Trapping of organophosphorus chemical nerve agents in water with amino acid functionalized baskets

Article abstract of DOI:10.1002/chem.201304779

We prepared eleven amino-acid functionalized baskets and used ¹H NMR spectroscopy to quantify their affinity for entrapping dimethyl methylphosphonate (DMMP, 118 A³) in aqueous phosphate buffer at pH=7.0±0.1; note that DMMP guest is akin in size to chemical nerve agent sarin (132 A³). The binding interaction (K_a) was found to vary with the size of substituent groups at the basket′s rim. In particular, the degree of branching at the first carbon of each substituent had the greatest effect on the host-guest interaction, as described with the Verloop′s B1 steric parameter. The branching at the remote carbons, however, did not perturb the encapsulation, which is important for guiding the design of more effective hosts and catalysts in future. Nervous trapping: The binding affinity (K_a) of amino acid functionalized baskets toward a dimethyl methylphosphonate (DMMP) guest, akin in size to the chemical nerve-agent sarin, is a function of the size of the substituent R groups at the basket′s rim. In particular, the greater degree of branching at the first carbon atom of each substituent lowers the host affinity toward DMMP (see figure).

Full text of DOI:10.1002/chem.201304779

DOI: 10.1002/chem.201304779
Communication
&
Host–Guest Systems
Trapping of Organophosphorus Chemical Nerve Agents in Water
with Amino Acid Functionalized Baskets
Yian Ruan,[a] Erdin DalkiliÅ,[b] Paul W. Peterson,[a] Aroh Pandit,[a] Arif Dastan,[b]
Jason D. Brown, Shane M. Polen, Christopher M. Hadad, and Jovica D. Badjic*
[a]
[a]
[a]
[a]
´
ficial hosts[1h] might engender a useful strategy for removing
undesired OP compounds from the environment. In particular,
the advent of supramolecular encapsulation chemistry[8] has
led to the understanding that the formation of “molecule
within molecule” complexes[9] (kin) is a rapid process, which
could be controlled by gating.[10] However, the dissipation of
encapsulation complexes is slower with the rate coefficient koff
often corresponding to the thermodynamic stability Ka.[11] Ac-
cordingly, we reason that preparing artificial hosts complemen-
tary to OP nerve agents could be important for 1) creating
practical and catalytic alternatives to BuChE/PON1; and 2) ob-
taining new supramolecular sensors[12] and/or degradation cat-
alysts.[13] We hereby describe an important step toward reach-
ing such an objective: a series of baskets of type 1–7 were
found to trap dimethyl methylphosphonate (DMMP, 118 ꢀ3),
akin in size to sarin (132 ꢀ3), and in water (Figure 1). The guest
populates the hydrophobic interior of these concave hosts
while interacting with amino acid residues at the rim.
Abstract: We prepared eleven amino-acid functionalized
baskets and used H NMR spectroscopy to quantify their
1
affinity for entrapping dimethyl methylphosphonate
(DMMP, 118ꢀ3) in aqueous phosphate buffer at pH=7.0Æ
0.1; note that DMMP guest is akin in size to chemical
nerve agent sarin (132ꢀ3). The binding interaction (Ka) was
found to vary with the size of substituent groups at the
basket’s rim. In particular, the degree of branching at the
first carbon of each substituent had the greatest effect on
the host-guest interaction, as described with the Verloop’s
B1 steric parameter. The branching at the remote carbons,
however, did not perturb the encapsulation, which is im-
portant for guiding the design of more effective hosts and
catalysts in future.
