Clicked and long spaced galactosyl- and lactosylcalix[4]arenes: New multivalent galectin-3 ligands

Article abstract of DOI:10.3762/bjoc.10.175

Four novel calix[4]arene-based glycoclusters were synthesized by conjugating the saccharide units to the macrocyclic scaffold using the CuAAC reaction and using long and hydrophilic ethylene glycol spacers. Initially, two galactosylcalix[4]arenes were prepared starting from saccharide units and calixarene cores which differ in the relative dispositions of the alkyne and azido groups. Once the most convenient synthetic pathway was selected, two further lactosylcalix[4]arenes were obtained, one in the cone, the other one in the 1,3-alternate structure. Preliminary studies of the interactions of these novel glycocalixarenes with galectin-3 were carried out by using a lectin-functionalized chip and surface plasmon resonance. These studies indicate a higher affinity of lactosylover galactosylcalixarenes. Furthermore, we confirmed that in case of this specific lectin binding the presentation of lactose units on a cone calixarene is highly preferred with respect to its isomeric form in the 1,3-alternate structure.

Full text of DOI:10.3762/bjoc.10.175

Clicked and long spaced galactosyl- and
lactosylcalix[4]arenes: new multivalent galectin-3 ligands
Silvia Bernardi1, Paola Fezzardi1, Gabriele Rispoli1, Stefania E. Sestito2,
Francesco Peri*2, Francesco Sansone1 and Alessandro Casnati*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1672–1680.
1Dipartimento di Chimica, Università degli Studi di Parma, Parco Area
delle Scienze 17/a, 43124 Parma, Italy and 2Dipartimento di
Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca,
Piazza della Scienza 2, 20126 Milano, Italy
doi:10.3762/bjoc.10.175
Received: 05 March 2014
Accepted: 23 June 2014
Published: 23 July 2014
Email:
Francesco Peri* - francesco.peri@unimib.it; Alessandro Casnati* -
casnati@unipr.it
This article is part of the Thematic Series "Multivalent glycosystems for
nanoscience".
* Corresponding author
Guest Editor: B. Turnbull
Keywords:
© 2014 Bernardi et al; licensee Beilstein-Institut.
License and terms: see end of document.
glycocalixarenes; cluster glycoside effect; multivalency; click
chemistry; surface plasmon resonance
Abstract
Four novel calix[4]arene-based glycoclusters were synthesized by conjugating the saccharide units to the macrocyclic scaffold
using the CuAAC reaction and using long and hydrophilic ethylene glycol spacers. Initially, two galactosylcalix[4]arenes were
prepared starting from saccharide units and calixarene cores which differ in the relative dispositions of the alkyne and azido groups.
Once the most convenient synthetic pathway was selected, two further lactosylcalix[4]arenes were obtained, one in the cone, the
other one in the 1,3-alternate structure. Preliminary studies of the interactions of these novel glycocalixarenes with galectin-3 were
carried out by using a lectin-functionalized chip and surface plasmon resonance. These studies indicate a higher affinity of lactosyl-
over galactosylcalixarenes. Furthermore, we confirmed that in case of this specific lectin binding the presentation of lactose units on
a cone calixarene is highly preferred with respect to its isomeric form in the 1,3-alternate structure.
