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Dynamic Combinatorial Chemistry The Unexpected Choice of Receptors by Guest Molecules.

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Highlights
DOI: 10.1002/anie.200504480
Receptor Libraries
Dynamic Combinatorial Chemistry: The Unexpected
Choice of Receptors by Guest Molecules
Bas de Bruin, Peter Hauwert, and Joost N. H. Reek*
Keywords:
dynamic combinatorial chemistry · molecular
recognition · receptors · supramolecular chemistry
Although our knowledge in the broad
field of chemistry has increased enormously over the past decades, we are
still unable to give precise predictions
on the behavior of molecules in solution.
Therefore, combinatorial approaches
and high-throughput experimentation
have become increasingly important by
facilitating the rapid discovery of lead
compounds and the optimization of
processes in which trial-and-error is the
dominant approach. In the mid-1990s, a
fundamentally new concept in this area,
dynamic
combinatorial
chemistry
(DCC), was introduced by the groups
of Sanders,[1] Lehn,[2] and others.[3, 4]
Whereas traditional combinatorial libraries are based on the preparation of
kinetically stable compounds and subsequent screening for their function, this
new concept takes advantage of reversible bonds, covalent or noncovalent, by
generating a random (virtual) library
whose members are in dynamic equilibrium.
The formation of the library is under
thermodynamic control, which gives rise
to new properties such as adaptation;
that is, the library readjusts its distribution by external stimuli. Upon addition
of a target molecule, the mixture of
potential receptors in the library reequilibrates in favor of the best receptor(s) for the target. By using this
strategy the preparation and screening
[*] Dr. B. de Bruin, P. Hauwert,
Prof. Dr. J. N. H. Reek
Van’t Hoff Institute for Molecular Sciences
University of Amsterdam
Nieuwe Achtergracht 129
1018 WS Amsterdam (The Netherlands)
Fax: (+ 31) 20 525-6437
E-mail: reek@science.uva.nl
2660
of the receptor for a certain target is
integrated in one step,[4d] as the receptor
is chosen by the target. Libraries of
receptors of variable complexity have
been constructed, with the simplest
comprised of a mixture of macrocycles
of variable sizes based on identical
building blocks (type A; Figure 1 a).
target. In these complex systems, in
which receptors are in dynamic equilibrium, the energetically most favorable
situation of the entire system determines the outcome of an amplification
experiment. In situations where the
concentration of the receptor depends
on the composition of the library, the
best receptor is not likely
to be amplified at the
expense of a lower total
concentration of receptor.
This problem does not
arise for conventional, kinetically stable receptors
because the composition
of the receptor remains
the same during the entire
experiment. The amplifiFigure 1. A dynamic combinatorial library (DCL) consisting of
cation of a receptor from
macrocycles of variable sizes based on identical building
a DCL can only happen
blocks (type A), and a DCL of similar-sized macrocycles based
on different building blocks (type B).
because the receptors
compete simultaneously
for both the building
More complex systems are composed blocks that they are built from and the
of a mixture of different building blocks, target guest. As different receptors are
thus forming receptors based on homo- commonly built from the same building
and heteroaggregates (type B; Fig- blocks, an increase in the concentration
ure 1 b). These approaches have been of certain receptors causes a decrease in
successfully applied to obtain a variety the concentration of others (Figure 1).
Importantly, a shift in the equilibriof receptors to bind different classes of
guests, such as Li+ and ammonium ions, um as a result of binding the guest leads
in some scenarios to a decrease in the
and even a neurotransmitter.[5–7]
The elegance and power of the total concentration of relevant recepconcept of amplification (and thus iden- tors. For example, amplification of the
tification) of the best receptor was an larger macrocycles of type A (An) leads
issue of recent debate. Computer simu- to a decrease in the number of the
lations[8] and thermodynamic/statistical smaller ones and, thus, reduces the total
analysis, supported by experimental da- concentration of receptors available for
ta,[8a, 9] on dynamic combinatorial libra- guest binding. A comparable situation
ries (DCLs) of the types shown in can occur for the type B receptors
Figure 1 indicated that certainly not in (Figure 1) if significant binding of the
all situations does the best receptor need target guest requires the presence of a
to be amplified by the addition of the specific building block (e.g. building
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 2660 – 2663
Angewandte
Chemie
Table 1: Free-energy “economics” in the relative concentrations (crel) of library members of type B
(Figure 1) as a function of the relative binding affinities (Krel) of targets.
