the neuromuscular blocking agents
rocuronium and vecuronium which are steroidal diammoniums
Figure 4. PSDs constructed for mixtures of containers (1a, ■; 1b, ●;
c, ▲; 1d, ▼; 1e, ◆; HP-β-CD, ◀) with selected insoluble drugs: (a)
estradiol (18), (b) 17, (c) camptothecin (14). Conditions: 20 mM
1
9
−1 11d
sodium phosphate buffered D O (pH = 7.4, rt). The red data points
2
with K > 10 M . In combination, these results allow us to
a
were not used in the linear regression.
conclude that acyclic CB[n]-type containers (but especially 1b)
are better receptors for steroids than HP-β-CD.
our acyclic CB[n]-type containers. Figure 4a shows the PSDs
measured for all six containers toward estradiol (18) which is
illustrative. All five acyclic CB[n]-type containers 1a−1e
Developmental Anticancer Agent 17. Compound 17 is a
developmental drug with documented in vivo anticancer activity
using a DMSO formulation, but which could not be formulated
in water using the standard techniques including cyclo-
solubilize estradiol more efficiently (slope = 0.35 to 0.92; K
rel
1
8a
from 2.4 to 51) than HP-β-CD (slope =0.18; K = 1.0). Figure
dextrins.
Accordingly, we decided to investigate the
rel
1
6
a−c shows the H NMR spectra recorded for estradiol alone
in DMSO-d and in the presence of 1a and 1b in buffered D O.
formulation of 17 using containers 1a−1e (Table 1 and Figure
4b). All five acyclic CB[n]-type containers solubilize 17 (slope
= 0.14−0.89) whereas HP-β-CD is incapable of solubilizing this
drug. Interestingly, although 17 is most efficiently solubilized by
1b (slope = 0.89), container 1a (slope = 0.71) generates a
solution with the highest concentration of 17 because of the
higher inherent solubility of 1a. Compound 17 is also nicely
solubilized by 1d which is perhaps unsurprising given that the
6
2
The large upfield shifts observed for the axial Me-group (H )
k
3
and the protons on the sp -hydridized C atoms of the steroidal
skeleton indicate that the containers bind preferentially to this
region of the steroids. Container 1b solubilizes 17-α-
ethynylestradiol (19) with 1:1 stoichiometry which is indicative
of a very large association constant K for this complex. Only
a
9
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CD is unable to solubilize camptothecin under these
conditions. Among containers 1a−1e, container 1e displays
the narrowest scope of solubilizing abilities with 9 out of 19
drugs displaying no solubilization. We attribute the poor
solubilization abilities of 1e to the half-chair conformation of its
tetrahydronaphthalene walls which sterically impede π−π
interactions. We believe that the strategic merging of the
structural features of CB[n] receptors (to deliver strong
hydrophobic binding and ammonium binding) with the
aromatic walls of cyclophanes to impart affinity toward the
wide variety of insoluble aromatic drugs positions acyclic
CB[n]-type receptors as a powerful alternative to cyclodextrins
that expands the scope of insoluble drugs that can be
formulated with molecular container technology.
Some Drugs Are Solubilized by a Narrow Set of
Containers. Four drugs are solubilized by only one acyclic
CB[n]-type container: paclitaxel (8) and docetaxel (23) by 1a,
fenofibrate (22) and fulvestrant (25) by 1b. Cinnarizine (12) is
only solubilized by two containers; it is best solubilized by 1a
and less well by 1e. On the basis of this data we believe that
containers 1a and 1b are the most versatile and general purpose
solubilizing agents and that these containers are best positioned
for further development as novel solubilizing excipients for
practical applications.
1
Figure 6. H NMR recorded (400 MHz, rt, 20 mM sodium phosphate
buffered D O, pH 7.4) for (a) estradiol 18 (in DMSO-d ), (b) 1a (10
2
6
Container 1d Is Structurally and Functionally Intermedi-
ate between 1a and 1b. The dimethyl substituted o-xylylene
walls of container 1d are intermediate in length between 1a and
mM) with estradiol 18, (c) 1b (10 mM) with estradiol 18, (d)
camptothecin 14 (in DMSO-d ), (e) 1d (15 mM) with camptothecin
4, and (f) 1b (10 mM) with camptothecin 14.
