Maltodextrin recognition by a macrocyclic synthetic lectin

Article abstract of DOI:10.1039/c8cc05074k

A monocyclic “temple” synthetic lectin, with extended electron-rich aromatic surfaces, shows enhanced affinities for carbohydrates in water. The methoxy substituents favour binding to α-linked maltodextrins, against the all-equatorial substrates normally

Full text of DOI:10.1039/c8cc05074k

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: P. Stewart, C.
Renney, T. J. Mooibroek, S. Ferheen and A. Davis, Chem. Commun., 2018, DOI: 10.1039/C8CC05074K.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/C8CC05074K
Journal Name
COMMUNICATION
Maltodextrin recognition by a macrocyclic synthetic lectin
Patrick Stewart,1 Charles M Renney,1 Tiddo J Mooibroek,2 Sadia Ferheen1 and Anthony P Davis1,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A monocyclic “temple” synthetic lectin, with extended electron-
rich aromatic surfaces, shows enhanced affinities for carbohydrates
in water. The methoxy substituents favour binding to α-linked
maltodextrins, against the all-equatorial substrates normally
favoured by this family of receptors.
The recognition of polar molecules in water presents a challenge for
supramolecular chemistry.1 Both substrate and receptor are likely to
bind strongly to water molecules, creating a barrier to complex
formation. Binding will only occur if receptor-substrate interactions
are so favourable and well—organised that they can overwhelm
solvation. The problem is especially difficult for carbohydrates,
where substrate and solvent are quite similar. Carbohydrate-binding
proteins such as lectins often show low affinities for their targets,2
and the design of synthetic analogues remains problematic.3
We have reported a series of “synthetic lectins” aimed at the all-
equatorial family of carbohydrates (glucose, N-acetylglucosamine,
cellobiose etc.).4,5 The receptors employ a common “temple”
architecture4e in which parallel aromatic surfaces are separated by
A key advantage of this receptor architecture is its variability. In
principle, a range of modifications can be made with relative ease to
allow tuning of binding and physical properties. Previously we have
shown that altering the side-chains can moderate recognition, by
enhancing polar and electrostatic interactions.5b We now report the
first changes to the anthracene units which form the roof and floor
of the cavity. We find that the addition of eight methoxy groups (see
5) raises affinities in general with especially strong effects for
extended substrates (e.g. oligosaccharides). Notably, a clear
preference is shown for maltodextrins, possessing α-linkages and
therefore outside the all-equatorial family. The results therefore
suggest that temple carbohydrate receptors may be more versatile
than previously thought.
polar, water-solubilising spacers.
The hydrophobic surfaces
complement the axial carbohydrate CH, while the spacers can
hydrogen bond to equatorial polar substituents. Most of the
structures are polycyclic cages requiring quite lengthy syntheses, but
recent work has shown that readily-accessible monocycles 1 are
surprisingly effective.5 For example, the affinities (Ka) for 1a and 1b
binding glucose are 56 and 90 M-1 respectively. Although moderate,
these values compare well with those for more complex, polycyclic
structures, and may be sufficient for applications such as glucose
sensing.
Receptor 5 was designed with a view to extending the
hydrophobic surfaces while increasing the electron density in the
roof/floor π-system, thereby enhancing CH-π interactions.4e,6 The
synthesis
of
5
is
summarised
in
Scheme
1.
1School of Chemistry of the University of Bristol
Cantock's Close, BS8 1TS, Bristol, UK
E-mail: Anthony.Davis@bristol.ac.uk
Dimethyltetramethoxyanthracene 2 was available via a large-scale
procedure from acetaldehyde and veratrole.7 Bromination followed
by displacement with azide and Staudinger reduction gave diamine 3
in excellent yield. Macrolactamisation with bis-pentafluorophenyl
ester 4 under high dilution, followed by removal of side-chain
protecting groups, gave macrocycle 5. 1H NMR spectra of 5 in D2O
2van ’t Hoff Institute for Molecular Sciences, University of Amsterdam,
Science Park 904, 1098 XH, Amsterdam, The Netherlands.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: Synthetic procedures, details
of NMR and ITC measurements, spectra and binding analysis curves. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
View Article Online
DOI: 10.1039/C8CC05074K
Scheme 1 Synthesis of receptor 5. (i) H2SO4 aq. (70% v/v), -10 °C, 55%; (ii) NBS, ABCN, DCM, 40 °C, 98%; (iii) NaN3, MeCN, 40 °C, 95%; (iv)
PPh3, THF, H2O, 87%; (v) 4, DIPEA, THF, 27%. R = dendrimeric side-chain with O-t-butyl protection. [3] = [4] = 0.2 mM. (vi) TFA, DCM, then
NaOH aq. Also shown is the labelling scheme used for discussions of 1H NMR spectra.