A paucity of chemoreceptors capable of recognizing organo-
phosphorus (OP) chemical nerve agents[1] contribute to difficul-
ties related to developing effective sensors, degradation cata-
lysts and/or sequestration agents.[2] In particular, recent devel-
opments in Syria attest to the challenges pertaining to the
identification of sarin and its by-products in the environment,
following acts of chemical warfare.[3] Notably, chemical nerve
agents have a sufficiently long lifetime in water[4] to act as
potent inhibitors of acetylcholinesterase (AChE), causing the
accumulation of acetylcholine in neuromuscular junctions and
therefore overstimulation of muscles, which in severe cases re-
sults in asphyxiation and death.[5] Butyrylcholinesterase
(BuChE)[6] and paraoxonase-1 (PON1)[7] enzymes are biosca-
vengers of OP nerve agents and could remove these toxic
compounds from the bloodstream, thereby constituting poten-
tial prophylactic, as well as post-exposure, therapeutic meas-
ures.[3] As an alternative to these particular therapies, which re-
quire significant quantities of enzymes, one can envision that
the isolation of OP nerve agents in the interior of concave arti-
Symmetric baskets C3 of type 1–7 were designed to carry
three negatively charged carboxylates (pH 7.0) at the rim for
enhancing their solubility in water (Figure 1A and B). The ques-
tion to be answered is whether these cavitands, comprising
two nonpolar regions and a polar belt aggregate in water (Fig-
ure 1B)[14] will bind to small organophosphonates in the
manner akin to previously studied baskets?[14–15]
Cavitands 1–7 were prepared by the conjugation of tris(an-
hydride) 8 and hydrophobic amino acids in DMSO at 1208C
(yield 32–57%). Upon chromatographic purification, each of
the baskets was dissolved in CDCl3/CD3OH (9:1) and then de-
protonated with (CH3)4NOH to give the corresponding carbox-
ylate salts. Subsequently, each tetramethylammonium com-
pound (0.1–5.0 mm) was solubilized in aqueous phosphate
buffer (pH 7.0Æ0.1) and then used in our experiments.
1H NMR spectra of [1–7]3À revealed a set of signals corre-
sponding to C3 or, perhaps, even more symmetric species
(Figure 2; see also Figures S1–S5 in the Supporting Informa-
tion). In particular, the resonance frequency of proton nuclei,
comprising amino acid residues, were found upfield in [1-7]3À
with respect to the analogous signals corresponding to model
compounds [9–15]1À (Figure 2); note that the magnetic shield-
ing was particularly manifested in the case of phenylalanine
basket [7]3À (Figure 2B). Although the model compounds are
symmetric about the flat phthalimide ring, baskets [1–7]3À pos-
sess two distinct environments that we hereby refer to as their
inner and outer sides (Figure 1B and Table 1). With this desig-
nation, our NMR results suggest that aliphatic/aromatic side
[a] Y. Ruan, P. W. Peterson, A. Pandit, J. D. Brown, S. M. Polen,
´
Prof. C. M. Hadad, Prof. J. D. Badjic
Department of Chemistry and Biochemistry, The Ohio State University
100 West 18th Avenue, Columbus OH 43210 (USA)
Fax: (+1)614-292-1685
E-mail: badjic@chemistry.ohio-state.edu
[b] E. DalkiliÅ, Prof. A. Dastan
Department of Chemistry, Ataturk University, Faculty of Sciences
25240 Erzurum (Turkey)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304779.
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Figure 1. A) Baskets 1–7 were prepared by the condensation of tris(anhydride) 8 and hydrophobic amino acids having increasingly bigger functional groups.
B) Energy-minimized (MMFFs, Spartan) structure of basket 2 containing (S)-alanine at the rim. C) The inspection of solid-state structures of 18 amino acid con-
jugates of phthalimide (CSD) reveals a conformational bias about the c1 torsion with a disposition toward c1 =11.1Æ7.98.
viation). Indeed, our computational studies concurred a prefer-
Table 1. Diffusion coefficients (D) for baskets (1.0 mm) obtained from
ence of the CÀH bond to nearly eclipse the phthalimide ring
DOSY NMR spectroscopic measurements at 298.1 K.
due to a) the minimization of the unfavorable van der Waals
Basket
D [10À10 m2 sÀ1
]
rH [ꢀ][a]
r [ꢀ][b]
rH [ꢀ][c]
À
type of strain between the juxtaposed C=O and CO2 /R
groups[16]; and b) the maximization of n-to-s* hyperconjuga-
tion, whereby CÀC bonds act as an electron acceptor, and the
lone pair on the phthalimide nitrogen acts as an electron
donor (see the Supporting Information). Importantly, the more
sizeable R groups in compounds 12 and 14 (Figure 1A)
become almost perpendicular with respect to the imide unit
(see the Supporting Information). To summarize, the amino
acid side chains of [1–7]3À in water point to the basket inner
side, with the CÀH bond almost eclipsing the phthalimide
group, to face the incoming guest molecule (Figure 1B).