6
1
1b which feature benzene and napthalene derived sidewalls.
Compound 1d is also intermediate between 1a and 1b in terms
of its self-association properties but possesses superior solubility
characteristics (353 mM) in buffered water. Accordingly, and
perhaps unsurprisingly, we find that 1d exhibits solubilization
abilities that are similar to those of 1a and 1b. For example, for
albendazole (9), melphalan (10), amiodarone (13), indome-
Me-substituted sidewalls of 1d makes it intermediate in size
(
Figure 5) between 1a and 1b.
Acyclic CB[n]-type Containers Are Good Solubilizing
Agents for Insoluble Drugs Containing Aromatic Rings.
The X-ray crystal structures of 1a and 1b (Figure 5) show that
the aromatic sidewalls are oriented roughly perpendicular to
one another and define a hydrophobic box. Accordingly, it
would be expected that insoluble drugs that contain aromatic
rings would be good guests for acyclic CB[n]-type containers.
The majority of drugs studied in this paper contain aromatic
rings within their structure, and we generally observed upfield
thacin (15), and tolfenamic acid (16), the slopes and K values
rel
for 1d are comparable to those of 1a but significantly smaller
than the corresponding values measured for 1b. For other
drugs, namely voriconazole (24) and ziprasidone (26), the
slope and Krel values measured for 1d are more comparable to
those of 1b than 1a.
Comparison of the Binding Affinity of 1a−1e with HP-
β-CD toward Insoluble Drugs. It is also possible to
1
shifting of the H NMR resonances of these aromatic rings
upon complexation with 1a−1e. Those aromatic rings with
attached ammonium functional groups (e.g., anilines, benzimi-
dazoles, N-arylpiperazines) constitute preferred binding sites.
determine the absolute K value for container·drug complexes
a
from the PSDs if the solubility of the uncomplexed drug (S ) is
0
In only one case (amiodarone, 13) was complexation at an
+
known. Accordingly, we measured the inherent solubility for 13
aliphatic ammonium (Pr NHR ) moiety predominant. The
2
of the 19 drugs studied and used these S values to determine
0
observed upfield shifting of the aromatic protons confirms that
the aromatic residues of the drugs are encapsulated within the
hydrophobic box that is defined by the two aromatic walls and
the methylene bridged glycoluril tetramer backbone. For
the absolute K values for this selection of drugs as given in
a
Table 1. The binding constants for these 13 drugs toward HP-
β-CD span the range 160−36 000 M− which is in line with the
1
−1
1
well-known low affinity (log K = 2.5 ± 1.1 M ) and low
a
20
example, Figure 6d−f shows the H NMR spectra recorded
selectivity of cyclodextrins toward their guests. In contrast,
the K values measured for these 13 drugs toward 1a−1e fall in
for camptothecin (14) alone in DMSO-d and in water in the
6
presence of containers 1d and 1b. Obviously, the protons on
the aromatic rings of camptothecin (H −H ) undergo
a
6
−1
the range 1300 to 1.9 × 10 M with three additional
complexes too tight to measure using the PSD. For drugs that
are solubilized by HP-β-CD, the best acyclic container (e.g.,
1a−1e) always forms significantly stronger container·drug
complexes (29- to 630-fold stronger) than HP-β-CD. In
many cases the acyclic containers bind to and solubilize drugs
[e.g., camptothecin (14) and aripiprazole (21)] that cannot be
solubilized at all with HP-β-CD under these conditions. The
ability of 1a−1e to solubilize drugs that cannot be solubilized
with HP-β-CD and to do so more efficiently (larger slope and
a
f
substantial upfield shifts upon complexation. Larger upfield
shifts are observed upon complexation with 1b probably
because of the larger anisotropic shielding effect of the
naphthalene walls of 1b relative to the o-xylylene walls of 1d.