(pH = 7) appeared somewhat broadened at low temperatures, cases, consistent with the introduction of an asymmetric guest into
sharpening and shifting as the temperature was raised to 70 oC. the D2h binding site.8 The movements of signal F gave good fits to a
However, dilution from 1 mM down to 64 μM caused no appreciable 1:1 binding model in most cases, giving the binding constants
changes in the spectra (see Figures S9 and S10, ESI). This suggests summarised in Table 1. Corresponding values for 1b are also shown.
that the temperature-dependence is due to conformational Spectra and the binding analysis curve for the titration with maltose
movement and that aggregation is not significant. Preliminary work are shown as examples in Fig. 1. Isothermal titration calorimetry
highlighted the importance of this issue. An analogous macrocycle (ITC) was used to obtain confirmatory Ka values in the case of glucose,
with the side-chain employed for 1a was found to be sparingly cellobiose and maltose (see Table 1). Thermodynamic data from the
soluble at pH 7, giving strongly broadened 1H NMR spectra.
ITC measurements indicated that binding was both enthalpically and
The binding of a series of carbohydrates 6-19 by 5 was entropically driven (see Table S1, ESI).
1
investigated through H NMR titrations in D2O. Addition of mono-
and oligo-saccharides to 5 in D2O caused downfield shifts of the Table 1 Association constants measured for 5 to carbohydrates,
signal due to protons F and smaller movements for protons B, compared to reported values for 1b.
indicative of complex formation which is fast on the 1H NMR
timescale. The signal due to B was also observed to split in some
-1 a
Ka [M ]
Carbohydrate
5
1b
D-Glucose 6
120 (140)b 90c
Methyl β-D-glucoside 7
Methyl a-D-glucoside 8
N-Acetyl-D-glucosamine 9
340
30
50e
115c
d
-
31c
d
Methyl β-D-N-acetylglucosaminide 10 68e
-
D-Galactose 11
D-Mannose 12
D-Cellobiose 13
D-Cellotriose 14
D-Cellotetraose 15
D-Lactose 16
19e
~0f
7c
~0c,f
410 (530)b 29g
d
610
330
140
-
-
31g
D-Maltose 17
580 (660)b 49g
D-Maltotriose 18
D-Maltotetraose 19
1150
1620
55g
-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
ChemComm
Please do not adjust margins
Journal Name
COMMUNICATION
differences are observed. For cellobiose 13, maltose 17 and
View Article Online
a Measured by NMR titration in D2O at 298 K unless otherwise stated. maltotriose 18, receptor 5 is >10 times as effective as 1b. The
DOI: 10.1039/C8CC05074K
b
c
d
Values in brackets obtained by ITC in H2O. See ref. 5b. Not enhancement of CH-π interactions by the MeO groups should apply
e
measured. Poor fit consistent with some host:guest:1:2 complex to all substrates, including glucose, so the results suggest that this
formation. Analysis employing a 1:1+1:2 binding model gives effect is relatively small. Meanwhile the improved affinities for larger
somewhat higher value for 1:1 binding constant. For more details substrates could result from the increased surface area of 5,
f
g
see ESI. Signal movements nearly linear with concentration.
presumably operating via the hydrophobic effect.
Reported in ref. 9.
