A small-molecule guanidinium receptor: The arginine cork

Article abstract of DOI:10.1002/(SICI)1521-3773(19990903)38:17<2543::AID-ANIE2543>3.0.CO;2-9

A highly preorganized, artificial receptor for guanidinium cations binds arginine with high affinity in polar solvents, even in water! The X-ray crystal structure of its bis(N-ethylguanidinium) complex shows the formation of hydrogen bonds between the rec

Full text of DOI:10.1002/(SICI)1521-3773(19990903)38:17<2543::AID-ANIE2543>3.0.CO;2-9

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F. Eiden, Pharm. Unserer Zeit 1998, 257, in particular Figure 28 on
p. 269.
[11] Structure 9 appears in electronic data bases: Beilstein Command-
er 4.0, search March 1999.
tors capable of binding the N-alkylguanidinium moiety of
arginine could be used in numerous ways, such as antiviral
drugs and molecular probes for arginine-rich proteins. Re-
ported herein is a designed, small-molecule receptor that
binds N-alkylguanidinium cations. Binding selectivity for
arginine, relative to lysine, is observed in water and methanol
solvents. The solid-state structure of its complex with two N-
alkylguanidinium cations suggests that it should have a special
affinity for the dipeptide ArgArg, and this prediction has been
confirmed by microcalorimetric titration in water.
[12] Cossy and her co-workers have reported the ring enlargement of an
l-proline derivative in the synthesis of
( )-pseudoconhydrine
(Scheme 6):
The amino acid arginine is a critical component of many
RNA-binding proteins that mediate a wide range of biological
processes.[1, 2] While the ªbasic-domainº class of RNA-binding
proteins contain arginine-rich sequences of 10 ± 15 amino
acids, highly conserved arginine residues often make specific
electrostatic contacts with phosphate groups in the polyribo-
nucleotide backbone. Two examples of such proteins that
regulate important steps in the replication of the human
immunodeficiency virus type I (HIV-1) are the transcriptional
activator Tat[1±4] and the Rev protein.[1, 2, 5] The recently
determined structure of the HIV-1 nucleocapsid protein
bound to the genomic Y-RNA recognition element[6] displays
a specific arginine ± base interaction (Arg32 A8). RNA
recognition processes have become important targets for the
development of antiviral and antibiotic drugs.[7, 8] Small
molecules tailored to bind specifically to arginine residues
could lead to novel pharmaceuticals, as well as molecular
probes that could facilitate the characterization of RNA-
binding proteins.
There have been a few reports of artificial receptors that
bind arginine or arginine derivatives,[9±11] but what is the best
design for the recognition of the arginine side chain in
peptides? To be useful for biological applications, such a
receptor must be reasonably soluble in water, it must have
high affinity for the N-alkylguanidinium moiety, and it must
display selectivity relative to other cations, particularly versus
the N-alkylammonium side chain of lysine. We can recognize
arginine by means of a hydrogen-bond array that either
imitates one of the natural patterns or seeks to improve on
nature by de novo design. By following the former biomimetic
route Schrader[11] synthesized ªmolecular tweezersº contain-
ing two phosphonate groups capable of binding guanidinium
cations by four hydrogen bonds (Figure 1a). The structure of
the resulting complex resembles that of the critical arginine
residue of Tat (Arg52) bound to phosphodiesters P22 and P23
of HIV-1 TAR RNA, a feature dubbed the ªarginine forkº
(Figure 1b) by Frankel et al.[3] Despite the presence of
electrostatic interactions between the guanidinium cation
and two anionic phosphonate groups of molecular tweezer 2,
only modest binding was observed, even in methanol (Kd ꢀ
2 mm). This can be attributed to incomplete preorganization
of the hydrogen-bond acceptor sites in 2.
Scheme 6. Top: inside-flap attack, bottom: SN2-type attack; a)
(CF3CO)2O, then Et3N; b) NaOH.
J. Cossy, C. Dumas, D. G. Pardo, Synlett 1997, 905; further recent
examples: J. Wilken, M. Kossenjans, W. Saak, D. Haase, S. Pohl, J.