[1]3À
[2]3À
[4]3À
[7]3À
3.3Æ1.0
3.4Æ1.0
2.9Æ1.1
3.0Æ1.1
7.4Æ1.8
7.2Æ1.6
8.3Æ2.2
8.2Æ2.1
7
7
7
8
6.6Æ0.3
6.0Æ0.4
8.6Æ2.2
–
[a] Hydrodynamic radius. [b] Computed radius; MMFFs (Spartan). [c] With
a large excess of DMMP guest. The hydrodynamic radii were computed
by using the Stokes–Einstein equation; the viscosity of 10.0 mm phos-
phate buffer at pH 7.0Æ0.1 is similar to that of pure water (h=
0.89 MPas at 25.08C).
chains in [1–7]3À reside at the basket inner side, that is, in the
vicinity of the concave hydrophobic cavity. In this way, the aro-
matic rings comprising the cavity of baskets alter the magnetic
environment of juxtaposed proton nuclei to, by diamagnetic
shielding, reduce their chemical shift (Figure 2). While the hy-
drophobic side chains point to the basket nonpolar interior,
the carboxylic groups become situated at the outer side in the
polar water solvent (Figure 1B).
A fifty-fold dilution of 5.0 mm solution of baskets [1]3À, [2]3À,
[4]3À, and [7]3À in water (pH 7.0Æ0.1) led to a small decrease
1
in the linewidth of their well-resolved H NMR proton resonan-
ces (Figures S6–S9 in the Supporting Information). Likewise,
a dilution of 5.0 mm aqueous solution of corresponding model
compounds [9]1À, [10]1À, [12]1À, and [15]1À caused a negligible
perturbation of their proton resonances (Figures S10–S13 in
the Supporting Information). To additionally probe the aggre-
gation, we completed pulse-field gradient NMR spectroscopic
measurements of the diffusion of baskets (DOESY, Table 1) and
model compounds (Table S1 in the Supporting Information).[17]
At 298.1 K, the translational diffusion coefficients were compa-
rable for all four baskets (Table 1), with the corresponding hy-
Furthermore, we examined the solid-state structures of
eighteen phthalimide derivatives of type PhtÀCHRÀCO2H by
using the Cambridge structural database (CSD, Figure 1C). Im-
portantly, there is a conformational bias about the c1 torsion
with a disposition toward c1 =11.1Æ7.98 (meanÆstandard de-
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[1]3À host are comparable and in
line with their similar size in so-
lution (Table 1).
The interaction of DMPP with
basket 1 was additionally exam-
ined with molecular dynamics
and molecular docking computa-
tional protocols (see the Sup-
porting Information). In brief, the
simulations confirmed that the
[1ꢀDMPP] complex was domi-
nated by the PÀCH3 group of
the guest populating the cavity
of
1 (Figure 3C). The methyl
group is positioned above the
basal aromatic ring, in complete
support of the experimental
findings.
We subsequently completed
the titration of DMMP as a guest
to monomeric hosts [2–7]3À
,
each carrying increasingly larger
amino acids at the rim (Fig-
ure 1B, see also Figures S15–S20
in the Supporting Information).
Interestingly, the association
constants (Ka) varied across the
series of hosts: [1]3À had the
largest Ka, whereas [6]3À had the
lowest propensity for entrapping
DMMP (Figure 4B). Interestingly,
basket [7]3À showed no measur-
able affinity toward complexa-
Figure 2. A) 1H NMR spectra (400 MHz, 300.1 K) of basket [1]3À and model compound [9]1À (1.0 mm) in aqueous
phosphate buffer at pH 7.0Æ0.1. B) 1H NMR spectra (400 MHz, 300.1 K) of basket [7]3À and model compound
1
[15]1À (1.0 mm) in aqueous phosphate buffer (10.0 mm) at pH 7.0Æ0.1; H NMR signals at approximately 4.7 ppm
are missing because of the suppression of the water’s resonance.