Also notable is the selectivity for α-linked maltodextrins over β-
linked cellodextrins. Some sign of this is observed for the parent 1b,
which binds maltose 17 slightly more strongly than cellobiose 13, but
the preference is especially pronounced for 5 + higher oligomers (18
vs 14 and 19 vs 15). Molecular modelling (Fig. 2) suggests an
explanation for these differences. In the case of maltodextrins, the
curved profile of the substrates creates surfaces which match the
methoxy-anthracene floor component, so that contact is made with
glycosyl units external to the cavity. This contact provides additional
hydrophobic interactions which supplement the binding energy. The
effect does not apply to cellodextrins, which are therefore bound less
strongly. The affinities of 5 for maltodextrins 18 and 19 are among
the highest observed for uncharged and unglycosylated
[maltose] (mM)
carbohydrates, exceeded only by
a few systems which are
considerably more difficult to synthesise.4g,10
0.08
0.07
0.06
0.05
0.04
0.03
0.02
Δδobs
0.01
Δδcalc
0.00
0.00
0.01
0.02
0.03
0.04
0.05
0.06
[maltose]t M-1
Fig. 2 Models11 of maltotriose 18 (top) and cellotriose 14 (bottom)
binding to receptor 5. In both cases the substrate is oriented such
that the reducing terminus (β anomer) enters the cavity.
Isophthalamide spacers are shown as yellow sticks, side-chains are
omitted for clarity.
1
Fig. 1 Top: Partial H NMR spectra from addition of maltose to 5 in
D2O. Bottom: Plot of experimental vs. calculated data from 1:1
binding analysis (proton F).
The Ka values in Table 1 reveal significant differences between
octamethoxy receptor 5 and the parent system 1b. Although the
methoxy groups affect binding to glucose 6 by a relatively small
amount (increase of ~30%), a large effect is observed for more
extended substrates. Methyl β-D-glucoside 7 is bound ~3 times more
strongly by 5 than by 1b, and for oligosaccharides still larger
In conclusion, we have illustrated the versatility of anthracene-based
synthetic lectins by introducing substituents which substantially alter
the binding properties. By extending the cavity and increasing
electron density in the anthracene units, the added methoxy groups
enhance affinities and confer new selectivity. A variety of other
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
modifications can be envisaged, and we hope to explore these in
future work.
View Article Online
DOI: 10.1039/C8CC05074K
This research was supported by the Engineering and Physical
Sciences Research Council through grant number EP/I028501/1 and
a
PhD studentship to C.M.R. (Chemical Synthesis CDT,
EP/G036764/1, co-funded by Novartis). T.J.M. thanks the
Netherlands Organisation for Scientific Research (NWO) for a VIDI
grant (723.015.006), and S.F. thanks the Pakistan Higher Education
Commission for a Postdoctoral Fellowship.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1. A. P. Davis, S. Kubik and A. D. Cort, Org. Biomol. Chem., 2015, 13,
2499-2500. E. A. Kataev and C. Muller, Tetrahedron, 2014, 70,
137-167. G. V. Oshovsky, D. N. Reinhoudt and W. Verboom,
Angew. Chem., Int. Ed., 2007, 46, 2366-2393.
2. a) D. Solis, N. V. Bovin, A. P. Davis, J. Jimenez-Barbero, A. Romero,
R. Roy, K. Smetana and H. J. Gabius, Biochim. Biophys. Acta-Gen.
Subj., 2015, 1850, 186-235. M. Ambrosi, N. R. Cameron and B. G.
Davis, Org. Biomol. Chem., 2005, 3, 1593-1608.
Angew. Chem., Int. Ed., 2009, 48, 1775-1779; (e) A. P. Davis, Org.
Biomol. Chem., 2009, 7, 3629-3638; (f) N. P. Barwell and A. P.
Davis, J. Org. Chem., 2011, 76, 6548-6557; (g) T. J. Mooibroek, J.
M. Casas-Solvas, R. L. Harniman, C. M. Renney, T. S. Carter, M. P.
Crump and A. P. Davis, Nature Chem., 2016, 8, 69-74; (h) P. Rios,
T. S. Carter, T. J. Mooibroek, M. P. Crump, M. Lisbjerg, M.
Pittelkow, N. T. Supekar, G.-J. Boons and A. P. Davis, Angew.
Chem., Int. Ed., 2016, 55, 3387-3392; (i) P. Rios, T. J. Mooibroek,
T. S. Carter, C. Williams, M. R. Wilson, M. P. Crump and A. P.
Davis, Chem. Sci., 2017, 8, 4056-4061.
