A Synthetic Galectin Mimic

Article abstract of DOI:10.1002/anie.202104924

Galectins are a galactoside specific subclass of carbohydrate binding proteins (lectins) involved in various cellular activities, certain cancers, infections, inflammations, and many other biological processes. The molecular basis for the selectivity of g

Full text of DOI:10.1002/anie.202104924

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Accepted Article
Title: A synthetic galectin mimic
Authors: Tiddo Jonathan Mooibroek, Brian Timmer, Xander
Schaapkens, and Arjaan Kooijman
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10.1002/anie.202104924
Angewandte Chemie International Edition
RESEARCH ARTICLE
A synthetic galectin mimic
Brian J. J. Timmer,[a] Arjaan Kooijman, [a] Xander Schaapkens[a] and Tiddo J. Mooibroek*[a]
[a]
Dr. B. J. J. Timmer, A. Kooijman, X. Schaapkens and Dr. T. J. Mooibroek
Van ‘t Hoff Institute for Molecular Sciences, University of Amsterdam
Science Park 904, 1098 XH, Amsterdam, The Netherlands.
E-mail: t.j.mooibroek@uva.nl
Supporting information for this article is given via a link at the end of the document
Abstract: Galectins are
a galactoside specific subclass of
carbohydrate binding proteins (lectins) involved in various cellular
activities, certain cancers, infections, inflammations and many other
biological processes. The molecular basis for the selectivity of
galectins is well-documented and revolves around appropriate
interaction complementarity: an aromatic residue for C–H···π
interactions and polar residues for (charge assisted) hydrogen bonds
with the axial hydroxyl group of a galactoside. Despite this knowledge,
no synthetic mimics are currently available. Here, we report on the
design and synthesis of the first galectin mimic (6), and show that it
has a higher than 65-fold preference for n-octyl-β-galactoside (8) over
n-octyl-β-glucoside (7) in CD2Cl2 containing 5% DMSO-d6 (with Ka ≥
4500 M-1 for 6:8). Molecular modelling informed by nOe studies reveal
a high degree of interaction complementarity between 6 and
galactoside 8, which is very similar to the interaction complementarity
found in natural galectins.
Introduction
Galectins are
a galactoside-selective subclass of lectins
(carbohydrate binding proteins)[1] and play an important role: in
regulating cellular activities;[2] in certain cancers,[3] infections,[4]
and inflammations;[5] and in heart (dis)functioning[6] and liver
fibrosis.[7] Technologies to study, monitor or intervene in such
processes are predicated on our ability to selectively bind
galactosides. The affinities of galectins towards simple
saccharides is typically in the order of Ka ≈ 103 M-1 for
disaccharides,[8] even less for galactose itself, while
immeasurably small for a carbohydrate such as glucose.[8c] The
structural characteristics that underpin the selectivity of galectins
Figure 1. a) Galactoside binding domain of human galactin-3 (1A3K) bound to
the galactose residue of N-acetyl-D-lactosamine (H-bonded water molecules
are shown as red spheres); b) the structures of O-linked β-D-
glucoside/galactoside with OH-4 highlighted in blue; c) covalent cage as lectin
mimic for all-equatorial carbohydrates; d) new design presented here aimed to
mimic galectins. R = solubility handle.
Despite the well-known origin for their selectivity, there are no
galectin mimics reported to date.[11] There does exist an
interesting class of lectin–mimics that target the all-equatorial
family of carbohydrates.[12] One such ‘temple’ design is illustrated
in Figure 1c.[12a, 12c, 12e] In this particular covalent macrocycle, two
aromatic biphenyl surfaces (magenta) are separated by polar
isophthalamide units (green). Despite their successes,[12f, 12g, 12i, 12l,
for galactosides are well-understood and involve
a well-
9]
preserved[1b,
tryptophan residue for C–H···π interactions,[10]
together with several polar residues for hydrogen bonding (HB)
with hydroxyl groups. This is illustrated in Figure 1a for human
5b, 6-7, 9]
galectin-3[1d,
in complex with N-acetyl-D-lactosamine
12n]
(PDB-code 1A3K).[9] In Figure 1a, the C–H···π interactions with
tryptophan-181 are shown in magenta and the HB interaction
between asparagine-174 and the galactoside methylene OH are
shown in green. The selectivity for galactosides stems largely
from the HBs between histidine-158/arginine-162 and the axial
hydroxyl at the 4-postion (in blue). This axial hydroxyl is
equatorially oriented in analogous O-linked β-glucosides (Figure
1b), thus rationalising the selectivity.
