Recent Advances in the Chemistry of Glycoconjugate Amphiphiles

Review Recent Advances in the Chemistry of Glycoconjugate Amphiphiles

Laurent Latxague, Alexandra Gaubert and Philippe Barthélémy * ID

ARNA Laboratory, Inserm U1212, CNRS UMR 5320, Université de Bordeaux, F-33000 Bordeaux, France; [email protected] (L.L.); [email protected] (A.G.) * Correspondence: [email protected]; Tel.: +33-055-757-4843

Received: 30 November 2017; Accepted: 28 December 2017; Published: 2 January 2018

Abstract: Glyconanoparticles essentially result from the (covalent or noncovalent) association of nanometer-scale objects with carbohydrates. Such glyconanoparticles can take many different forms and this mini review will focus only on soft materials (colloids, liposomes, gels etc.) with a special emphasis on glycolipid-derived nanomaterials and the chemistry involved for their synthesis. Also this contribution presents Low Molecular Weight Gels (LMWGs) stabilized by glycoconjugate amphiphiles. Such soft materials are likely to be of interest for different biomedical applications.

Keywords: carbohydrates; glycoconjugate; amphiphiles; colloids; liposomes; gels

1. Introduction Carbohydrates are found in all living systems as simple sugars, polysaccharides or glycoconjugates. Thanks to their molecular complexity and connectivity, this class of biomolecules represents the third alphabet of life beside proteins and nucleic acids [1,2]. They are involved in numerous biological processes and events, including bacterial/viral interactions, immune response, cell proliferation/differentiation, growth regulation, cell signaling, recognition, adhesion, routing etc. [3–9]. At the molecular level, carbohydrates interact with other molecular partners to form supramolecular complexes, which serve as markers for signal transduction. Importantly, carbohydrates fully express their molecular code in these complexes by interacting with ligands such as proteins via multivalent contacts. These cooperative interactions, named the “glyco cluster effect” [4,10], provide strong binding affinity and specificity to the carbohydrates-ligands complexes, which are required to mediate the different biochemical and/or biological processes. Very often carbohydrates are conjugated with lipids in living systems. The resulting amphiphilic properties of the glycolipid conjugates favor their anchoring to biological membranes, where they form supramolecular assemblies through morphological changes with sugar-clustered architectures, for example [11]. Thus, biomimetic approaches have been developed to emulate natural glycolipids anchored in biological membranes [12]. In this field, many different synthetic glycoconjugate amphiphiles have been investigated, including glycoliposomes [13], glycodendrimers [14], or self-assembled monolayers (SAM) [15]. In this contribution, we will present recent advances on bioinspired glycoconjugates based amphiphiles. We wish to underline that these bioinspired molecules offer new perspectives in the fields of biomedicine or soft materials. Metal-based (Au, Ag, etc.) glyconanoparticles, glycosylated quantum dots or glycopolymers will not be addressed here. Comprehensive reviews can be found elsewere [16–19]. In the first section, the synthetic access to this class of amphiphiles is presented. Second, we summarize recent contributions on functionalized carbohydrate scaffolds. This part

Molecules 2018, 23, 89; doi:10.3390/molecules23010089 www.mdpi.com/journal/molecules Molecules 2018, 23, 89 2 of 25 includes: (1) glycocyclodextrins (2) glycocalixarenes and (3) glycodendrimers. Vesicles and liposomes featuring glycoconjugates are highlighted in the third section. This article culminates in the last section with very recent developments on soft materials and in particular promising gels for biomedical applications.