drodynamic radii consistent with the preponderance of mono-
meric species. No evidence of aggregation was observed for
model compounds [9]1À, [10]1À, [12]1À, and [15]1À (Table S1 in
the Supporting Information), in which the self-diffusion coeffi-
cients (D=6.1–7.6ꢂ10À10 m2 sÀ1) suggested the abundance of
monomeric species (rH =3.2–3.7 ꢀ).
tion of DMMP (Figure S20 in the Supporting Information), due
to perhaps a high propensity of its benzene moiety for occu-
pying the host’s inner space. Because the cup-shaped cavity is
retained in all baskets, we presumed that the hydrophobic
chains at the rim must be affecting the binding by steric inter-
actions (Figure 4A). To quantify the steric effects,[20] however,
one could use various steric parameters of which the Charton’s
v constants (derived from Taft’s Es values) ascribe a single
number to the substituent of interest, thereby approximated
as a sphere.[21] Correspondingly, the linear free-energy relation-
ship (LFER) of logKa as a function of v was found to be rather
inconsistent (R2 =0.63, Figure S21 in the Supporting Informa-
tion), suggesting that the shape of amino acid substituents in
[1–6]3À cannot be treated as spherical.[20] To account for the re-
sults, we reasoned that a restricted rotational preference of the
hydrophobic groups necessitate a consideration of their multi-
faceted nature. Indeed, Verloop and co-workers developed
a computational program (Sterimol)[22] for characterizing the di-
mension of functional groups by using three independent pa-
rameters: B1 corresponds to the minimal width, B5 to the maxi-
mal width, and L to the length of the substituent of interest.[23]
In particular, minimal width B1 is a measure of the steric bulk
at the first carbon atom of the substituent (Figure 4B) such
that the branching at this position affects its value. Notably,
An incremental addition of DMMP to [1]3À in water caused
a perturbation of the magnetic environment of proton nuclei
1
in both host and guest, as was monitored by H NMR spectros-
copy (Figure 3A). In particular, the process of complexation
was accompanied with a greater shielding of the guest PÀCH3
(Dd=0.40 ppm) than PÀOCH3 (Dd=0.16 ppm) resonances to
indicate the insertion of PÀCH3 group inside the cup-shaped
scaffold of [1]3À (Figure 3C).[15] Because the method of continu-
ous variation was in line with 1:1 binding stoichiometry (Fig-
ure S14 in the Supporting Information),[18] we subjected the
1H NMR titration data to nonlinear least-square analysis by
using a model describing 1:1 complexation occurring at a fast
rate on the NMR time scale (Figure 3B).[19] The computed bind-
ing isotherm (298.1 K) fits well to the experimental data (R2 =
0.997) and with an association constant of Ka =465Æ10mÀ1
(Figure 3). The formation of 1:1 complex was additionally sup-
ported with the results of DOSY NMR measurements: the
translational diffusion coefficients of [1ꢀDMMP]3À and free
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versus SB1 (Figure 4C, see also
Figures S22–S25 in the Support-
ing Information).
To account for the result, we
compared 1H NMR spectra of
baskets [4]3À, [16]3À, and [17]3À
containing a variable number of
valines (3, 2, and 1) at the rim, as
well as the valine model com-
pound [12]1À (Figure 5B). Thus,
1H NMR spectra of [12]1À and
[4]3À revealed resonances at d=
0.3–1.0 ppm corresponding to
two
diastereotopic
methyl
groups of which one is more
shielded than another (Fig-
ure 5B). Perhaps, this is in line
with the conformational bias,
whereby only one methyl is jux-
taposed to the phthalimide ring,
with the rotamer III dominating
the equilibrium (Figure 5C). In
fact, the solid-state structure of
12[24] shows the existence of this
particular conformer (Figure 5C).