Martens, Liebigs Ann. 1997, 573 and references therein.
[13] Bicyclic systems with strained bridgehead imine double bonds (E and
Z isomers) have been obtained in a matrix in the dark at low
temperature: a) R. S. Sheridan, G. A. Ganzer, J. Am. Chem. Soc. 1983,
105, 6158; b) J. G. Radziszewski, J. W. Downing, C. Wentrup, P.
Kaszynski, M. Jawdosiuk, P. Kovacic, J. Michl, J. Am. Chem. Soc. 1985,
107, 2799.
[14] J. I. Seeman, Chem. Rev. 1983, 83, 83.
[15] P. Rabe, Chem. Ber. 1908, 41, 62.
[16] Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge
Crystallographic Data centre as supplementary publication nos.
CCDC-115800 (7), -115801 (8), and 115802 (2c). Copies of the data
can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (‡44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
A Small-Molecule Guanidinium Receptor:
The Arginine Cork**
Thomas W. Bell,* Alisher B. Khasanov,
Michael G. B. Drew, Anton Filikov, and
Thomas L. James
Individual arginine residues are critical to the function of
many nucleotide-binding proteins.[1, 2] Small-molecule recep-
[*] Prof. Dr. T. W. Bell, A. B. Khasanov
Department of Chemistry, University of Nevada
Reno, NV 89557-0020 (USA)
Fax: (‡1)775-784-6804
E-mail: twb@unr.edu
Dr. M. G. B. Drew
Department of Chemistry
University of Reading (UK)
Dr. A. Filikov, Prof. Dr. T. L. James
Department of Pharmaceutical Chemistry
University of California, San Francisco (USA)
Most receptors designed for the guanidinium cation are
flexible crown ether derivatives.[9, 12±16] Our approach to
recognition of small, planar molecules is to construct a
relatively rigid, planar array of hydrogen-bonding groups by
fusing together a series of six-membered rings.[17±23] Nearly
perfect host ± guest complementarity results from registry
between the N N and N O hydrogen bond distances and the
[**] We thank the State of Nevada for funding the synthetic chemistry and
spectroscopic studies at UNR, the North Atlantic Treaty Organization
for a travel grant to T.W.B. and M.G.B.D., as well as the E.P.S.R.C.
(UK) and the University of Reading for funding the Image Plate
system used for X-ray crystallography.
Supporting Information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the author.
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Scheme 1. Synthesis of the target arginine receptor as the dipotassium salt
(13). Conditions: a) H2 (1 atm), 10% Pd/C, CF3CO2H, 208C; b) benzalde-
hyde, Ac2O, 150 ± 1608C; c) 1) O3/O2, CH2Cl2/CH3OH, 778C; 2) Me2S,
CH2Cl2/CH3OH,
77 !208C; d) CrO3/H2SO4, (CH3)2CO, 208C; e) 4-
Figure 1. Postulated structures of guanidinium complexes. a) Complexes
between N-methylguanidinium and ªmolecular tweezersº;[11] b) the ªargi-
nine forkº of the complex formed between the HIV-1 Tat and TAR;[3, 4]
c) the target arginine receptor in the dicarboxylic acid (3) and dianion (4)
forms, and complex of an N-alkylguanidinium guest (5).
amino-5-pyrimidinecarbaldehyde,[26] KOH, CH3OH, reflux; f) HCl, H2O,
reflux; g) 10, KOH, EtOH, reflux; h) ethylguanidinium sulfate, H2O,
reflux. See Supporting Information for microanalytical and spectroscopic
details on 13.
host hexagonal lattice distance (determined by C N and C C
covalent bonds), which bear an approximate 2:1 relationship.
Previously reported hexagonal lattice receptors, including a
guanidinium-binding torand,[19] are neutral molecules with
hydrophobic n-alkyl side chains. Such compounds are useful
as extractants and membrane transport agents,[17, 18] but their
poor water solubilities limit homogeneous binding studies to
organic solvents. The dicarboxylic acid 3, which lacks alkyl
side chains, was expected to be soluble in water, particularly in
the dianionic form 4 (Figure 1c). The nitrogen and oxygen
hydrogen-bond acceptor sites in 4 are preorganized for
binding N-alkylguanidinium cations to form complex 5.