Figure 4c shows the PSDs created for mixtures of camptothecin
(
14) with containers 1a−1e and HP-β-CD which display A -
L
type PSDs indicative of 1:1 complexation. All five acyclic
CB[n]-type containers (1a−1e) solubilize camptothecin (14)
nicely, with 1b doing so in equimolar amounts whereas HP-β-
9
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Journal of Medicinal Chemistry
Article
Ka) suggests that acyclic CB[n]-type containers will become an
important tool to formulate insoluble pharmaceutical agents.
dioxane as internal reference): δ 156.1, 155.5, 149.7, 130.9, 127.6, 78.0,
7
6.9, 72.1, 70.7, 70.5, 52.1, 47.8, 47.3, 35.6, 24.3, 15.8, 14.8, 11.8. HR-
2−
MS (ESI): m/z 753.1997 ([M − 4Na + 2H] , C H N O S , calcd
for 753.1972).
58
74 16 24 4
CONCLUSIONS
■
1
-Propanesulfonic Acid, 3,3′,3″,3‴-[[(22bα,22cα,24bα,24cα,26bα,
In summary, we have compared the ability of 1a−1e to
solubilize insoluble drugs relative to HP-β-CD. Compounds
a−1e do not undergo strong self-association (K ≤ 624 M )
26cα,28bα,28cα)-6, 14,21,22b,22c,24b,24c,26b,26c,28b,28c,29-
dodecahydro-22b,22c,28b,28c-tetramethyl-7,9,11,13,22,24,26,28-
octaoxo-7H,8H,9H,10H,11H,12H,13H,22H,23H,24H,25H,26H,27H,
−1
1
s
2
2
[
8H-6a,7a,8a,9a,10a,11a,12a,13a,21a,22a,23a,24a,25a,26a,27a,
in buffered water and possess good solubility characteristics.
We created PSDs for mixtures of containers 1a−1e and HP-β-
CD with 19 drugs. We find that the solubilizing ability of the
best container (1a−1e) is superior to HP-β-CD in all cases;
8a-hexadecaazacycloocta[1,2,3:3″,4″;5,6,7:3‴,4‴]dipentaleno-
1″,6″:5,6,7:1‴,6‴:5′,6′,7′]dicycloocta[1,2,3:3″,4″;1′,2′,3′:3‴,4‴]
dipentaleno[1″,6″:4,5,6;1‴,6‴:4′,5′,6′]dicyclohepta[1,2-b:1′,2′-b′]
di-5,6,7,8-tetrahydronaphthalene-5,15,20,30-tetrayl]tetrakis(oxy)]-
tetrakis-, Sodium Salt (1:4) (1e). Compound 3e (1.1 g, 2.5 mmol) was
1
a−1e even solubilize 8 drugs that are completely insoluble
added into a solution of 2 (0.50 g, 0.64 mmol) in TFA/Ac O (5.0 mL,
2
with HP-β-CD. The superior solubilizing ability can be traced
to the 29- to 630-fold higher binding affinity of the best acyclic
CB[n]-type container toward the drugs compared to HP-β-CD.
Less container is needed, therefore, to achieve a given [drug]. A
notable achievement was the solubilization of the devel-
opmental anticancer agent 17. The acyclic CB[n]-type
containers display an affinity for the steroid ring system,
aromatic moieties of insoluble drugs, and cationic ammonium
v:v = 1:1). The mixture was stirred and heated at 70 °C for 3 h. The
solvent was removed under reduced pressure, and the solid was dried
under high vacuum. The solid was recrystallized from a mixture of
water and EtOH (1:2, v/v, 0.30 L) twice and then dissolved in water
and adjusted to pH = 7 by adding 1 M aqueous NaOH. The solvent
was removed under reduced pressure, and the solid was dried under
high vacuum to yield 1e as a white solid (0.30 g, 30%). Mp >300 °C.
−1
IR (ATR, cm ): 2930w, 2875w, 1724s, 1471s, 1375m, 1320m, 1233s,
1
groups. Compound 1b is generally the most potent (K up to
1171s, 1084m, 1041s, 824w, 801m, 759w. H NMR (400 MHz, D
2
O,
a
6
−1
with added p-xylenediamine): δ 5.64 (d, J = 15.8, 4H), 5.49 (d, J =
and exceeding 10 M ) container whereas both 1a and 1b
display excellent solubility enhancement toward a broad range
of insoluble drugs. The broad scope of insoluble drugs that can
be formulated with 1a and 1b, in many cases where HP-β-CD
fails completely, makes acyclic CB[n]-type containers partic-
ularly attractive alternatives to cyclodextrins as solubilizing
excipients for practical applications.