the synthetic routes towards these macrocycles require at
least one macrocyclization reaction near the end of the synthesis
scheme, which rarely surpassed 20% yield. Moreover, it is not
obvious how the selectivity of this design can be fine-tuned to
accommodate axial hydroxyl substituents. To remedy these
drawbacks and inspired by recent reports about the carbohydrate
binding properties of M2L4 coordination cages,[13] we designed the
system shown in Figure 1d. It was envisioned that synthesis of
the parent tetradentate ligand would give a quantitative cyclization
1
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10.1002/anie.202104924
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RESEARCH ARTICLE
product upon reaction with a square-planar metal such as Pd(II).
Moreover, the design was anticipated to compliment the structure
of certain carbohydrates, such as galactosides, by providing an
aromatic biphenyl surface (magenta), polar isophthalamide
spacers (green) and a cationic [Pd(pyridyl)4]2+ complex for charge
assisted CH hydrogen bonding to an axial hydroxyl group.[13c, 14]
of the desymmetrized b3α must be facing ‘outwards’ relative to
the b4/s4/p2 portal and indeed has an nOe with b2, not b4.
Moreover, DOSY-NMR of 6 and 5 (Figure S30) shows that both
have a very similar diffusion constant, thus excluding larger
structures with multiple Pd2+ nuclei.
Results and Discussion
As is shown in Scheme 1, the synthesis of 5 was realized by
reaction of pentafluorophenyl(PFP)-activated isophthalamide
derivative 1 with tetra amine salt 2,[15] followed by a derivatization
of the resulting PFP-ester 3 using 3-aminopyridine 4. After the
reaction forming 3, most of the unreacted starting material 1 could
be recovered during column chromatographic purification of 3.
Tetrapyridyl ligand 5 could also be isolated with conventional
silica gel column chromatography.
Figure 2. a) Formation of 6 (bottom) from 5 (top) by addition of the indicated
equivalent of Pd(BArF)2, as followed by 1H-NMR (spectra partially assigned).
Solvent is 5% DMSO-d6 in CD2Cl2; b) schematic representation and labelling of
6; c) partial NOESY spectrum of 6 zoomed-in on the nOe’s between b3α and
b2 / b4. See Figures S28–S33 for complete spectra and full assignments.
As is detailed in section S5a of the supporting information, a
molecular model of 6 was based on the observed NOESY
spectrum and calculated using density functional theory (DFT).
Two space-filling representations of this model are shown in
Figure 3, as viewed along the smaller portal involving b4 (Figure
3a) and the larger portal involving b2 (Figure 3b). As intended, the
interior of 6 provides a flat aromatic biphenyl surface at the
‘bottom’ (Figure 3c, magenta) and an uneven surface formed by
the cationic [Pd(pyridyl)4]2+ at the ‘top’ (Figure 3d, blue). Both are
held together by the four polar isophthalamides (green). The inner
dimensions of this model for 6 are generally congruent with the
size of a carbohydrate (Figure S51). In particular, the internal
height of 6 of 4.0 – 5.4 Å is in between the typical height of amide-
linked covalent carbohydrate receptors (3.9 Å) and a related urea-
linked glucose receptor (5.5 Å).[12l]
Scheme 1. Synthesis of tetrapyridyl ligand 5. PFP = pentafluorophenyl, DIPEA
= N,N-diisopropylethylamine, THF = tetrahydrofuran. The given yields in
percentages (bottom) are non-optimized isolated yields. Compound 1 can be
prepared on multiple gram scale in > 30% isolated yield from p-bromo-t-
butylbenzene as detailed in the supporting information.
The identity of 5 was verified by various NMR techniques (see
section S2d) and high resolution mass spectroscopy. Stepwise
addition of 1 equivalent a Pd2+ source to 5 (Figure 2a), resulted in
the signal of 5 disappearing and a new set of resonances
appearing. These resonances are consistent with formation of the
cage-like complex 6 illustrated Figure 2b. For example, the large
shifts for s3-NH (10.04  10.55 p.p.m.) p2 (8.74  9.75 p.p.m.)