1H NMR spectrum of [16]3À, with
two glycines and one valine at
the rim, revealed an additional
upfield shift of one methyl
group (d=À0.19 ppm), whereas
another stayed unperturbed
(Figure 5B). Because this particu-
lar basket has a single hydropho-
bic amino acid, we deduce that
the rotamer II is now dominating
the equilibrium, so that both
methyl groups populate its hy-
drophobic inner space in polar
water solvent (Figure 5C). In
1
Figure 3. A) Selected H NMR spectra (600 MHz, 298.1 K) of basket [1]3À (1.0 mm), in aqueous phosphate buffer
(10.0 mm) at pH 7.0Æ0.1, obtained upon an incremental addition of DMMP. B) Nonlinear least-square analysis of
the binding data (1:1 binding stoichiometry) gave the association constant Ka =465Æ10mÀ1 (R2 =0.999, Sigma-
Plot) for the formation of [1ꢀDMMP]3À. C) Clustering histogram from molecular docking of DMMP into basket of
type 1 (top left). Molecular-dynamics results for a subsequent trajectory of the dominant binding mode as a func-
tion of time (bottom right), in which the different distances (d) between moieties of the DMMP were monitored
relative to the centroid of the basal aromatic ring of the basket, leading to a percentage distribution (top right).
Energy-minimized structure of [1ꢀDMMP]3À complex (MMFFs, Spartan).
the LFER plot of logKa as a function of B1 showed a more rea-
sonable correlation (R2 =0.90, Figure 4C) to denote that the
proximal steric bulk is important in the recognition. That is to
say, the greater the degree of branching at the receptor’s rim,
the lower the binding affinity of the host towards the DMMP
guest. It follows that the branching at the remote carbon does
not considerably perturb the encapsulation of organophospho-
nates, which is useful for guiding the design of more effective
hosts in the future.
consequence of the conformational transition within [16]3À
,
the protons of one methyl group became more magnetically
shielded (Figure 5C); note that comparable conformational
changes were also taking place with other C1 symmetric bas-
kets 18–19 (Figure S26 in the Supporting Information). Because
the Verloop’s steric parameters were derived for groups in
their most stable conformation,[25] the change in the geometry
of amino acids within 16–19 are not accounted for with the re-
ported B1 values to, in part, contribute to the observed trend
(Figure 4C). Indeed, Verloop and co-workers envisioned that
conformational dynamics could be problematic for completing
quantitative correlations and in some cases derived another
set of parameters.[25] Furthermore, reducing the symmetry of
hosts, from C3 to C1, could also affect the binding, because less
symmetric [16–19]3À give diastereomeric complexes with
DMMP guest adopting different orientations in their cavity.[26]
In conclusion, baskets with amino acids at the rim trap
DMMP as an OP guest, akin to sarin in size, in water and near
To probe the validity of the LFER in Figure 4C, we prepared
four additional baskets 16–19, each carrying two types of
amino acids at the rim (Figure 5A). Importantly, the translation-
al diffusion of [16]3À–[19]3À (D=3.3–3.8ꢂ10À10 m2 sÀ1, Table S2
in the Supporting Information) suggested that these com-
pounds stayed monomeric in aqueous solvent at pH 7.0Æ0.1.
The baskets were found to trap DMMP although the stability
of [16–19ꢀDMMP]3À complexes (Ka) appeared to be much
lower than expected from the established correlation of logKa
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Figure 4. A) Top view of energy-minimized complexes [1ꢀDMMP]3À, [2ꢀDMMP]3À, and [4ꢀDMMP]3À (MMFFs, Spartan), showing increasingly larger alkyl
groups at the basket rim. B) The degree of branching at the first carbon (blue) of the substituent (B1) is somewhat related to the stability of the complex (Ka
from one measurement). C) The linear free-energy relationship (LFER) of log Ka (the arithmetic mean of two measurements), corresponding to the formation
of [1–6ꢀDMMP]3À complexes, versus B1 steric parameters (blue, R2 =0.90). The binding affinity (log Ka) of C1 symmetric baskets [16]3À–[19]3À (see Figure 5 for
structures) toward DMMP (red) does not obey the established LFER.
Figure 5. A) Chemical structures of baskets 16–19, each containing two different amino acids; Ka pertaining the entrapment of DMMP with 16–19 is described
1
in Figures S22–S25 in the Supporting Information. B) Segments of H NMR spectra (400 MHz, 298.1 K) of valine-containing model [12]1À and baskets [4]3À
,
[17]3À, and [16]3À (1.0 mm in phosphate buffer at pH 7.0Æ0.1) showing the resonances corresponding to diastereotopic methyl groups. C) Major conforma-
tional isomers of basket [16]3À and model [12]1À (MMFFs, Spartan).