Introduction
Lectins are carbohydrate-binding proteins (CBP) [1-3] without saccharides are called galectins and play important roles in a
any catalytic or immunogenic activity. In the latest decades, series of pathological events such as inflammation, fibrosis,
they attracted an increasing interest due to their involvement in heart diseases and cancer [4,5]. The role of one member of this
a series of fundamental biological processes such as cell adhe- family in particular, namely galectin-3 (Gal-3), has been inten-
sion, cell activation, cell growth, differentiation and apoptosis. sively investigated lately and it was shown that it is deeply
Among different families of lectins, the ones showing a selec- involved in cancer metastasis and migration. Based on these
tivity for β-D-galactoside and β-D-galactose-terminating oligo- findings and with the aim to inhibit its activity and to target it
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Results and Discussion
for therapeutic or diagnostic purposes, Gal-3 became a rather
important target in medicine. Remarkably interesting is the Synthesis of the glycocalixarenes
intra-family selectivity and, especially, the ability to block Gal- “Click Chemistry” [23] reactions are extensively used to conju-
3 but not Gal-1. Gal-1, in fact, can act as anti-inflammatory gate (oligo)saccharides to macrocyclic structures due to the
agent, while Gal-3 has a pro-inflammatory activity [6]. Further- mild conditions and the high yields [24]. For the synthesis of
more, Gal-3 can act as a competitive inhibitor against Gal-1 glycocalixarenes the amino–isothiocyanate condensation [25-
which, on the other side, induces anoikis of tumor cells [7,8]. 30] or the 1,3-dipolar cycloaddition have been widely studied in
Glycocalixarenes [9-12], calixarenes [13-15] adorned with their scope and limitations [10,31]. In particular, the Huisgen
carbohydrates at the upper and/or at the lower rims, have been cycloaddition reaction was first applied to a calixarene in 2000
demonstrated to be efficient multivalent ligands for a series of by Santoyo-González [32]. Later on, Marra et al. [33] demon-
pathological lectins. For instance, cholera toxin is bound rather strated that the copper-catalyzed azide–alkyne cycloaddition
efficiently by calix[4]arene [16] and calix[5]arene [17] deriva- (CuAAC) [34,35] at room temperature could afford divalent
tives, while examples of Pseudomonas aeruginosa LecB and tetravalent glycocalixarenes in very high yields and regiose-
binding were reported with galactosylcalixarenes blocked in lectivity. Following these studies, a wide series of other exam-
different conformations [18,19]. A few years ago we [20,21] ples appeared in the literature [18,36-39] also exploiting the use
reported about the synthesis and inhibitory properties of a small of microwaves, ionic liquids and protected or even deprotected
library of lactosylthioureidocalixarenes and found that the cone [17] saccharides. Usually, either the strategy of reacting an
derivatives I and III (Figure 1) were able to efficiently inhibit alkynylated-saccharide with a polyazide calixarene (dipo-
the adhesion of Gal-3 to tumor cells in vitro, but not that of larophile-on-the-sugar) or an azido-sugar and a polyalkynoca-
galectin-1 [22].
lixarene (dipolarophile-on-the-calix) work smoothly [33].
However, a sort of autocatalytic effect was evidenced in the
The opposite behavior was observed for the 1,3-alternate case of the reaction between a 1-ethynyl-C-glycoside with a
derivative II, able to inhibit Gal-1 but not Gal-3. On the basis of tetraazidocalix[4]arene (dipolarophile-on-the sugar strategy). It
these findings, we herein report the synthesis of a new was suggested by the authors that the first intermolecular reac-
subfamily of galactosyl- and lactosylcalix[4]arenes 1–4 tion, leading to a Cu-triazolide adduct, allows the copper ion to
(Figure 2) which are characterized by long hydrophilic spacers coordinate an ethynyl glycoside, thus entailing an intramolec-
between the glycosyl units and the multivalent calixarene scaf- ular CuAAC reaction with an adjacent azido-arm [37].
fold. We also report on preliminary studies of the interaction of
the novel subfamily of galactosyl- and lactosylcalix[4]arenes Firstly, we decided to evaluate the effectiveness of the two
with Gal-3 by surface plasmon resonance (SPR).
approaches dipolarophile-on-the-calix and dipolarophile-on-the-
Figure 1: Lactosylthioureidocalix[4]arenes I–III used to inhibit Gal-3 [20,21].
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Figure 2: The new glycocalix[4]arenes 1–4 synthesized in this study.
sugar by using a galactose and cone calixarene scaffolds. This yield. Due to the concurrent formation of dicyclohexylurea
investigation was carried out with the idea to extend the study (DCU), several purification steps were necessary to obtain pure
to stronger ligating units for galectins such as lactose and calix[4]arene 8. The use of 1-ethyl-3-(3-dimethylaminopropyl)-
different calixarene structures, also including the 1,3-alternate carbodiimide (EDC) as an alternative coupling agent allowed us
isomer. The first route explored (dipolarophile-on-the-calix) to isolate pure compound 8 in a more straightforward way and
was applied to the preparation of the multivalent compound 1, higher yield (66%). Any attempts to connect the alkyne func-
which could be synthesized by exploiting a convergent syn- tionality in closer proximity to the calixarene core by
thetic approach. This approach was based on the connection, by decreasing the number of carbon atoms between the carboxylic
CuAAC reaction, of the azido-terminating tetraacetylgalactose 5 group and the triple bond did not give fruitful results. Reactions
[40,41] to calix[4]arene 8 decorated at the upper rim with between amino-calix[4]arene 6 and propiolic acid were carried
alkyne terminating chains (Scheme 1).