and p3/p5 (~8.17  8.89 and 8.28 p.p.m.) are congruent with Pd-
coordination of the aminopyridyl moieties of 5.[13c, 13d] What also
stands out from these spectra is that the singlet of the α-
methylene proton b3α (4.46 p.p.m.) is desymmetrized to two
multiplets around 4.68 and 4.51 p.p.m.. This is typical for cage-
formation,
which
renders
the
methylene
hydrogens
diastereotopic.[12g, 12i] Analysis of the 2D-NOESY NMR spectrum
of the newly formed species was also fully consistent with the
structure of 6 (Figure S31). In particular, as is illustrated in Figure
2c, one half of the desymmetrized b3α had a nuclear Overhauser
effect (nOe) cross peak with b4; not with b2. This [b3α; b4] nOe
involves four b3α hydrogens that can be seen as pointing ‘inwards’
with respect to the portal formed by b4, s4 and p2. The other half
Figure 3. Molecular model of 6 with partial assignment as calculated with DFT
(ωB97X-D / 6-31G*) and viewed: a) facing the smaller p2/s4/b4 portal; b) facing
the larger p2/s2/b2 portal; c) from the interior looking down at the flat biphenyl;
d) from the interior looking at the uneven surface of the [Pd(pyridyl)4]2+ complex.
The solubilizing groups are omitted and the distances are corrected for the van
der Waals radii of the atoms. See also section S5a for details.
2
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10.1002/anie.202104924
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RESEARCH ARTICLE
The 1H-NMR spectra of [6][BArF]2 between 0.8 and 3.0 mM
(Figure S36) showed minute shifts (Δδmax. = 0.05 p.p.m.) of the
resonances in the aromatic region. The most significant shift was
observed for s5-NH, yet all shifts were linear when plotted as a
function of concentration (Figure S37). It was thus assumed that
any self-association is negligible in this concentration range. In a
control titration experiment with phenol (see also entry 1 in Table
1), similar small shifts were observed that were ascribed to the
varying concentration during the experiment.
With increasing concentration of 7, most resonances of 6 shifted.
For example, the inwards facing s3-NH, p2, s4 and s5-NH shifted
significantly and broadened somewhat near the end of the titration.
The doublet of p3 (~8.89 p.p.m.) and the singlet of b2 (~8.15
p.p.m.) appear to fully split into, respectively, two doublets and
two singlets. Such splitting is in line with a symmetrical molecule
such as 6 hosting an asymmetrical guest like 7 in fast
exchange.[12g] The methylene resonances of b3α also shifted and
broadened. As is shown in the inset figure of Figure 4a, these data
could be fitted to a 1:1 binding model with a Ka of 67 M-1.
Interestingly, addition of approximately one equivalent of
galactoside 8 to 6 resulted in the disappearance of most signals
(Figure 4b). All resonances reappear –albeit broadened– upon
cooling the sample to –30 °C (top spectrum in Figure 4b) and
disappear again when heated to room temperature (see Figure
S40). Integration of the disappearing resonances of s3-NH
(~10.54 p.p.m.) and p2 (~9.75 p.p.m.) plotted against the
concentration of 8 could be fitted to a 1:1 model suggesting Ka ≈
4500 M-1, but with an excessive error of 23%. This large error
likely originates from integration difficulties (see Figure S40 for
details), but the order of magnitude is clearly around ≥ 103-104 M-
Table 1. Overview of binding studies performed between [6][BArF]2 and phenol
and n-octyl-glycosides 7–10 with axial groups highlighted in blue.
5% DMSO-d6 in CD2Cl2
10% DMSO-d6 in CD2Cl2
Guest
Entry
Ka (M-1)
Entry
Ka (M-1)
[a]
[a]
phenol
1
2
3
4
5
-
6
-
[a]
7
67 [b]
7
-
8
≥ 4500 ± 23 % [c]
21 [b]
8
550 ± 5 % [b, c]
1
and 6 thus appears to be selective for galactoside 8 over
[a]
9
9
-
glucoside 7 in this medium. The binding studies with the α-O-
linked n-octyl glycosides 9 (Figure S41) and 10 (Figure S42) also
displayed concentration dependent spectral changes such as
shifting and broadening of resonances. The observed shifts could
be fitted to a 1:1 binding model with Ka = 21 M-1 for 9 and 16 M-1
for 10 (see also entries 4-5 in Table 1). These data suggest that
6 is more selective for β-O-linked n-octyl glycosides 7 and 8 than
α-n-octyl glycosides 9 and 10. Moreover, the cage is not merely
selective for carbohydrates with an axial hydroxyl but very specific
for galactoside 8 (compare with mannoside 10).