Electronic interactions (conjugation) between the carboxy-
late groups and the neighboring pyridine rings should stabilize
the coplanar conformation. Rotation about the pyridine ±
carboxylate bond is expected, but identical structures are
produced as a result of the symmetry of the carboxylate group.
The combination of receptor preorganization and attractive
electrostatic interactions between the dianionic host and
cationic guest led to our hypothesis that complexes of type 5
would be stable, even in aqueous media.
veniently purified by vacuum distillation. Ozonolysis[25] of 8
gave ketoaldehyde 9, which underwent Jones oxidation to
ketoacid 10. Friedländer condensation of 10 with 4-amino-
pyrimidine-5-carbaldehyde[26] gave 11, which was hydrolyzed
to the aminoaldehyde 12. A second condensation of 10 with 12
gave receptor 13, which was purified by recrystallization and
obtained in 18% overall yield from quinaldine. The molecular
symmetry of 13 results from the use of the same ketone (10) in
both Friedländer condensations (steps e and g), but two
different ketones could be used to make unsymmetrical
molecules of type 13 bearing functional groups other than
carboxylate. This route could also be used for the preparation
of arginine receptors that are substituted to allow immobili-
zation, attachment of other recognition sites, or conjugation
to biomolecules.
As anticipated, dipotassium salt 13 has a relatively high
solubility in water (about 0.3m). It is slightly soluble in
methanol and insoluble in dimethyl sulfoxide (DMSO),
dichloromethane, and chloroform. The corresponding car-
boxylic acid (3) has very low water solubility (about 4 mm), but
it is moderately soluble in DMSO. The ability of 13 to bind N-
alkylguanidines was tested by mixing an aqueous solution
with a dilute solution of ethylguanidinium sulfate in water,
which resulted in the formation of a yellow precipitate.
Crystals of this complex formed when a hot aqueous solution
was cooled to room temperature but crumbled upon drying
under vacuum or in air. According to results of combustion
microanalysis and 1H NMR spectroscopy dried samples of the
The target arginine receptor was synthesized in seven steps
as the dipotassium salt 13 (Scheme 1). The benzene ring of
quinaldine (6) was selectively reduced by catalytic hydro-
genation with palladium-on-carbon in trifluoroacetic acid, by
using a modification of the procedure of Vierhapper and
Eliel.[24] Condensation of 7 with benzaldehyde in acetic
anhydride gave dibenzylidene derivative 8, which was con-
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complex consisted of the receptor dianion (4) and N-ethyl-
guanidinium cation in exactly a 1:2 ratio. This stoichiometry is
expected for a simple salt of a dicarboxylic acid with a base,
but the predicted binding motif (5, Figure 1c) was proven by
X-ray crystallographic analysis[27] of a single crystal of
Receptor 13 and its complexes apparently aggregate in water
through hydrophobic interactions between nonpolar regions
of the molecule that are remote from the charged carboxylate
groups. The UV/Vis absorption spectra of aqueous solutions
of 13 follow Beerꢁs Law over the concentration range of 1 ±
100 mm, which suggests the absence of aggregation at low
concentration. In order to understand the ionization states of
13 in water we performed a series of pH titrations and
followed changes in the UV/Vis spectrum (Figure 3). Addi-
tion of HCl to aqueous solutions of 13 caused a bathochromic
shift of the p-p* band (lmax ˆ 384 nm) and a loss of fine
structure (Figure 3b). As previously observed for pyridine-2-
carboxylic acid,[28] initial protonation apparently occurs main-
ly on the nitrogen atom to form a monoanion with a half-
zwitterionic structure (see Figure 3a). The second protona-
tion gives a neutral molecule, probably consisting of three
forms that are in rapid equilibrium. A plot of the absorbance
at 414 nm versus pH gave a titration curve that was modeled
graphically (see Supporting Information) to give the equili-
brium values pKa1 ˆ 4.7 and pKa2 ˆ 6.0. These first and
second ionization constants are lower and higher, respective-
ly, than that of pyridine-2-carboxylic acid (pKa ˆ 5.2),[28]
which indicates that the two protonation sites interact
significantly.