3. For reviews see ref 2a and: A. P. Davis, in Comprehensive
Supramolecular Chemistry II, Elsevier, Oxford, 2017, p. 181-201;
C. E. Miron and A. Petitjean, ChemBioChem, 2015, 16, 365-379; 5. (a) C. Ke, H. Destecroix, M. P. Crump and A. P. Davis, Nature
A. Draganov, D. Wang, J. Holmes, K. Ji, B. Wang, S. K. Shaw and B.
D. Smith, in Synthetic Receptors for Biomolecules : Design
Principles and Applications, ed. B. D. Smith, Royal Society of
Chem., 2012, 4, 718-723; (b) H. Destecroix, C. M. Renney, T. J.
Mooibroek, T. S. Carter, P. F. N. Stewart, M. P. Crump and A. P.
Davis, Angew. Chem., Int. Ed., 2015, 54, 2057-2061.
Chemistry, Cambridge, 2015, p. 177-203; Y. Nakagawa and Y. Ito, 6. V. Spiwok, Molecules, 2017, 22, 1038; J. L. Asensio, A. Arda, F. J.
Trends Glycosci. Glycotechnol., 2012, 24, 1-12; S. Jin, Y. F. Cheng,
S. Reid, M. Y. Li and B. H. Wang, Med. Res. Rev., 2010, 30, 171-
257; A. P. Davis and R. S. Wareham, Angew. Chem., Int. Ed., 1999,
38, 2978-2996. Recent examples: M. Yamashina, M. Akita, T.
Canada and J. Jiménez-Barbero, Acc. Chem. Res., 2013, 46, 946-
954; K. L. Hudson, G. J. Bartlett, R. C. Diehl, J. Agirre, T. Gallagher,
L. L. Kiessling and D. N. Woolfson, J. Am. Chem. Soc., 2015, 137,
15152-15160.
Hasegawa, S. Hayashi and M. Yoshizawa, Science Advances, 2017, 7. A. Muller, M. Raltschewa and M. Papp, Ber. Dtsch. Chem. Ges.,
3, e1701126; Y. Ohishi, H. Abe and M. Inouye, Eur. J. Org. Chem., 1942, 75, 692-703.
2017, 6975-6979; G. Fukuhara, M. Sasaki, M. Numata, T. Mori 8. Exchange of the guest between four equivalent orientations
and Y. Inoue, Chem. Eur. J., 2017, 23, 11272-11278; Y. Jang, R.
Natarajan, Y. H. Ko and K. Kim, Angew. Chem., Int. Ed., 2014, 53,
1003-1007. O. Francesconi, M. Martinucci, L. Badii, C. Nativi and
S. Roelens, Chem. Eur. J., 2018, 24, 6828-6836.
splits the eight protons B into two groups of four. For precedent
see ref. 4a and; A. P. Davis and R. S. Wareham, Angew. Chem.,
Int. Ed., 1998, 37, 2270-2273.
9. H. Destecroix, Ph.D. thesis, University of Bristol, 2014.
4. For example: (a) E. Klein, M. P. Crump and A. P. Davis, Angew. 10. B. Sookcharoenpinyo, E. Klein, Y. Ferrand, D. B. Walker, P. R.
Chem., Int. Ed., 2005, 44, 298-302; (b) Y. Ferrand, M. P. Crump
and A. P. Davis, Science, 2007, 318, 619-622; (c) N. P. Barwell, M.
Brotherhood, C. F. Ke, M. P. Crump and A. P. Davis, Angew.
Chem., Int. Ed., 2012, 51, 4586-4590.
P. Crump and A. P. Davis, Angew. Chem., Int. Ed., 2009, 48, 7673- 11. Energy minimised using Batchmin 11.0/Maestro 10.4.018,
7676; (d) Y. Ferrand, E. Klein, N. P. Barwell, M. P. Crump, J.
Jimenez-Barbero, C. Vicent, G. J. Boons, S. Ingale and A. P. Davis,
OPLS2005 force field, GB/SA water solvation.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/C8CC05074K
This carbohydrate receptor achieves high affinities in water and shows an unusual preference for αꢀlinked
maltodextrins.