2. Glycolipids Synthesis Overview Molecules 2018, 23, 89 2 of 25 Molecules 2018,, 23,, 8989 2 of 25 GlycolipidsMolecules 2018 (GLs), 23, 89 are sugar-containing lipids and as such, are amphiphilic molecules2 of 25 able to section with very recent developments on soft materials and in particular promising gels for self-assemblesection in with supramolecular very recent developments structures on givingsoft materials rise and to variousin particular soft promising materials. gels Conjugationfor of sectionbiomedical with applications. very recent developments on soft materials and in particular promising gels for biomedical applications. carbohydratesbiomedical to a applications. lipid scaffold relies on a few general methods illustrated below for simple GLs (Table1). Copper2. Glycolipids catalyzed Synthesis azido-alkyne Overview cycloaddition (CuAAC) also known as “click”-chemistry with 2. Glycolipids Synthesis Overview its high chemo-2. GlycolipidsGlycolipids and region-selectivity, Synthesis (GLs) are Overview sugar-containing its tolerance lipids toand a wideas such, variety are amphiphilic of solvents molecules (including able to water) offers Glycolipids (GLs) are sugar-containing lipids and as such, are amphiphilic molecules able to self-assembleGlycolipids in (GLs)supramolecular are sugar-containing structures lipidsgiving andrise asto such, various are softamphiphilic materials. molecules Conjugation able toof mild reactionself-assemble conditions in supramolecular particularly structures useful ingiving glycoconjugate rise to various synthesissoft materials. [20 Conjugation]. When copper of catalysis self-assemblecarbohydrates in to supramoleculara lipid scaffold reliesstructures on a fewgiving general rise tomethods various illustrated soft materials. below Conjugationfor simple GLs of carbohydrates to a lipid scaffold relies on a few general methods illustrated below for simple GLs is not desirablecarbohydrates(Table owing1). Copper to to a catalyzed thelipid metalscaffold azido-alkyne cytotoxicity relies on cycloadditiona few or general its difﬁcult (CuAAC)methods eliminationillustratedalso known below as from“click”-chemistry for simple the reaction GLs medium, (Table 1). Copper catalyzed azido-alkyne cycloaddition (CuAAC) also known as “click”-chemistry a strain-promoted(Tablewith its 1). high Copper azide-alkyne chemo- catalyzed and region-selectivity, cycloadditionazido-alkyne cycloaddition its (SPAAC) tolerance (CuAAC) to with a wide cyclooctynes,also variety known of as solvents “click”-chemistry also (including termed ‘copper-free’ with its high chemo- and region-selectivity, its tolerancelerance toto aa widewide varietyvariety ofof solventssolvents (including(including withwater) its offers high chemo-mild reaction and region-selectivity, conditions particularly its tolerance useful toin aglycoconjugate wide variety of synthesis solvents [20].(including When click-chemistry,water) offers has beenmild reaction developped conditions by particularly Bertozzi useful et al. in [21 glycoconjugate] This strategy synthesis is based [20]. When on the distorted water)copper offerscatalysis mild is notreaction desirable conditions owing toparticularly the metal cytotoxicityuseful in glycoconjugate or its difficult synthesis elimination [20]. from When the sp-bond anglescopper catalysis in cyclooctyne is not desirable derivatives owing to the (~160 metal◦ cytotoxicityvs. 180◦ orin its a difficult linear elimination alkyne) from which the dramatically copperreaction catalysis medium, is anot strain-promoted desirable owing azide-alkyne to the metal cycloadditioncytotoxicity or (SPAAC) its difficult with elimination cyclooctynes, from also the reaction medium, a strain-promoted azide-alkyne cycloaddition (SPAAC) with cyclooctynes, also acceleratesreactiontermed the azide-alkyne ‘copper-free’medium, a strain-promoted click-chemistry, cycloaddition azide-alkynehas rate been [22 deve]. cycloaddition Besidelopped by CuAAC Bertozzi (SPAAC) and et withal. its [21] variants—thecyclooctynes, This strategy also is thiol-yne/ene termedtermed ‘copper-free’‘copper-free’ click-chemistry,click-chemistry, hashas beenbeen devedeveloppedlopped byby BertozziBertozzi etet al.al. [21][21] ThisThis strategystrategy isis termedbased on ‘copper-free’ the distorted click-chemistry, sp-bond angles has in cyclooctynebeen developped derivatives by Bertozzi (~160° vs.et al.180° [21] in Thisa linear strategy alkyne) is click-chemistrybased on (a the radical distorted mediated sp-bond additionangles in cyclooctyne of thiols derivatives to alkynes) (~160° may vs.also 180° bein a appointed—a linear alkyne) Staudinger basedwhich ondramatically the distorted accelerates sp-bond anglthe esazide-alkyne in cyclooctyne cycloaddition derivatives rate(~160° [22]. vs. Beside180° in CuAACa linear alkyne)and its reaction betweenwhich dramatically glycosylated accelerates alkyl the azidesazide-alkyne and cycloaddition fatty acid rate chlorides [22]. Beside is alsoCuAAC interesting and its (not to be whichvariants—the dramatically thiol-yne/ene accelerates click-chemistry the azide-alkyne (a radi cycloadditioncal mediated additionrate [22]. of Beside thiols CuAACto alkynes) and may its variants—the thiol-yne/ene click-chemistry (a radical mediated addition of thiols to alkynes) may confused withvariants—thealso be the appointed—a Staudinger thiol-yne/ene Staudinger ligation, click-chemistry reaction see Sectionbetween (a radi 4glycosylatedcal). mediated Finally, alkyl GLsaddition azides are of still andthiols fatty often to acidalkynes) formed chlorides may in accordance also be appointed—a Staudinger reaction between glycosylated alkyl azides and fatty acid chlorides alsois also be interesting appointed—a (not Staudinger to be confused reaction with betweenthe Staudinger glycosylated ligation, alkyl see azidesSection and 4). Finally, fatty acid GLs chlorides are still with standardisis alsoalso glycosidation interestinginteresting (not(not toto reactions bebe confusedconfused with withwith thethe carbohydrate StaudingerStaudinger ligation,ligation, donors seesee SectionSection (thioglycosides, 4).4). Finally,Finally, GLsGLs halogenoglycosides, areare stillstill isoften also interestingformed in (notaccordance to be confused with standardwith the Staudinger glycosidation ligation, reactions see Section with 4).carbohydrate Finally, GLs aredonors still peracetylatedoften glycosides, formed in accordance etc.) or awith combination standard glyc ofosidation one of thereactions above with methods. carbohydrate donors often(thioglycosides, formed in halogenoglycosides, accordance with standardperacetylated glyc osidationglycosides, reactions etc.) or awith combination carbohydrate of one donors of the (thioglycosides, halogenoglycosides, peracetylated glycosides, etc.) or a combination of one of the (thioglycosides,above methods. halogenoglycosides, peracetylated glycosides, etc.) or a combination of one of the above methods. Tableabove 1. Some methods. illustrative synthetic strategies for GL formation. More detailed examples will be discussed inTable the 1. following Some illustrative paragraphs. synthetic strategies for GL formation. More detailed examples will be Table 1. SomeSome illustrativeillustrative syntheticsynthetic strategiesstrategies forfor GLGL formation.formation. MoreMore detaileddetailed examplesexamples willwill bebe Tablediscussed 1. Some in the illustrative following paragraphs.synthetic strategies for GL formation. More detailed examples will be discussed in the following paragraphs. discussed in the following paragraphs.