‡
hydrated complex [4 ´ 2EtNHC(NH2)2 ].
In the solid-state structure of the complex (Figure 2) one of
the two N-ethylguanidinium cations resides in the receptor
cleft, as expected. The second cation binds externally to one of
‡
Figure 2. The crystal structure of [4 ´ 2EtNHC(NH2)2
] showing the
The UV/Vis absorption spectrum of receptor 13 in water or
methanol is not significantly affected by complexation of
guanidinium cations, so the binding of various guests was
evaluated by 1H NMR spectroscopy and microcalorimetry. As
mentioned previously, receptor 13 aggregates in water at
concentrations needed for NMR spectroscopy, so methanol
receptor molecule and the two N-ethylguanidinium cations. Also shown
are three water molecules that act as hydrogen bond acceptors for three
N H donors of the cations. The fourth water molecule (not shown) is
hydrogen bonded only to other water molecules. Hydrogen bonds are
shown as dotted lines. a) Conformation of the complex in the crystal;
b) diagram representing the idealized structure of the complex.
1
was chosen as the solvent for NMR titrations. The H NMR
signals of the hydrogen atoms at positions 7 and 8 (see
Figure 2b) shift downfield upon complexation of cationic
guests in CD3OD. A sample binding isotherm is shown in
Figure 3c for the complexation of the amino acid (‡)-l-lysine,
which bears a primary ammonium group on its side chain. The
experimental data points best fit the theoretical curve
calculated from a dissociation constant (Kd) of 34 mm (see
Supporting Information). Similar titrations with methylgua-
nidinium chloride or arginine gave Kd values for the 1:1
complexes that were too large to be measured accurately by
this experimental method. As shown in Table 1 lower limits of
10 mm were estimated for the Kd values of these guests. Thus,
receptor 13 binds guanidinium cations in methanol at least
three times more strongly than a primary ammonium guest,
and 13 binds the methylguanidinium cation at least 200 times
more strongly than does molecular tweezer 2.[11] Also shown
in Table 1 are the corresponding Kd values in water as
measured by microcalorimetry (see Supporting Information).
Again, the two molecules bearing guanidinium groups
(methylguanidinium and Arg) are bound by 13 more strongly
than lysine, which has a primary ammonium group. Dipep-
tides bearing two positive charges (ArgArgNH2, ArgArgOH,
and LysLysOH), are all bound more strongly than the
monocations (methylguanidinium, Arg, and Lys). Thus, the
primary interaction between cationic guests and the dianionic
receptor is electrostatic, but molecular recognition based on
hydrogen-bond complementarity distinguishes between
guests of the same charge. As expected from the solid-state
the two carboxylate groups. The receptor is not completely
planar, but is folded to form a structure with approximate
mirror symmetry (Figure 2a). Figure 2b is an idealized
version of the structure showing the positions of the two N-
ethylguanidinium cations and the pattern of hydrogen bonds.
The hydrogen-bonded N O distances (2.83, 2.87 Š), and
N N distances (3.00 ± 3.06 Š) are relatively small, as expected
for strong hydrogen bonds. The six heteroatoms of the
receptor (O(18), N(1), N(16), N(15), N(14), and O(21))
deviate only slightly from a plane (rms 0.14 Š), which
intersects the plane of the cleft-bound N-ethylguanidinium
ion (atoms N(33), C(34), N(35), and N(36)) at an angle of 6.78.
This good fit is aided by a twisting of the carboxylate groups;
thus the N(14)-C-C-O(21) and N(1)-C-C-O(18) torsion angles
are 26.5 and 11.88, respectively. It is particularly important to
note that the ethyl fragments of the two guests are in close
proximity, which suggests that receptor 13 might form strong
complexes with the dipeptide diarginine and might recognize
ArgArg sequences in proteins.