1
4
2
2
1
5.5, 2H), 5.45 (d, J = 8.8, 2H), 5.28 (d, J = 8.8, 2H), 5.23 (d, J = 16.4,
H), 4.38 (d, J = 16.4, 4H), 4.29 (d, J = 15.8, 4H), 3.97 (d, J = 15.5,
H), 4.00−3.80 (m, 4H), 3.75−3.65 (m, 4H), 3.25−3.15 (m, 8H),
.65−2.50 (m, 4H), 2.30−2.15 (m, 12H), 1.88 (s, 6H), 1.83 (s, 6H),
13
.60−1.55 (m, 4H), 1.35−1.20 (m, 4H). C NMR (125 MHz, D O,
2
with added p-xylenediamine and 1,4-dioxane as internal reference): δ
1
7
56.5, 155,7, 149.7, 132.0, 131.6, 127.8, 126.7, 78.3, 77.2, 71.7, 71.2,
1.0, 52.7, 48.4, 47.6, 41.6, 35.6, 24.7, 22.9, 21.0, 15.5, 14.8. HR-MS
2
−
EXPERIMENTAL SECTION
(ESI): 779.2154 ([M − 4Na + 2H] , C H N O S , calcd for
7
62
78 16 24 4
■
79.2129).
General Experimental. Starting materials were purchased from
commercial suppliers and were used without further purification.
Compounds 1a−1c, 2, 5, and 6 were prepared according to literature
Sodium 3,3′-((2,3-dimethyl-1,4-phenylene)bis(oxy))bis(propane-
1
-sulfonate) (3d). A solution of 4 (18 g, 0.15 mol) in 1,4-dioxane
11b,c,e,13
(130 mL) was added into a solution of 2,3-dimethylhydroquinone (8.0
g, 58 mmol) in aqueous NaOH solution (1.0 M, 0.10 L). The mixture
was stirred at rt for 12 h and then filtered to collect the crude solid.
The solid was stirred with acetone (0.20 L) and then dried under high
vacuum to yield 3d as a pale red solid (18 g, 73%). Mp >280 °C. IR
procedures.
Melting points were measured on a Meltemp
apparatus in open capillary tubes and are uncorrected. IR spectra were
measured on a JASCO FT/IR 4100 spectrometer by attenuated total
−1
reflectance (ATR) and are reported in cm . NMR spectra were
1
13
measured at 400 or 600 MHz for H and 125 MHz for C. Integration
−1
1
(ATR, cm ): 2938w, 2869w, 1625m, 1489m, 1472m, 1205s, 1157s,
of the H NMR spectra indicates that the new compounds have a level
1
1
112s, 1059s, 801m, 624m, 551m. H NMR (400 MHz, D O): δ 6.88
of purity ≥95%. Mass spectrometry was performed using a JEOL
AccuTOF electrospray instrument using the electrospray ionization
technique.
2
(
1
s, 2H), 4.10 (t, J = 5.6, 4H), 3.10 (t, J = 7.2, 4H), 2.15−2.05 (m, 8H),
.71 (s, 6H). 13C NMR (125 MHz, D O, 1, 4-dioxane as internal
2
reference): δ 150.5, 127.6, 111.8, 68.2, 47.6, 24.1, 11.1. HR-MS (ESI):
1
-Propanesulfonic Acid, 2,3, 15,16-Tetramethyl-
−
3
1
2
1
1
,3′,3″,3‴-[[(19bα,19cα,21bα,21cα,23bα,23cα,25bα,25cα)-5,13,18,
9b,19c,21b,21c,23b,23c,25b,25c,26-dodecahydro-19b,19c,25b,
5c-tetramethyl-6,8,10,12,19,21,23,25-octaoxo-6H,7H,8H,9H,10H,
1H,12H,19H,20H,21H,22H,23H,24H,25H-5a,6a,7a,8a,9a,10a,11a,
2a,18a,19a,20a,21a,22a,23a,24a,25a-hexadecaazabisbenzo-
m/z 381.0694 ([M − 2Na + H] , C14H O S , calcd for 381.0678).