out with a variety of coupling agents. In the presence of DCC
the tetra-condensation product was only obtained in very low
In order to introduce the alkyne units at the upper rim of the yields. Furthermore, it was not possible to purely isolate it from
macrocycle, we decided to exploit the easily available and the crude reaction mixture due to the high amount of byprod-
highly versatile p-aminocalixarene 6 prepared according to ucts formed during the reaction. The CuAAC reaction between
literature procedures [25]. The coupling reaction between the tetraalkyne calix[4]arene 8 and azido-galactoside 5 to give
amino-calix[4]arene 6 and 4-pentynoic acid (7) in the presence glycocluster 9 (83% yield) was carried out in DMF and H2O
of dicyclohexylcarbodiimide (DCC) led to compound 8 in 44% with CuSO4 and sodium ascorbate following a microwave-
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Scheme 1: Synthesis of the cone galactosylcalix[4]arenes 1. Reaction conditions: (i) DCC, DMAP, CH2Cl2, under reflux, 5 h, 44%; (ii) EDC,
CH2Cl2/py (7:3), rt, 18 h, 66%; (iii) CuSO4·5H2O, Na-ascorbate, DMF/H2O, μW (150 W), 80 °C, 20 min, 83%; (iv) CH3ONa, CH3OH, rt, 1 h –
IR120/H+, rt, 30 min, quantitative.
assisted procedure (20 min, 150 W, 80 °C). No partially func- etamido compound 11 [43]. Subsequent substitution of the chlo-
tionalized compounds or other byproducts were detected in the rine ions with azide groups led to the formation of the tetra-
crude mixtures.
azidocalixarene derivative 12 (1 h, 75% yield).
The second strategy studied (dipolarophile-on-the-sugar) also The CuAAC conjugation reaction was carried out following
exploits a convergent approach, but in this case an alkyne-func- exactly the same procedure as for compound 9 and allowed the
tionalized galactose 10 was prepared according to literature isolation of 13 in very high yields (81%). Glycoconjugates 9
[42], so that it reacts with calixarene 12, which was previously and 13 were fully characterized by 1H and 13C NMR spec-
functionalized with azido terminating arms (Scheme 2). This troscopy, which displayed the disappearance of the alkyne
latter compound was synthesized in two steps starting again protons and the appearance of the typical broad signal of 1,4-
from tetraamino derivative 6. In the first step compound 6 was disubstituted triazole protons at 7.75–7.85 ppm (CD3OD/
treated with chloroacetyl chloride to give the α-choloroac- CDCl3). ESIMS (+) analyses showed peaks for the [M + 2Na]2+
Scheme 2: Synthesis of the cone galactosylcalix[4]arenes 2. Reaction conditions: (i) DIPEA, CH2Cl2, rt, 6 h, 55%; (ii) NaN3, CH3OH/DMF, reflux, 1 h,
75%; (iii) CuSO4·5H2O, Na-ascorbate, DMF/H2O, μW (150 W), 80 °C, 20 min, 81%; (iv) CH3ONa, CH3OH, rt, 1 h – IR120/H+, rt, 30 min, quantitative.
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and [M + 3Na]3+ adducts, which indicates the conjugation of all which is very difficult to separate by flash chromatographic
four macrocycle arms to the saccharide units. On the basis of methods. On the other hand, the recently reported glycosylation
the comparison between the efficiency of the conjugation steps reactions of lactose peracetate exploiting SnCl4 and CF3CO2Ag
bringing to glycoconjugates 9 and 13 (yields >80% in both as promoters [46] gave compound 14 mainly as a β-anomer (α/β
cases) and contrary to the observation by Marra et al. [37], we ratio 1:4) in 74% isolated yield.
could not collect any evidence for an autocatalytic effect in the
dipolarophile-on-the-sugar approach [44]. The deprotection of The subsequent substitution reaction of chloride with NaN3
compounds 9 and 13 from the acetyl groups was carried out by (Scheme 3) led to the corresponding azido derivative 15, which
a transesterification reaction in the presence of CH3ONa in was used to “click” both the cone (8) and 1,3-alternate (18)
CH3OH at room temperature according to the standard Zemplén pentynoic amides. Compound 18 was obtained from the corres-
procedure. Complete deacetylation was achieved in 1 hour, as ponding 1,3-alternate p-aminocalix[4]arene 17 [47] by a reac-
confirmed by NMR and ESIMS(+) spectra of compounds 1 and tion with EDC in CH2Cl2 and pyridine 7:3 as previously
2. It is noteworthy that while compound 1 exhibited a high described for compound 8. The CuAAC “click” reaction was
stability under Zemplén conditions even if the reaction was carried out as previously described for the galacto-clusters 9
continued overnight, compound 2 started to decompose after and 13 and afforded the cone calix[4]arene 16 (Scheme 3) and
18 hours. ESIMS profiles showed the presence of products orig- 1,3-alternate calix[4]arene 19 (Scheme 4) in 46% isolated yield.