The ability of receptor 13 to bind guanidinium guests in
1
water was examined by several methods, including H NMR
and UV/Vis spectroscopy, as well as microcalorimetry. The
signals of 13 in D2O solutions are significantly shifted in the
1H NMR spectrum upon addition of guanidinium or N-
ethylguanidinium sulfate. In the absence of guanidinium
1
guests the H NMR chemical shifts of 13 are also concen-
tration-dependent in the range of 0.1 mm to 0.1m, which
complicates the calculation of the dissociation constants.
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Figure 3. Acid ± base and host ± guest titrations of the arginine receptor. a) Ionization states and tautomeric forms, color-coded to pH titration (Figure 3b):
magenta: neutral forms of dicarboxylic acid 3, including zwitterionic tautomers; green: monoanionic forms, including half-zwitterionic tautomer; blue:
dianionic form; b) UV/Vis absorption spectra of an aqueous solution of 13 (38.8 mm) during titration with aqueous HCl, color-coded to Figure 3a; c) plot of
1H NMR chemical shifts of hydrogen atoms 7 and 8 of the bis(tetramethylammonium) salt of receptor 13 (see Figure 2b) as a function of lysine concentration
in CD3OD (receptor concentration: 80 mm). The solid line is the best-fit curve calculated from Kd ˆ 34 mm. See Supporting Information for experimental
details.
complex of this latter host with an arginine-containing
dipeptide has a comparable binding energy (5.8 kcalmol )
Table 1. Thermodynamic data for 1:1 complexes of receptor 13 as
determined by 1H NMR spectroscopic and microcalorimetric titration
methods.[a]
1
to that of the ArgArg complex of 13, which exhibits high
selectivity for ArgArg relative to LysLys. This ªarginine corkº
may eventually lead to novel chemotherapeutic approaches,
as mentioned previously, and it may also prove useful as a
molecular probe for arginine residues. Its magnetically
anisotropic aromatic rings could make it useful as an NMR
probe, and by binding to arginine side chains 13 might be used
to aid crystallization of ªbasic regionº proteins. Both effects
could assist the structural characterization of numerous,
biologically important peptides and proteins.
1
Guest
Kd [mm]
(CD3OD)
Kd [mm]
(H2O)
DH8 [kcalmol
(H2O)
]
methylguanidinium
arginine (Arg)
lysine (Lys)
ArgArgNH2
ArgArgOH
ꢁ 10
4300 Æ 400
1100 Æ 100
7000 Æ 2000
60 Æ 6
‡ 1.3 Æ 0.3
‡ 0.49 Æ 0.05
0.14 Æ 0.02
5.6 Æ 0.6
ꢁ 10
34 Æ 3
50 Æ 20
2.1 Æ 0.2
LysLysOH
250 Æ 30
1.5 Æ 0.2
[a] Kd ˆ dissociation constant; DH8 ˆ enthalpy. Values were determined
by 1H NMR titration (CD3OD) and microcalorimetry (H2O). See
Supporting Information for experimental details.
Received: October 7, 1998
Revised version: May 5, 1999 [Z12502IE]
German version: Angew. Chem. 1999, 111, 2705 ± 2709
structure of the 2:1 complex of N-ethylguanidinium with 13
(see Figure 2), the best dipeptide guest is diarginine, which is
bound with remarkably high affinity in water.