21 8 2
Sodium 3,3′-((5,6,7,8-tetrahydronaphthalene-1,4-diyl)bis(oxy))-
bis(propane-1-sulfonate) (3e). A solution of 4 (8.6 g, 70.0 mmol)
in 1,4-dioxane (60 mL) was added to a solution of 7 (4.0 g, 28 mmol)
in aqueous NaOH solution (1.0 M, 45 mL). The mixture was stirred at
rt for 12 h and then filtered to collect the crude solid. The crude solid
was stirred with acetone (0.10 L), filtered, and then dried under high
vacuum to yield 3e as a white solid (7.6 g, 60%). Mp >280 °C. IR
[
5″,6″]cyclohepta[1″,2″,3″:3′,4′]pentaleno[1′,6′:5,6,7]cycloocta-
[
1
1,2,3-gh:1′,2′,3′-g′h′]cycloocta[1,2,3-cd:5,6,7-c′d′]dipentalene-1,4,
4,17-tetrayl]tetrakis(oxy)]tetrakis-, Sodium Salt (1:4) (1d). Com-
pound 3d (0.65 g, 1.5 mmol) was added into a solution of 2 (0.30 g,
.38 mmol) in TFA/Ac O (3.0 mL, v/v = 1:1). The mixture was
−
1
(
ATR, cm ): 2946w, 2846w, 1652w, 1471w, 1256m, 1194s, 1094m,
0
2
1
1
4
2
045s, 791w, 604w, 521w. H NMR (400 MHz, D O): δ 6.83 (s, 2H),
stirred and heated at 70 °C for 3 h. The solvent was removed under
reduced pressure, and the solid was dried under high vacuum. The
solid was recrystallized from a mixture of water and EtOH (1:2, v/v,
2
.09 (t, J = 6.0, 4H), 3.08 (t, J = 6.2, 4H), 2.65−2.55 (m, 4H), 2.35−
13
.15 (m, 4H), 1.75−1.60 (m, 4H). C NMR (125 MHz, D O, 1, 4-
2
dioxane as internal reference): δ 150.0, 128.1, 110.2, 67.4, 47.6, 24.0,
2
1
0 mL) twice and then dissolved in water and adjusted to pH = 7 with
M aqueous NaOH. The solvent was removed under reduced
−
2
2.7, 21.2. HR-MS (ESI): m/z 407.0842 ([M − 2Na + H] ,
C H O S , calcd for 407.0834).
pressure. The resulting solid was dried under high vacuum to yield 1d
as a white solid (0.26 g, 43%). Mp >300 °C. IR (ATR, cm ): 2999w,
2
1
16 23
8 2
−1
5,6,7,8-Tetrahydronaphthalene-1,4-diol (7). A solution of 6 (5.3 g,
33 mmol) in EtOH (0.16 L) was mixed with palladium on activated
952w, 2875w, 1733s, 1652s, 1474s, 1368m, 1321m, 1233s, 1185s,
1
093m, 1044s, 960w, 823w, 800m, 795m. H NMR (400 MHz, D O):
carbon (3.5 g, 10 wt %, 3.3 mmol). The mixture was stirred under H
2
2
δ 5.68 (d, J = 15.3, 2H), 5.59 (d, J = 15.7, 4H), 5.43 (d, J = 7.8, 2H),
gas (15 Psi) for 3 days at rt. The heterogeneous reaction mixture was
filtered, and the filtrate was concentrated under reduced pressure.
After the residual solvent was removed under high vacuum, the
product was obtained as a light purple solid (4.57 g, 85%).
5
4
3
1
.36 (d, J = 7.8, 2H), 5.17 (d, J = 16.1, 4H), 4.35 (d, J = 16.1, 4H),
.25 (d, J = 15.7, 4H), 4.07 (d, J = 15.3, 2H), 4.00−3.80 (m, 4H),
.75−3.55 (m, 4H), 3.25−3.05 (m, 8H), 2.25−2.15 (m, 8H), 1.82 (s,
2H), 1.78 (s, 6H), 1.74 (s, 6H). 13C NMR (125 MHz, D O, 1,4-
Characterization data matches the literature report.