Entry
1
2
3
Krel
crel [%]
DDG0 [kcal mol1]
Krel
crel [%]
DDG0 [kcal mol1]
Krel
crel [%]
DDG0 [kcal mol1]
AAA
AAB
BBA
BBB
BBC
BCC
CCC
AAC
ACC
ABC
1
3.7
0
1000
28.1
4.1
900
0.1
4.0
1
11.1
0
1
0.5
0
600
2.1
3.8
1
11.1
0
1
3.4
0
300
22.8
3.4
1
3.7
0
1
7.2
0
1
0.5
0
1
11.1
0
1
21.5
0
1
1.6
0
1
11.1
0
1
21.5
0
1
1.6
0
1
3.7
0
1
7.2
0
1
0.5
0
1
11.1
0
1
0.5
0
600
2.1
3.8
1
11.1
0
1
3.4
0
300
22.8
3.4
1
22.2
0
1
6.8
0
300
45.7
3.4
block A, as shown in entry 3 of Table 1).
Amplification of the homoreceptors
entirely built from this building block
(A-A-A) occurs at the expense of the
heteroreceptors that contain this building block (e.g. A-A-B, A-B-C, etc.) and
thus leads to a decrease in the total
concentration of receptors that make a
significant contribution to the total free
energy of the entire system. This phenomenon can easily lead to amplification of the weaker binding receptors at
the cost of the better receptors, because
the total free energy gained by guest
binding by a few strong receptors can be
less beneficial than a multitude of somewhat weaker interactions (see Table 1,
entry 3). This effect is especially important when the relative free energies
(DG0 = R T lnK) associated with binding of the target are of the same order of
magnitude[8–10] and when the concentration of the target is relatively high.[9b, 10]
To explain this phenomenon, the
selection procedure in a DCC can be
compared to the economic trade situation of retailers with respect to their
customers. If sufficient customers
(guests) are available, the most profit-
able situation is reached when as many
shops (receptors) as possible are available to satisfy (bind) as many customers
(guests) as possible, even though the
profit per shop (binding energy per
receptor) is not as high for all shops as
that for the most profitable one. A
turning point is reached at lower demands, and below a critical value the
situation is reversed and a higher profit
(binding energy) per shop (receptor)
becomes most important. Therefore, the
target-induced amplification in a DCL
depends on the relative concentration of
the guest. This behavior was first simulated by Severin and co-workers[8] and
was recently experimentally confirmed
by Otto, Sanders, and co-workers, as
well as by Saur and Severin.[9] Indeed, at
high concentrations of guest competition among receptors that are based on
the same building blocks dominates the
selection procedure, whereas at low
concentrations of guest the receptor
with the largest affinity is selected by
the guest according to the best fit (most
profit) principle. A recent theoretical
analysis by Otto, Sanders, and co-workers[10] revealed that also in very large
DCLs, which consist of many potential
receptors, moderately good hosts that
are already present in relatively high
concentrations in the absence of the
guest are likely to be amplified further
upon addition of an excess of the guest.
On the basis of these findings, the
groups of Sanders and Severin have
reported a general strategy to select
the best receptor from a DCL: 1) It is
recommended to use conditions under
which the building blocks (not the
assemblies) are the dominant species in
solution. 2) A DCL should be designed
such that all receptors contain a common building block, which should be
present in substoichiometric amounts
with respect to the other subunits. 3) A
relatively low concentration of the target should be used during the amplification experiment (a 1:10 ratio with
respect to the total concentration of
building blocks is used as a rule of
thumb, taking the detection limitations
into account).
