Design, synthesis and photochemical properties of the first examples of iminosugar clusters based on fluorescent cores

Article abstract of DOI:10.3762/bjoc.11.74

The synthesis and photophysical properties of the first examples of iminosugar clusters based on a BODIPY or a pyrene core are reported. The tri- and tetravalent systems designed as molecular probes and synthesized by way of Cu(I)-catalysed azide-alkyne c

Full text of DOI:10.3762/bjoc.11.74

Design, synthesis and photochemical properties of the first
examples of iminosugar clusters based on fluorescent cores
Mathieu L. Lepage1, Antoine Mirloup2, Manon Ripoll1, Fabien Stauffert1,
Anne Bodlenner1, Raymond Ziessel*2 and Philippe Compain*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 659–667.
1Laboratoire de Synthèse Organique et Molécules Bioactives
(SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole
Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue
Becquerel, 67087 Strasbourg, France, 2Institut de Chimie et Procédés
pour l’Energie, l’Environnement et la Santé (ICPEES), Laboratoire de
Chimie Organique et Spectroscopie Avancées (LCOSA), Université
de Strasbourg/CNRS (UMR 7515), Ecole Européenne de Chimie,
Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087
Strasbourg, France and 3Institut Universitaire de France, 103 Bd
Saint-Michel, 75005 Paris, France
doi:10.3762/bjoc.11.74
Received: 27 February 2015
Accepted: 17 April 2015
Published: 06 May 2015
This article is part of the Thematic Series "Multivalency as a chemical
organization and action principle".
Guest Editor: R. Haag
Email:
© 2015 Lepage et al; licensee Beilstein-Institut.
License and terms: see end of document.
Raymond Ziessel* - ziessel@unistra.fr; Philippe Compain* -
philippe.compain@unistra.fr
* Corresponding author
Keywords:
BODIPY; fluorescent probes; iminosugars; 4-methylumbelliferone;
multivalency; pyrene
Abstract
The synthesis and photophysical properties of the first examples of iminosugar clusters based on a BODIPY or a pyrene core are
reported. The tri- and tetravalent systems designed as molecular probes and synthesized by way of Cu(I)-catalysed azide–alkyne
cycloadditions are fluorescent analogues of potent pharmacological chaperones/correctors recently reported in the field of Gaucher
disease and cystic fibrosis, two rare genetic diseases caused by protein misfolding.
Introduction
Since the isolation in the 1970’s of 1-deoxynojirimycin (DNJ) proteinases [3], protein kinases [4] and cholinesterases [5],
from natural sources and the finding of its biological activity as which are enzymes that act on non-sugar substrates. The versa-
an α-glucosidase inhibitor, thousands of sugar mimetics with a tility of iminosugars as inhibitors of enzymes of therapeutic
nitrogen atom replacing the endocyclic oxygen have been interest has been harnessed to cure a diversity of diseases in-
reported in the literature [1,2]. Iminosugars are mainly known cluding diabetes, viral infection, lysosomal storage disorders,
to be inhibitors of a number of carbohydrate-processing tumour metastasis and cystic fibrosis [1]. First therapeutic
enzymes with an emphasis on glycosidases [1,2]. In the early successes have been obtained as demonstrated by the number of
2000’s, iminosugars were, remarkably, found to inhibit metallo- structures involved in clinical trials and two medicines on the
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Beilstein J. Org. Chem. 2015, 11, 659–667.
market: Glyset (N-hydroxyethyl DNJ) for the treatment of
complications associated with type II diabetes and Zavesca
(N-Bu DNJ, 1), the first oral treatment for Gaucher and
Niemann–Pick diseases (Figure 1) [1,6-8]. Despite their high
therapeutic potential, the extensive studies in the field and the
myriad of compounds synthesized, very few examples of multi-
valent iminosugars were reported in the literature until recently
[9,10]. From 2010, the field has however experienced a major
take-off with the discovery of the first strong multivalent effects
in glycosidase inhibition observed with DNJ clusters based on
β-cyclodextrin or C60 cores showing strong affinity enhance-
ments over the corresponding monomers (up to 610-fold per
DNJ unit) [11,12]. In the following years, an impressive ever-
growing number of multivalent iminosugars based on various
scaffolds, ligands and linkers have been synthesized to further
investigate the impact of multivalency on glycosidase inhibi-
tion [9-26]. The interest of the inhibitory multivalent effect for
drug discovery was demonstrated by targeting glycosidases
involved in rare genetic diseases linked to misfolded proteins
[24-26]. The first examples of multivalent iminosugars such as
2 and 3 acting as pharmacological chaperones were thus
disclosed in the field of Gaucher disease, the most common
lysosomal storage disorder (Figure 1) [24,25]. DNJ clusters 2
and 3 are indeed able to increase mutant β-glucocerebrosidase
(GCase) residual activity levels as much as 3.3-fold in cells of
Gaucher patients at micromolar concentrations. In another rare
genetic disease, the rescue by multimeric correctors of the
mutant CFTR protein implied in cystic fibrosis led to the first
report of a multivalent effect for amending protein folding
Figure 1: N-Bu DNJ (1) and examples of potent multivalent pharmaco-
logical chaperones and CFTR correctors (2 and 3).