[a]
10
16 [b]
10
-
As the affinity of 6 towards galactoside 8 appeared so much
higher than the others, yet could not be accurately quantified in
the solvent mixture used, the titrations were repeated in 10%
DMSO-d6 in CD2Cl2 and the results are summarized in entries 6-
10 of Table 1. In the case of phenol (Figure S43) only marginal
shifts were observed, in line with the lack of binding already
observed in 5% DMSO-d6 in CD2Cl2 (Table 1, entry 1).
[a] Insignificant peak shifts similar to dilution were observed and the data could
not be fitted to a 1:1 binding constant. At best, we estimate such constants to
be in the order of < 5 M-1. [b] r2 ≥ 0.97. [c] determined by integration as detailed
in the supporting information. The larger error of 23% is probably due to
integration issues. See section S3 for all titrations.
The titration with n-octyl-β-D-glucoside 7 in 5% DMSO-d6 in
CD2Cl2 (entry 2 in Table 1) appeared markedly different compared
to addition of phenol and selected 1H-NMR spectra of the titration
are shown in Figure 4a.
Figure 4. a) Partial 1H-NMR spectra and HypNMR curve fitting analysis of 1.9 mM [6][BArF]2 titrated with glucoside 7. Fitting was done on protons s3-NH, p3, s4
and p4, giving Ka = 67 M-1 with r2 = 0.9963 over all 52 data points. b) Partial 1H-NMR spectra of 3.3 mM [6][BArF]2 titrated with galactoside 7 up to about three
equivalents. The top spectrum is taken at the end of the titration at –30 °C. The solvent is in CD2Cl2 with 5% DMSO-d6. See also Figure S39 and Figure S40.
3
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10.1002/anie.202104924
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RESEARCH ARTICLE
For the carbohydrates 7 (Figure S45), 9 (Figure S47) and 10
(Figure S48) the shifts were somewhat larger than for phenol, yet
far less than observed with these carbohydrates in 5% DMSO-d6
in CD2Cl2. In particular, peak broadening was hardly observed
and the splitting of resonances observed for glucoside 7 was far
less than observed in 5% DMSO-d6 in CD2Cl2. These data are
consistent with very weak binding of 7, 9 and 10 in the regime
preceding appreciable saturation. Interestingly, in the titration with
galactoside 8 (Figure S46), most of the resonances of 6 again
disappeared. In this matrix, the data could be fitted accurately (±
5% based on integration) to a 1:1 binding constant of about 550
M-1, confirming the selectivity of 6 towards galactoside 8.
hydrogen bonding, both models display CH-π interactions
between the CH-moieties of the pyranose rings and the biphenyl
(magenta).
To verify if the observed spectral changes were indeed caused by
binding of glycosides, a series of selective 1D nOe spectra were
measured in 5% DMSO-d6 in CD2Cl2 of the final titration solutions
in the titration with glucoside 7 at room temperature and
galactoside 8 at –30 °C.§ As can be seen in the resulting spectra
in Figure 5, excitation of the outwards facing p3 did not result in
significant nOe spin transfer with resonances in the pyranose
region around 4 p.p.m. (highlighted in green). In sharp contrast,
irradiation of b2 and the inwards facing s4 gave clear nOe’s with
the pyranose regions of both 7 and 8. These nOe data thus
provide evidence that binding with 7 and 8 is genuine and in
particular the nOe with s4 evidences binding to the interior of 6.
Figure 6. a) Truncated view of a molecular model of [6  7]2+ in space-filling
mode (left) and as capped sticks visualizing four of the seven HB interactions
found. b) idem for [6  8]2+ with five out of ten HBs. Both models were DFT
optimized (ωB97X-D / 6-31G*) and the complex with 7 was calculated to be 12
kcal·mol-1 less stable. Only polar hydrogens and hydrogens involved in CH-π
interactions are shown for simplicity. See section S5b for full details.