inating from a cleavage at the amide bond with a loss of the Microwave irradiation (150 W, 80 °C) facilitated the complete
entire glycosylated chain and the formation of an amine group tetra-functionalization in only 40 minutes. Subsequent deacetyl-
at the upper rim of the calixarene. For this reason and on the ation with the Zemplén method led to target compounds 3 and
basis of the synthetic availability of intermediates, we decided 4, both of which were characterized by 1D and 2D NMR tech-
to privilege the dipolarophile-on-the-calix route to synthesize niques and ESIMS analyses.
the triazole-containing lactosylcalixarenes 3 and 4.
Gal-3/glycocalixarenes interaction studies by
We first attempted to prepare the lactoside derivative 14 by SPR
reacting peracetylated-lactose with 2-(2-(2-chloroethoxy)eth- His6-tagged full-length Gal-3 was expressed in E. coli BL21
oxy)ethanol in the presence of BF3·Et2O [45]. However, we and purified on IMAC (immobilized metal ion affinity chroma-
could only obtain a mixture of α and β-anomers (α/β ratio 2:3), tography) columns. Purified protein was characterized by SDS-
Scheme 3: Synthesis of the cone lactosylcalix[4]arenes 3. Reaction conditions: (i) NaN3, n-Bu4NI, DMF, 90 °C, 24 h, 60%; (ii) CuSO4·5H2O,
Na-ascorbate, DMF/H2O, μW (150 W), 80 °C, 40 min, 46%; (iii) CH3ONa, CH3OH, rt, 2 h – IR120/H+, rt, 30 min, 73%.
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Scheme 4: Synthesis of the 1,3-alternate lactosylcalix[4]arenes 4. Reaction conditions: (i) EDC, CH2Cl2/py (7:3), rt, 18 h, 65%; (ii) CuSO4·5H2O,
Na-ascorbate, DMF/H2O, μW (150 W), 80 °C, 40 min, 46%; (iii) CH3ONa, CH3OH, rt, 2 h – IR120/H+, rt, 30 min, 71%.
PAGE electrophoresis, circular dichroism (CD), and MS/MS However, the three synthetic molecules showed a very similar
analysis upon digestion on trypsin gel (see Figure S15, trend of Gal-3 binding affinity in three independent measure-
Supporting Information File 1). A preliminary evaluation of the ments (experiments A, B and C in Figure 4a). In particular,
interaction between the glycocalixarenes 1, 3, 4 and Gal-3 was glycocalixarene 3 (cone structure, four lactosides) exhibited the
obtained by SPR analysis by using a His-tagged Gal-3 immobi- highest affinity for Gal-3 in all experiments, while 4, (1,3-alter-
lized on a Ni-NTA chip and the glycocalixarenes in solution. nate structure, four lactosides) displayed a lower affinity and 1
This approach differs from other SPR studies of the (cone structure, four galactosides) showed no interaction at all.
calixarene–galectin interaction with the protein in solution [38] The more efficient ligand, compound 3, showed a dose-depen-
and is tailored to have the immobilized protein properly dent affinity for the protein.
oriented for the interaction with ligands. The sensorgrams
shown in Figure 3 were obtained by fluxing an 1 mM solution The higher affinities of lactose-containing compounds 3 and 4
of calixarenes over the protein-coated chip.
for Gal-3 compared to galactose-containing compound 1 reflect
the higher affinity of lactose over galactose for Gal-3. The
The small increases of resonance units in the sensograms lactosylcalixarene with the cone structure appears to bind better
(Figure 3) showed a weak affinity of all calixarenes for Gal-3. to Gal-3 than the corresponding isomer in the 1,3-alternate
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Beilstein J. Org. Chem. 2014, 10, 1672–1680.
Figure 3: SPR sensorgrams of binding experiment between immobilized Gal-3 and glycocalixarenes 1, 3 and 4.
structure. This confirms the data previously obtained in a series
of inhibition experiments of the same lectin in surface-immobi-
lized asialofetuin and on cells with the lactosylthioureidocal-
ixarenes (I–III) [20,21]. A direct comparison with ligands
(I–III) was, however, not feasible since the lactosylthioreido
derivatives tend to aggregate and precipitate under the condi-
tions used for SPR experiments.