defects in cells [26]. As judged by EC50 (half-maximal effec- linked to a central core via an alkyl chain spacer (Figure 1) [24-
tive concentration) values, trivalent DNJ clusters 2 were indeed 26]. The choice of the fluorophore core is naturally primordial
up to 225-fold more efficient as CFTR correctors than the clin- for the design of photostable, water-soluble and biocompatible
ical candidate N-Bu DNJ (1), a potent inhibitor of trimming ER probes with the required photophysical properties. An addition-
glucosidases [26]. Taken together, these recent studies provide al challenge is that, as the central core of a multivalent system,
new therapeutic answers for a number of protein folding disor- the fluorophore structure defines also its valency, size and
ders [27,28] but also raise many fundamental questions shape. Difluoroboradiaza-s-indacenes, commonly named boron-
concerning the mechanisms at play. In the present paper, we dipyrromethene dyes (F-BODIPY), were logically selected for
report the first examples of fluorescently-labeled multivalent the construction of the probes. These compounds indeed
iminosugars designed as molecular tools to investigate the mode combine high fluorescence quantum yields and high molar
of action of pharmacological chaperones/correctors in cells and extinction coefficients, strong chemical and photochemical
in vivo, and get insights into the multivalent effect observed in stability in solution and in solid state. In addition, they can be
CFTR correcting activity. The originality of our approach relies easily derivatized [31-37]. If the optical properties of BODIPY
on the fact that, in the structures designed, this is the scaffold are very sensitive to modification of the pyrrole core [38,39],
itself [29,30], based on a pyrene or a boron-dipyrromethene they are less sensitive to the substitution of the central pseudo
(F-BODIPY) dye, which has fluorescence activity.
meso position [40,41]. Additionally, the fluorine substitution at
the boron has less influence on the spectroscopic properties of
the dyes [42]. So far, major endeavors have been dedicated to
the preparation of classical F-BODIPY structures and less
Results and Discussion
Synthetic design
The fluorescent probes were designed as analogues of the best common E-BODIPY (E for ethynyl) and the examination of
multivalent pharmacological chaperones/correctors reported so their spectroscopic and salient physical properties [43-47]. We
far that typically display three to four copies of a DNJ ligand have recently argued the case that the fluoro-substitution of
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Beilstein J. Org. Chem. 2015, 11, 659–667.
boraindacene was a mean to considerably increase the solu- {2’-(2-methoxyethoxy)ethoxy}ethoxy)ethoxy]prop-2-yne [61]
bility, the stability and the steric hindrance avoiding the forma- and the BODIPY derivative 8. With these precursors in hands it
tion of aggregates [48]. In some cases, special sensing prop- was easy to transform the iodo function to yield the tri-
erties [49] may be induced by adequate tailoring, including methylsilylacetylene derivatives 9 and 11 using standard Sono-
fluorescence amplification [50], and ratiometric pH reporter for gashira–Hagihira cross-coupling reactions promoted by low
imaging protein–dye conjugates in living cells [51], or display valent palladium precursors [62]. Excellent yields were
physiological binding of D-glucose [52]. The pyrene nucleus obtained for the trisubstituted derivatives (88 to 95%). Two
was also selected as an alternative fluorophore since it may be diagnostic NMR signals of the poly(ethylene glycol) chains at
easily tetrafunctionalized at the 1, 3, 6 and 8 positions to give a 4.16 ppm (protons a, integration 4H) and at 3.65 ppm for the
suitable core for the synthesis of tetravalent clusters [53]. In methoxy groups (protons b, integration 6H) in addition to the
addition, this fluorophore was chosen for its biological/chem- presence of two TMS singlets at 0.20 and 0.28 ppm (respective
ical stability and its photophysical properties including high integration 18 and 9H) confirmed the substitution. Finally,
extinction coefficient with reliable fluorescence [54,55]. deprotection of the trimethylsilyl group using mild basic condi-
Another interest of the pyrene scaffold lies in its rigidity, a tions provided the target compounds 6a and 6b in good yields.