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J. 2013, 450, 231–242; b) M. Pohanka, Anal. Lett. 2013, 46, 1849–1868;
c) H. Mumford, C. J. Docx, M. E. Price, A. C. Green, J. E. H. Tattersall, S. J.
Armstrong, Chem.-Biol. Interact. 2013, 203, 160–166.
physiological pH. The binding is quantifiable with steric inter-
actions at the rim playing the critical role in the recognition.
The results are important for functionalization of baskets
toward creating effective artificial scavengers of OP nerve
agents and supramolecular degradation catalysts.
[7] a) T. T. Sanan, S. Muthukrishnan, J. M. Beck, P. Tao, C. J. Hayes, T. C. Otto,
D. M. Cerasoli, D. E. Lenz, C. M. Hadad, J. Phys. Org. Chem. 2010, 23,
357–369; b) D. T. Yeung, D. E. Lenz, D. M. Cerasoli, Proteins Cell Regul.
2008, 6, 151–170.
[8] a) D. J. Cram, Nature 1992, 356, 29–36; b) D. J. Cram, Science 1983, 219,
1177–1183.
[9] F. Hof, S. L. Craig, C. Nuckolls, J. Rebek, Jr., Angew. Chem. 2002, 114,
1556–1578; Angew. Chem. Int. Ed. 2002, 41, 1488–1508.
[10] S. Rieth, K. Hermann, B.-Y. Wang, J. D. Badjic, Chem. Soc. Rev. 2011, 40,
1609–1622.
[11] J. D. Badjic, S. Stojanovic, Y. Ruan, Adv. Phys. Org. Chem. 2011, 45, 1–37.
[12] D. Ajami, J. Rebek, Org. Biomol. Chem. 2013, 11, 3936–3942.
[13] B. M. Smith, Chem. Soc. Rev. 2008, 37, 470–478.
[14] S. Chen, Y. Ruan, J. D. Brown, J. Gallucci, V. Maslak, C. M. Hadad, J. D.
Badjic, J. Am. Chem. Soc. 2013, 135, 14964–14967.
Acknowledgements
This work was financially supported with funds obtained from
the Department of Defense, Defense Threat Reduction Agency
(HDTRA1-11-1-0042). The content of the information does not
necessarily reflect the position or the policy of the federal gov-
ernment, and no official endorsement should be inferred. Com-
putational support from the Ohio Supercomputer Center is
gratefully acknowledged.
[15] Y. Ruan, H. A. Taha, R. J. Yoder, V. Maslak, C. M. Hadad, J. D. Badjic, J.
Phys. Chem. B 2013, 117, 3240–3249.
[16] a) B.-Y. Wang, S. Stojanovic, D. A. Turner, T. L. Young, C. M. Hadad, J. D.
Badjic, Chem. Eur. J. 2013, 19, 4767–4775; b) S. Stojanovic, D. A. Turner,
A. I. Share, A. H. Flood, C. M. Hadad, J. D. Badjic, Chem. Commun. 2012,
48, 4429–4431; c) S. Stojanovic, D. A. Turner, C. M. Hadad, J. D. Badjic,
Chem. Sci. 2011, 2, 752–759.
Keywords: host–guest
relationship · molecular encapsulation · molecular recognition ·
nerve agents
systems
·
linear
free-energy
[17] Y. Cohen, L. Avram, L. Frish, Angew. Chem. 2005, 117, 524–560; Angew.
Chem. Int. Ed. 2005, 44, 520–554.
[18] K. Hirose, Anal. Methods Supramol. Chem. 2007, 17–54.
[19] Frontiers in Supramolecular Organic Chemistry and Photochemistry (Eds.:
H. J. Schneider, H. Duerr), Wiley, New York, 1991.
[20] K. C. Harper, E. N. Bess, M. S. Sigman, Nat. Chem. 2012, 4, 366–374.
[21] a) M. Charton, J. Org. Chem. 1976, 41, 2217–2220; b) M. Charton, J. Am.
Chem. Soc. 1975, 97, 1552–1556; c) M. Charton, J. Am. Chem. Soc. 1975,
97, 3691–3693.