These results show that the field of
DCL is more complex than previously
anticipated and amplification of the best
receptor is not always obvious. On the
other hand, one might argue that problems occur only when the differences
between the receptors are small. The
value of the DCC approach has been
recently demonstrated by some interesting examples that reveal receptors with
exceptionally strong affinities for the
target. A common feature of these
examples is that the hosts have unexpected structures, and it is very unlikely
that these receptors would have been
discovered by more traditional design
and synthesis strategies.[11, 7] For example, the DCL depicted in Figure 2 is
Figure 2. Unexpected amplification of a catenane receptor from a DCL of cyclic peptides by the addition of the neurotransmitter acetylcholine.[7]
TFA = trifluoroacetic acid; DMSO = dimethyl sulfoxide.
Angew. Chem. Int. Ed. 2006, 45, 2660 – 2663
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2661
Highlights
based on the reversible formation of a
hydrazone from the hydrazide and a
latent aldehyde (acetal functionality) of
the peptide building block pPFm (1),
which is a pseudopeptide based on proline and phenylalanine residues. The
library consists of mostly cyclic oligomers 2–5 (2–4 dominate). Most remarkably, addition of the neurotransmitter
acetylcholine (6) causes a gradual increase in catenane 7, which comprises
two interlocked three-membered rings 3
and is not detected in the absence of the
target. Acetylcholine binds to a single
diastereoisomer of 7 in one specific
conformation from the many possibilities, with an exceptionally high binding
constant (1.4 = 107 m 1). The affinity of
the trimer 3 and tetramer 4 for acetylcholine proved to be much weaker (1.5 =
103 and 5.7 = 103 m 1, respectively).
These results are remarkable because,
first, the amplification of a catenane is
highly unexpected. From rational design
one would never have predicted that
two interlocked rings would form the
most suitable binding motif for the
neurotransmitter, as there are no other
catenane structures known that strongly
bind cations.[12] Second, the DCC method proves useful as a synthetic method
to prepare a catenane receptor that
would have been most difficult to prepare without the template.[13]
A second remarkable example was
recently reported in which tetramethylACHTUNGREammonium salts were used as target
guests during the amplification process
(Figure 3). The initial DCL consisted of
macrocycles based on 8 and a smaller
disulfide formed by reversible SS bond
formation, and surprisingly the large
macrocycle 11 was discovered as a good
receptor. On the basis of size match–
mismatch arguments, one would expect
NMeþ4 to bind much less strongly to the
macrocyle meso-11 than to the macrocyles rac-9 and rac-10 (Figure 3). Detailed studies revealed that meso-11 is
by far the best host in the mixture
(reported binding constants of 4 =
106 m 1 and 8 = 102 m 1 for meso-11 and
rac-9, respectively). This unexpected
result, which is unlikely to have been
discovered by traditional strategies, was
explained by the induced-fit character of
the host; meso-11 encapsulates the
NMeþ4 ion by folding completely around
it (Figure 4).[11]
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Figure 3. Unexpected amplification of a large, size-mismatched cyclic host from a DCL by the
addition of NMeþ4 .[11]
Although “selection of the fittest”
from a DCL does not necessarily always
provide the “fittest”, the importance of
dynamic combinatorial chemistry is
clearer than ever before. DCLs are
theoretically well understood now and
it is clear that they behave as complex
systems. Examples of amplification of
unexpected receptors with high target
affinities superbly demonstrate the
proof of principle. The next challenge
is to apply the DCC approach to existing
problems that are hard to solve by
traditional strategies. In addition, the
application of DCC in new research
areas should be explored. In this regard,
supramolecular catalysis in which the
catalytic activity is based on the complexation of the transition state seems a
particularly promising area. An example
of the successful application of DCC in
catalysis has already been reported.[6b] A
DCL that is similar to the one depicted
in Figure 3 was used to select a supramolecular catalyst for a Diels–Alder
reaction by the addition of a transitionstate analogue (in this case the product).
The host that was amplified indeed
accelerated (although moderately) the
envisioned Diels–Alder reaction. The
relevance of DCC in, for example,
transition-metal catalysis is still open to
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Figure 4. CPK models of the complex formed
from meso-11 and NMeþ4 in a) extended and
b) folded conformations. The host binds the
guest through an induced-fit mechanism. Reprinted with permission from Reference [11]
investigation. However, in general, unexpected results, new synthetic methods,
and new applications are likely to result
from future studies.
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[12] a) For two examples of catenane receptors for anions, see: A. Andrievsky, F.
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2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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