property that may favourably impact inhibitory multivalent Terminal alkynes located in the 2,6 positions were found to
effects [9,11,16,19]. A convergent approach comprising the resonate at 3.32 ppm and the one in the pseudo meso position 8
attachment of azide-armed iminosugars 4 [11,12] on polyalkyne resonates at 3.20 ppm.
“clickable” scaffolds 5 and 6 via Cu(I)-catalyzed azide–alkyne
cycloaddition (CuAAC) was performed for achieving our syn- Fluorescent DNJ cluster synthesis
thetic goals (Figure 2) [56,57]. With the objective of increasing Following a robust strategy developed in our group [11,12], the
water solubility and chemical stability in biological medium, last stages of the multivalent probe synthesis involved the
triyne 6b, an analogue of F-BODIPY-based scaffold 6a was attachment of peracetylated azido iminosugars 4 on the scaf-
prepared by replacing the fluoro groups on the boron center folds via CuAAC reaction and afterwards O-deacetylation using
with ethynyl tetra(ethylene glycol)methyl groups [58,59].
an anion exchange resin. First attempts to perform CuAAC
reactions with triyne substrate 6b bearing a tetraethylene glycol
chain tethered to the boron center via an ethynyl bond proved
difficult. The use of copper(I) bromide dimethyl sulfide com-
plex [63] at room temperature led to a complex mixture of prod-
ucts. Better results were obtained with copper(II) sulfate and
sodium ascorbate under carefully degassed conditions and the
desired protected cluster 12b could be obtained in 56% yield
after purification on silica gel (Scheme 2). The major side-prod-
uct observed which could not be isolated in pure form may
correspond to CuAAC reaction of the azido iminosugar 4a with
the terminal alkyne resulting from the cleavage of the
carbon–boron bond in 6b. The same experimental protocol was
applied to functionalized BODIPY 6a, leading to the desired
trivalent cluster 12a in 83% yield. O-Deacetylation of com-
pounds 12 using anion exchange Amberlite IRA-400 (OH−)
resin provided the desired water-soluble clusters 13 in high
yields. As judged by 11B NMR, no fluoride displacement
occurred at the boron center during the deprotection step.
Figure 2: Azide-armed DNJ derivatives 4 and polyalkyne “clickable”
scaffolds 5 and 6.
The synthesis of the 4-valent pyrene-based iminosugars 15 was
Synthesis of the BODIPY precursors
performed in a similar manner than for BODIPY-based clusters
The synthesis of the tris-iodo functionalized BODIPY dyes and 13 (Scheme 3). The tetrayne 5 synthesized in 3 steps from
their acetylenic derivatives is sketched in Scheme 1. The syn- pyrene [53] was reacted with the azide precursors 4, and after-
thesis of derivatives 7 and 8 have previously been reported wards deprotected to give the desired tetravalent iminosugars 15
using a regioselective iodination reaction positions 2 and 6 of in 37 to 72% yields for the two steps. Despite the good water
the BODIPY [60]. Substitution of both fluoro groups on the solubility of alkylated DNJ ligands, pyrene-based multivalent
boron was realized using the Grignard reagent of 1-[2”’-(2”- iminosugars were only soluble in water/methanol or water/
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Scheme 1: Synthesis of trisubstituted BODIPY derivatives. (a) ICl, CHCl3/MeOH, rt, 15 min, quantitative; (b) 3-ethynyltrimethylsilane, [Pd(PPh3)2Cl2],
CuI, triethylamine, THF, 16 h, 60 °C, 88% (9), 95% (11); (c) K2CO3, DCM/MeOH/water, 50 °C, 16 h, 72% (6a), 88% (6b); (d) 1-[2”’-(2”-{2’-(2-
methoxyethoxy)ethoxy}ethoxy)ethoxy]prop-2-yne, EtMgBr, THF, 60 °C, 16 h, 61%.
DMSO mixtures, those mixtures prevent the agregation of the The BODIPY-based dye 13a displays an intense absorption at
pyrene core.