[22] a) A. Verloop, Pestic. Chem. Hum. Welfare Environ., Proc. Int. Congr. Pestic.
Chem. 5th 1983, 1, 339–344; b) Topics in Current Chemistry, Vol. 114:
Steric Effects in Drug Design (Eds.: M. Charton, I. Motoc), Springer,
Berlin–Heidelberg, 1983.
[23] P. Krogsgaard-Larsen, T. Liljefors, U. Madsen, Textbook of Drug Design
and Discovery, 3rd ed., Taylor & Francis, London, 2002.
[24] A. R. Raza, A. Saddiqa, M. N. Tahir, S. Saddiq, Acta Crystallogr. Sect. A
Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, o2435.
[25] Medicinal Chemistry, Vol. 11: Drug Design, Vol. 7: (Ed.: E. J. Ariens), Medici-
nal Chemistry Acadmeic Press, New York, 1976.
[1] a) A. E. Hargrove, S. Nieto, T. Zhang, J. L. Sessler, E. V. Anslyn, Chem. Rev.
2011, 111, 6603–6782; b) C. Tudisco, P. Betti, A. Motta, R. Pinalli, L. Bom-
baci, E. Dalcanale, G. G. Condorelli, Langmuir 2012, 28, 1782–1789;
c) M. R. Sambrook, J. R. Hiscock, A. Cook, A. C. Green, I. Holden, J. C. Vin-
cent, P. A. Gale, Chem. Commun. 2012, 48, 5605–5607; d) C. Montoro, F.
Linares, E. Quartapelle Procopio, I. Senkovska, S. Kaskel, S. Galli, N. Mas-
ciocchi, E. Barea, J. A. R. Navarro, J. Am. Chem. Soc. 2011, 133, 11888–
11891; e) C. Van Hooidonk, J. C. A. E. Breebaart-Hansen, Recl. Trav. Chim.
Pays-Bas 1970, 89, 289–299; f) B. Desire, S. Saint-Andre, Fundam. Appl.
Toxicol. 1986, 7, 646–657; g) R. Le Provost, T. Wille, L. Louise, N. Masuri-
er, S. Mueller, G. Reiter, P.-Y. Renard, O. Lafont, F. Worek, F. Estour, Org.
Biomol. Chem. 2011, 9, 3026–3032; h) M. Zengerle, F. Brandhuber, C.
Schneider, F. Worek, G. Reiter, S. Kubik, Beilstein J. Org. Chem. 2011, 7,
1543–1554; i) N. A. Esipenko, P. Koutnik, T. Minami, L. Mosca, V. M.
Lynch, G. V. Zyryanov, P. Anzenbacher Jr., Chem. Sci. 2013, 4, 3617–
3623.
[2] K. Kim, O. G. Tsay, D. A. Atwood, D. G. Churchill, Chem. Rev. 2011, 111,
5345–5403.
[3] D. Elie, Nat. Med. 2013, 19, 1194–1195.
[26] a) C. Moberg, Angew. Chem. 1998, 110, 260–281; Angew. Chem. Int. Ed.
1998, 37, 248–268; b) C. Moberg, Angew. Chem. 2006, 118, 4838–4840;
Angew. Chem. Int. Ed. 2006, 45, 4721–4723.
[4] a) S. S. Talmage, A. P. Watson, V. Hauschild, N. B. Munro, J. King, Curr.
Org. Chem. 2007, 11, 285–298; b) Y. C. Yang, J. A. Baker, J. R. Ward,
Chem. Rev. 1992, 92, 1729–1743.
[5] S. Chauhan, S. Chauhan, R. D’Cruz, S. Faruqi, K. K. Singh, S. Varma, M.
Singh, V. Karthik, Environ. Toxicol. Pharmacol. 2008, 26, 113–122.
[6] a) Z. Radic, T. Dale, Z. Kovarik, S. Berend, E. Garcia, L. Zhang, G. Amitai,
C. Green, B. Radic, B. M. Duggan, D. Ajami, J. Rebek, P. Taylor, Biochem.
Received: December 5, 2013
Published online on March 11, 2014
Chem. Eur. J. 2014, 20, 4251 – 4256
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4256
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