As can be seen in Figure 6b, accommodating the flat CH-surface
of galactoside 8 leaves the hydroxyls OH-4 and OH-2 oriented
towards the coarse CH/NH surface provided by the [Pd(Py)4]2+
moiety in 6 (see also Figure 3). A similar complementarity is
present for O1 and O5 (not shown here, see Figure S53b for
details). By accommodating the flat CH-surface of glucoside 7 on
the other hand, all hydroxyls directly connected to the pyranose
ring are equatorially oriented and are thus unable to connect to
the CH/NH surface of the [Pd(Py)4]2+ moiety. This is different for
the methylene hydroxyl OH-6 of 7, which actually adopts a
pseudo-axial orientation to establish the bifurcated HB highlighted
in Figure 6a. It is noteworthy that [6  8]2+ was computed to be
about 12 kcal·mol-1 more stable than [6  7]2+ and has ten instead
of seven HBs (see also Figure S53). While this relative energy is
likely inflated due to the computational method, these models do
provide a rationale for the observed selectivity of 6 for 8 in terms
of relative stability and increased interaction complementarity
(see also Figure S54a). Moreover, the orientation of 8 is nearly
identical to that found in galectins[1b, 9] such as 1A3K highlighted
in Figure 1a (see also Figure S54b for a partial structure overlay).
Figure 5. Partial 1H-NMR spectrum of [4  7][BArF]2 at 25 °C and [4  8][BArF]2
at –30 °C together with selective 1D nOe’s recorded at the same temperature
after excitation of p3, b2 or s4 (tm = 350 ms). The large signal at 3.16 p.p.m. in
the sample with 8 at –30 °C is from water.
As is detailed in section S5b, molecular modelling consistent with
the nOe data was used to obtain likely approximate geometries of
6 bound to glycosides 7 and 8. Perspective views of these models
are shown in Figure 6. As is highlighted in the right-hand side of
Figure 6a for [6  7]2+, bifurcated HB interactions[16] are a common
structural feature. This is structurally similar to bifurcated HBs
13d]
between ureas and carbohydrates.[11b,
The highlighted
example involves a pyridyl CH (p2) of ring A and the NH of the
connected amide (s3-NH), both bound to the O-atom of
methylene OH-6. This same pattern is observed with ring B and
O-5 of the pyranose ring, yet no HB was present at all with rings
C and D in the [6  7]2+ model. In [6  8]2+ (Figure 6b, right),
bifurcated HBs are present with rings A and C, and ring D is only
involved in a HB between the amide NH and O-5. Ring B is
involved in a CH···O and NH···O HB with O-1 and O-5
respectively (not shown). Hydrogen bonding interactions involving
the amides connected to the biphenyl ring are less numerous and
not shown in the Figure (see Figure S53 for full details). Besides
Conclusion
In summary, a Nature-inspired synthetic galectin mimic (6) was
designed, synthesized and shown to bind selectively to
galactoside 8 in CD2Cl2 containing 5% or 10% DMSO-d6 (v/v). The
selectivity of 6 for 8 versus glucoside 7 is at least 65 (~4500/67)
and even larger versus α-glycosides 9 and 10 (up to 280 ≈
4500/16). A selectivity exceeding 1:65 is rare for galectins[8] and
4
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RESEARCH ARTICLE
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a
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20-fold selectivity against galactose.[11b] The selectivity of 6 for 8
can be rationalized by the modelled interaction complementarity,
revealing CH···π interactions and ample (charge assisted)
hydrogen bonding interactions that are much like those observed
in natural lectins. It must be noted that the synthesis route to 6
can easily be diverted to a diverse range of variants. For example,
the solubility handle could be tweaked to make the binding core
of 6 water-soluble, or the pyridyl rings can be replaced by
(2-)substituted pyridyls for altered properties of the [Pd(Py)4]2+
moiety. Another prospect is the replacement of the square-planar
Pd(II) by octahedral metals that might aid in binding via an axial
vacant site.
It is concluded that 6 represents the first synthetic galectin mimic
and provides a platform that opens the venue towards the
preparation of a new family of carbohydrate binding molecules
that can target carbohydrates with axial substituents (such as
galactosides).
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This research was financially supported by the Netherlands
Organization for Scientific Research (NWO) with VIDI grant
number 723.015.006.
Keywords: carbohydrate recognition • galectin mimic •
galactosides • molecular recognition • carbohydrates
Notes and references
§ In addition to the nOe data, the spectra of 6 containing about 1 mM
of a carbohydrate revealed significantly broadened peaks of 7-10
compared to spectra of pure carbohydrates at the same concentration.
This too is highly indicative of binding (see Figure S49).
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10.1002/anie.202104924
Angewandte Chemie International Edition
RESEARCH ARTICLE
Entry for the Table of Contents
A synthetic galectin mimic was designed, synthesized and shown to bind selectively to n-octyl-β-D-galactoside.
6
This article is protected by copyright. All rights reserved.