Conclusion
Four glycocalixarenes 1–4 characterized by long hydrophilic
spacers between the glycosyl units and the macrocyclic scaf-
fold were synthesized by the copper(I)-catalyzed azido–alkyne
cycloaddition (CuAAC). The homogeneous series of ligands 1,
3 and 4 were subsequently studied in the binding to surface-
immobilized His-tagged Gal-3 by SPR experiments. In spite of
the weak intensity of the signals, an affinity order for the inter-
action of ligands 1, 3 and 4 with the immobilized Gal-3 was
obtained. A preference for the lactosyl clusters over the galac-
tose functionalized ones (3 > 4 >> 1) and a higher efficiency in
the binding of Gal-3 shown by the cone derivative compared to
its isomeric 1,3-alternate counterpart (3 > 4) were observed.
Work is in progress to study by SPR experiments the inter-
action between lactosylcalixarenes covalently immobilized on
the chip and Gal-3 samples in solution.
Figure 4: a) Relative affinities of glycocalixarene 1, 3, 4 (1 mM)
towards Gal-3, expressed in terms of the increase of the resonance
unit (RU) in three independent (A, B, C) SPR experiments. b) average
affinities of glycocalixarenes with standard deviations.
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11.Sansone, F.; Rispoli, G.; Casnati, A.; Ungaro, R. Multivalent
Glycocalixarenes. In Synthesis and Biological Applications of
Multivalent Glycoconjugates; Renaudet, O.; Spinelli, N., Eds.; Bentham
Science Publishers: Dordrecht, 2011; pp 36–63.
Supporting Information
Detailed experimental procedures (general information,
synthetic procedures, expression and purification of Gal-3,
Gal-3/glycocalixarene binding experiments), 1H NMR
spectra of selected intermediates, and final glycocalixarenes
1–4 together with electrophoresis gel, circular dichroism
spectrum and thermal unfolding of purified Gal-3.
doi:10.2174/978160805277611101010036
12.Sansone, F.; Casnati, A. Chem. Soc. Rev. 2013, 42, 4623–4639.
doi:10.1039/c2cs35437c
13.Gutsche, C. D. Calixarenes: An Introduction, 2nd ed.; Royal Society of
Chemistry: Cambridge, 2008. doi:10.1039/9781847558190
14.Baldini, L.; Sansone, F.; Casnati, A.; Ungaro, R. Calixarenes in
molecular recognition. In Supramolecular Chemistry: from Molecules to
Nanomaterials; Steed, J. W.; Gale, P. A., Eds.; John Wiley & Sons:
Chichester, 2012; pp 863–894. doi:10.1002/9780470661345.smc052
15.Casnati, A. Gazz. Chim. Ital. 1997, 127, 637–649.
16.Arosio, D.; Fontanella, M.; Baldini, L.; Mauri, L.; Bernardi, A.;
Casnati, A.; Sansone, F.; Ungaro, R. J. Am. Chem. Soc. 2005, 127,
3660–3661. doi:10.1021/ja0444029
Supporting Information File 1
Experimental part.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-175-S1.pdf]
17.Garcia-Hartjes, J.; Bernardi, S.; Weijers, C. A. G. M.; Wennekes, T.;
Gilbert, M.; Sansone, F.; Casnati, A.; Zuilhof, H. Org. Biomol. Chem.
2013, 11, 4340–4349. doi:10.1039/c3ob40515j
Acknowledgements
The authors gratefully acknowledge financial support from the
Italian Ministry of Instruction, University and Research (MIUR,
PRIN2010JMAZML MultiNanoIta) and EU-COST Action
CM1102 ‘MultiGlycoNano’. The Centro Interdipartimentale di
Misure (CIM) of the Parma University ‘G. Casnati’ is acknowl-
edged for the use of the NMR and Mass facilities.
18.Cecioni, S.; Lalor, R.; Blanchard, B.; Praly, J.-P.; Imberty, A.;
Matthews, S. E.; Vidal, S. Chem.–Eur. J. 2009, 15, 13232–13240.
doi:10.1002/chem.200901799
19.Moni, L.; Pourceau, G.; Zhang, J.; Meyer, A.; Vidal, S.; Souteyrand, E.;
Dondoni, A.; Morvan, F.; Chevolot, Y.; Vasseur, J.-J.; Marra, A.
ChemBioChem 2009, 10, 1369–1378. doi:10.1002/cbic.200900024
20.André, S.; Grandjean, C.; Gautier, F.-M.; Bernardi, S.; Sansone, F.;
Gabius, H.-J.; Ungaro, R. Chem. Commun. 2011, 47, 6126–6128.
doi:10.1039/c1cc11163a
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