14
2
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Journal of Medicinal Chemistry
Article
D.-S.; Liu, Y. Supramolecular chemistry of p-sulfonatocalix[n]arenes
ASSOCIATED CONTENT
■
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(c) Masson, E.; Ling, X.; Joseph, R.; Kyeremeh-Mensah, L.; Lu, X.
Cucurbituril chemistry: A tale of supramolecular success. RSC Adv.
2
012, 2, 1213−1247. (d) Nau, W. M.; Florea, M.; Assaf, K. I. Deep
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AUTHOR INFORMATION
Corresponding Author
E-mail: LIsaacs@umd.edu. Phone: 301-405-1884. Fax: 301-
14-9121.
■
*
(4) (a) Liu, S.; Ruspic, C.; Mukhopadhyay, P.; Chakrabarti, S.;
Zavalij, P. Y.; Isaacs, L. The cucurbit[n]uril family: Prime components
for self-sorting systems. J. Am. Chem. Soc. 2005, 127, 15959−15967.
3
Notes
(b) Rekharsky, M. V.; Mori, T.; Yang, C.; Ko, Y. H.; Selvapalam, N.;
The authors declare no competing financial interest.
Kim, H.; Sobransingh, D.; Kaifer, A. E.; Liu, S.; Isaacs, L.; Chen, W.;
Moghaddam, S.; Gilson, M. K.; Kim, K.; Inoue, Y. A synthetic host-
guest system achieves avidin-biotin affinity by overcoming enthalpy-
entropy compensation. Proc. Natl. Acad. Sci. U. S. A. 2007, 104,
ACKNOWLEDGMENTS
■
We thank the National Cancer Institute of the National
Institutes of Health (R01-CA168365) for financial support. B.Z.
thanks the University of Maryland for a Wylie Dissertation
fellowship. We thank Timothy Fouts, Jeffrey Meshulam, and
Kathryn Bobb (Rel-MD) for samples of 17.
2
0737−20742. (c) Cao, L.; Sekutor, M.; Zavalij, P. Y.; Mlinaric-
Majerski, K.; Glaser, R.; Isaacs, L. Cucurbit[7]uril guest pair with an
attomolar dissociation constant. Angew. Chem., Int. Ed. 2014, 53, 988−
9
93. (d) Isaacs, L. Stimuli responsive systems constructed using
cucurbit[n]uril-type molecular containers. Acc. Chem. Res. 2014, 47,
052−2062. (e) Ko, Y. H.; Kim, E.; Hwang, I.; Kim, K. Supra-
2
ABBREVIATIONS USED
■
molecular assemblies built with host-stabilized charge-transfer
interactions. Chem. Commun. 2007, 1305−1315. (f) Yang, H.; Yuan,
B.; Zhang, X.; Scherman, O. A. Supramolecular chemistry at interfaces:
Host-guest interactions for fabricating multifunctional biointerfaces.
Acc. Chem. Res. 2014, 2106−2115.
CB[n], cucurbit[n]uril; HP-β-CD, hydroxypropyl-β-cyclodex-
trin; K , binding constant; K , relative binding constant; K ,
a
rel
s
self-association constant; SBE-β-CD, sulfobutyl ether-β-cyclo-
dextrin; π−π, pi−pi; PSD, phase solubility diagram; A -type,
L
(5) (a) Lee, D.-W.; Park, K.; Banerjee, M.; Ha, S.; Lee, T.; Suh, K.;
linear PSD; S , inherent drug solubility; ATR, attenuated total
0
Paul, S.; Jung, H.; Kim, J.; Selvapalam, N.; Ryu, S.; Kim, K.
Supramolecular fishing for plasma membrane proteins using an
ultrastable synthetic host-guest binding pair. Nat. Chem. 2011, 3, 154−
reflectance; s, strong IR signal; m, medium IR signal; w, weak
IR signal
1
59. (b) Kasera, S.; Biedermann, F.; Baumberg, J. J.; Scherman, O. A.;
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