Keywords: amino acids
´ hydrogen bonds ´ molecular
recognition ´ peptides ´ supramolecular chemistry
Receptor 13 binds arginine in water at least four times more
strongly than does a previously reported water-soluble crown
ether.[9] The aqueous binding energy of 13 ´ Arg
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1
1
(4.0 kcalmol ) is about 1 kcalmol less than that of the
Arg NH2 complex of a recently reported cyclophane host
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salt bridge and cation p interactions.[29] The most stable
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The arrangement of special functional units with nanometer
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geometry was described (Figure 1a ).[4, 5] These complexes
were found to present interesting electronic, magnetic, and
structural properties, such as electronic interactions between
the metal centers and an antiferromagnetic transition at low
temperatures[5, 6] (Figure 1b). They are formed by the sponta-
neous self-assembly of 4,6-bis(2',2''-bipyridyl-6-yl)pyrimidine
ligands[4] (or its functionalized derivatives[7]) and suitable
metal ions such as CoII (Figure 1a).[5]
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‡
Besides the design and synthesis of ªisolatedº grid units, the
ordered and stable arrangement of such metallo-supramolec-
ular architectures on surfaces or in thin films is of special
[27] Crystal data for [4 ´ 2EtNHC(NH2)2 ]: C30H42N10O8, Mr ˆ 670.74,
Å
triclinic, space group P1, a ˆ 10.974(11), b ˆ 11.412(10), c ˆ
14.128(15) Š, a ˆ 70.56(1), b ˆ 79.36(1), g ˆ 88.51(1)8, U ˆ 1639 Š3,
Z ˆ 2, 1 ˆ 1.359 Mgm 3, F(000) ˆ 712. A total of 5828 independent
reflections was measured on a Marresearch Image Plate by using
MoKa radiation. Distances are O(18) N(36) 2.829(6), O(18) O(54)
2.710(7), O(21) N(35) 2.871(5), O(21) N(45) 2.912(5), O(22) N(46)
2.848(6), N(33) O(54) 3.037(7), N(43) O(52) 2.886(7), N(46) O(51)
2.890(7), O(51) O(52) 3.167(10), N(35) N(15) 3.060(5), N(36) N(16)
2.999(4) Š. Individual host and guest moieties are connected by
intermolecular hydrogen bonds between O(19) and N(45) (symmetry
element 1 x, y, 2 z), distance 2.936(6) Š, to form a helix. Other
hydrogen bonds involving water molecules are also present in the unit
[*] Prof. Dr. M. Möller, Dr. A. Semenov, Dr. J. P. Spatz
Organische Chemie III/Makromolekulare Chemie der Universität
D-89081 Ulm (Germany)
Fax: (‡49)731-502-2883
E-mail: martin.moeller@chemie.uni-ulm.de
Prof. Dr. J.-M. Lehn
Â
Laboratoire de Chimie Supramoleculaire, ISIS
Â
Universite Louis Pasteur
cell (O(18) ´´´ O(52) (2 x, y,
2
z) 2.882(8), O(19) ´´´ O(53)
4 Rue Blaise Pascal, F-67000 Strasbourg (France)
Fax: (‡33)388411020
(x,y,1 ‡ z) 2.753(6), O(19) ´´´ O(51) (x 1, y ‡ 1, z) 2.936(7), O(21)
´´´ O(53) (1 x, y, 1 z) 2.817(6) Š), as are water± water hydrogen
bonds. Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tion no. CCDC-103868. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge
CB21EZ, UK (fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.
ac.uk).
E-mail: lehn@chimie.u-strasbg.fr
Prof. Dr. D. Schubert, B. Sell
Institut für Biophysik der Universität
Theodor-Stern-Kai 7, Haus 74
D-60590 Frankfurt am Main (Germany)
Fax: (‡49)69-6301-5838
E-mail: schubert@biophysik.uni-frankfurt.de
Dr. U. S. Schubert, C. H. Weidl
[28] H. P. Stephenson, H. Sponer, J. Am. Chem. Soc. 1957, 79, 2050 ± 2056.
[29] S. M. Ngola, P. C. Kearney, S. Mecozzi, K. Russell, D. A. Dougherty, J.
Am. Chem. Soc. 1999, 121, 1192 ± 1201.
Lehrstuhl für Makromolekulare Stoffe
der Technischen Universität München
Lichtenbergstrasse 4, D-85747 Garching (Germany)
Fax: (‡49)89-289-13562
E-mail: ulrich.schubert@ch.tum.de
[**] We thank the Deutsche Forschungsgemeinschaft (DFG), the Bayer-
isches Staatsministerium für Unterricht, Kultus, Wissenschaft und
Kunst, and the Stiftung Stipendien-Fonds des Verbandes der Chem-
ischen Industrie e.V. for financial support.
Angew. Chem. Int. Ed. 1999, 38, No. 17
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
1433-7851/99/3817-2547 $ 17.50+.50/0
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