528 nm (ε = 27,000 M−1·cm−1) corresponding to the S0→S1
(π–π* transition). The slight red shift of this absorption
compared to unsubstituted BODIPY dyes in the 2,6-substitu-
Photophysical properties
The absorption and emission features of the BODIPY-based tion positions and measured under similar aqueous conditions,
cluster 13a and the pyrene-based cluster 15a dyes were investi- is likely due to the influence of both triazole rings. The second
gated in an aqueous buffer solution of glycine (0.1 M) at transition at 386 nm is assigned in light of previous studies to
pH 10.7. This buffer conditions were chosen to be as close as the S0→S2 of the BODIPY subunit [39,65-67]. The triazole
possible to the conditions used for β-glucocerebrosidase acti- rings absorb below 250 nm for the π–π* transition [68]. Excita-
vation assays (Gaucher disease) which are based on a fluores- tion at 510 nm affords a relatively intense emission with a
cent leaving group (4-methylumbelliferone) allowing fluores- quantum yield of 24% (in aqueous glycine buffer at pH 10.7),
cence recording after reaction quenching at pH 10.7 [64].
the profile of the band mirrors the absorption with a maximum
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Scheme 2: Synthesis of DNJ clusters 13: (a) CuSO4·5H2O cat., sodium ascorbate, THF/H2O (1:1), 83% (12a), 56% (12b); (b) Amberlite IRA 400
(OH−), MeOH/H2O (1:1), rt, quant. (13a), quant. (13b).
at 558 nm which is in keeping with little reorganization in the
excited state and characteristic of a singlet emitter. The modest
Stokes shift (Δss = 1020 cm−1) and the short excited state life
time (τ = 3.38 ns) are also in favor of a singlet emitting state.
The excitation spectra did display a slight shift compared to the
absorption spectra. This may be due to the presence of some
aggregates, a problem frequently encountered with aromatic
organic dyes in aqueous solutions [69,70]. Addition of 2.5% of
a surfactant such as sodium dodecyl sulfate (SDS) improves the
spectral overlap with the absorption spectra (Figure 3a), and
likely diminishes formation of potent aggregates.
For the pyrene-based cluster 15a two main absorptions maxima
at 391 and 292 nm were observed and safely assigned to the
successive pyrene excited states, S0→S1 at 391 nm and S0→S2
at 295 nm (Figure 3b) [71]. Emission maximum was recorded at
534 nm from an excitation at 390 nm or 295 nm with a quantum
of 43% (in aqueous glycine buffer at pH 10.7). Unlike the
BODIPY homologue, the pyrene-based cluster 15a has a large
Stokes shift of 6850 cm−1 and a longer excited state life time
Scheme 3: Synthesis of DNJ clusters 15: (a) CuSO4·5H2O cat.,
(τ = 71.7 ns) [72]. Again the excitation spectrum matches the
absorption one proving that aggregation is unlikely under the
used aqueous conditions.
sodium ascorbate, DMF/H2O (6:1), 80 °C (MW) or room temperature,
51% (14a), 75% (14b); (b) Amberlite IRA 400 (OH−), MeOH/H2O (1:1),
40 °C, 73% (15a), 96% (15b).
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Beilstein J. Org. Chem. 2015, 11, 659–667.
Figure 3: a) Absorption (orange line), corrected emission (green line)
(λexc = 510 nm), excitation (dashed black line) (λem = 630 nm) and
excitation with 2.5% of SDS (small dashed grey line) spectra for 13a;
b) Absorption (orange line), corrected emission (green line)
(λexc = 390 nm) and excitation (dashed black line) (λem = 550 nm)
spectra for 15a; in glycine buffer at pH 10.7 at rt.
Figure 4: a) Absorption (orange line), corrected emission (green line)
(λexc = 360 nm) and excitation (dashed black line) (λem = 445 nm)
spectra for the anion of 4-methylumbelliferone; b) Stern–Volmer plots
concerning the quenching of fluorescence of the anion of 4-methylum-
belliferone by 13a (red line) and 15a (blue line) and their linear
regression.
From a general point of view, fluorescent probes have been The fluorescence quantum yield is high ( fluo = 81%) as previ-
used for the detection of diverse analytes and in relevant ously determined under similar conditions [74]. In order to
biosensing and bioimaging applications [73]. One critical aspect record the efficiency of the fluorescence quenching of the anion
for the evaluation of biological activities using fluorescent dyes of 4-methylumbelliferone by the novel dyes, Stern–Volmer
(e.g., the deprotonated form of 4-methylumbelliferone) [74] is plots were carried out [75]. A titrated solution of the quencher
to determine their spectroscopic features in different environ- (13a or 15a) was dropwise added to a titrated solution of
ments (local pH, local polarity, potential quenchers, hydro- 4-methylumbelliferone (≈10−7 M at pH 10.7) and the fluores-
phobic environment, …). Here we focus on the UV–visible cence of the anion was recorded after each addition (Figure 4b).
characteristics of the anion of 4-methylumbelliferone, the dye This allows plotting the decrease of fluorescence versus the
commonly used for quantifying chaperoning activities (using concentration of quencher. The Stern–Volmer equation
4-methylumbelliferyl β-D-glucopyranoside as GCase substrate)
facilitates the calculation of the rates of
[64], to determine whether this assay would be compatible with bimolecular collisional quenching kq = 1.8 × 1013 M−1·s−1 and
the evaluation of fluorescent multivalent clusters 13 and 15 as 1.5 × 1013 M−1·s−1, respectively for 13a and 15a dyes using a
potential pharmacological chaperones.
lifetime τ = 5.31 ns for the 4-methylumbelliferone anion. The
quenching appears efficient in both cases due to suitable spec-
The same buffer conditions as those used for activation assays tral overlap between the emission of 4-methylumbelliferone
(quenched conditions at pH 10.7 in a glycine buffer) were used anion and the absorption of the BODIPY 13a or the pyrene-
for this study. The anion of 4-methylumbelliferone displays a based cluster 15a. This dynamic quenching process between
strong absorption at 360 nm and a broad emission around these multivalent iminosugars and the 4-methylumbelliferone or
446 nm (Figure 4a).
other coumarine derivatives has thus to be taken into account
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Conclusion
We have reported the preparation of multivalent iminosugar
clusters based on two fluorescent cores by way of Cu(I)-catal-
ysed azide–alkyne cycloadditions. To our knowledge these are
the first examples of the use of BODIPY or pyrene as a scaf-
fold to display multivalent ligands. Although the trivalent
BODIPY-derived DNJ clusters are water soluble, a co-solvent
is necessary to dissolve the tetravalent pyrene-derived DNJ
clusters in water. Photophysical properties of those multivalent
dyes in aqueous media (glycine buffer at pH 10.7), are interest-
ing, providing high quantum yields, 24% for 13a and 43% for
15a, and well-defined spectroscopic features. Altogether, these
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Supporting Information
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Supporting Information File 1
Characterization data and NMR spectra of all new
compounds.
15.Bonduelle, C.; Huang, J.; Mena-Barragán, T.; Ortiz Mellet, C.;
Decroocq, C.; Etamé, E.; Heise, A.; Compain, P.; Lecommandoux, S.
Chem. Commun. 2014, 50, 3350–3352. doi:10.1039/c3cc48190e
16.Lepage, M. L.; Meli, A.; Bodlenner, A.; Tarnus, C.; De Riccardis, F.;
Izzo, I.; Compain, P. Beilstein J. Org. Chem. 2014, 10, 1406–1412.
doi:10.3762/bjoc.10.144
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-11-74-S1.pdf]
Acknowledgements
17.Marradi, M.; Cicchi, S.; Sansone, F.; Casnati, A.; Goti, A.
Beilstein J. Org. Chem. 2012, 8, 951–957. doi:10.3762/bjoc.8.107
18.Cardona, F.; Isoldi, G.; Sansone, F.; Casnati, A.; Goti, A. J. Org. Chem.
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This work was supported by the Institut Universitaire de France
(IUF), the CNRS (UMR 7509), the University of Strasbourg,
the Agence Nationale de la Recherche (ANR, grant number
11-BS07-003-02), the International Centre for Frontier
Research in Chemistry (icFRC) and doctoral fellowships from
the French Department of Research to Mathieu L. Lepage and
Fabien Stauffert. Antoine Mirloup thanks the Rhin-Solar EC
Network supported by the European Fund for Regional Devel-
opment (FEDER) in the framework of the Programme
INTERREG IV Upper Rhine, Project no. C25 for financial
support of this work.
19.Brissonet, Y.; Ortiz Mellet, C.; Morandat, S.; Garcia Moreno, M. I.;
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