[23][23 ]CuAAC CuAAC click-chemistry click-chemistry [23] CuAAC click-chemistry [23] CuAAC click-chemistry

Thiol-yne click [24] Thiol-yneThiol-yne click click [24][24 ] Thiol-ynechemistry click [24] chemistrychemistry chemistry

Staudinger reaction + [25] StaudingerStaudinger reaction reaction + + [25][25 ] Staudingeractivated carbonylreaction + [25] activatedactivated carbonyl carbonyl activated carbonyl

Thioglycosidation [26] Thioglycosidation [26] ThioglycosidationThioglycosidationmethod [26][26 ] method methodmethod

Fisher glycosidation + [27] Fisher glycosidation + [27] FisherFishermetathesis glycosidation glycosidation + + [27][27 ] metathesis metathesismetathesis We will go into more details on the synthesis of more complex GLs featuring several sugar units. We will go into more details on the synthesis of more complex GLs featuring several sugar units. SomeWe of willthem—that go into more can fall details in that on therespect synthesis into theof more glycocluster complex category—areGLs featuring severalglycosphingolipids sugar units. Some of them—that can fall in that respect into thethe glycoclusterglycocluster category—arecategory—are glycosphingolipidsglycosphingolipids We willSomewith go potentof into them—that immunostimulant more detailscan fall in on properties.that the respect synthesis They into theact of asglycocluster more ligands complex of category—are CD1d (a GLs presentationfeaturing glycosphingolipids protein several of sugar units. with potent immunostimulant properties. They act as ligands of CD1d (a presentation protein of withantigen-presenting potent immunostimulant cells) and the properties. resulting They binding act ascomplex ligands is of recognized CD1d (a presentationby the natural protein killer ofT Some of them—thatantigen-presenting can fallcells)in and that the respectresulting binding into the complex glycocluster is recognized category—are by the natural glycosphingolipidskiller T antigen-presenting(NKT) cells which in cells) turn andsecrete the largeresulting quantities binding of variouscomplex cytokines is recognized that mediate by the andnatural regulate killer the T with potent(NKT) immunostimulant cells which in turn secrete properties. large quantities They of actvarious as ligandscytokines that of CD1dmediate (aand presentation regulate the protein of (NKT)immune cells response which in[28]. turn For secrete example, large α quantities-Lac Cer, Gb3of various and iGb3 cytokines were synthesized that mediate by and the regulate Wang [29]the immuneimmune responseresponse [28].[28]. ForFor example,example, α-Lac Cer, Gb3 and iGb3 were synthesized by the Wang [29] antigen-presentingimmuneand Savage response [30] cells) groups [28]. and For(Table the example, 2). resulting Glycosphingolip α-Lac Cer, binding Gb3ids and are complex iGb3found were naturally is synthesized recognized in the cellby themembranes by Wang the [29] natural of killer T and Savage [30] groups (Table 2). Glycosphingolipidsids areare foundfound naturallynaturally inin thethe cellcell membranesmembranes ofof (NKT) cellsand which Savage in [30] turn groups secrete (Table large 2). Glycosphingolip quantitiesids of variousare found naturally cytokines in the that cell mediate membranes and of regulate the

α immune response [28]. For example, -Lac Cer, Gb3 and iGb3 were synthesized by the Wang [29] and Savage [30] groups (Table2). Glycosphingolipids are found naturally in the cell membranes of almost all living organisms. Their lipidic moiety is made of sphingosine. Once acetylated by a fatty acid on Molecules 2018,, 23, 89 3 of 25 Molecules 2018, 23, 89 3 of 25 almost all living organisms. Their lipidic moiety is made of sphingosine. Once acetylated by a fatty almosttheir amino all living group, organisms. they give Their ceramide lipidic which moiety in turn is made can be of connected sphingosine. to one Once or several acetylated sugar by residues a fatty acid on their amino group, they give ceramide which in turn can be connected to one or several sugar acidon their on their primary amino hydroxyl group, they group. give The ceramide resulting which GL also in turn known can asbe sphingolipidconnected to isone called or several cerebroside sugar residues on their primary hydroxyl group. The resultinglting GLGL alsoalso knownknown asas sphingolipid is called withcerebroside one Glc with or Gal one residue, Glc or Gal organglioside residue, or ganglioside when attached when to anattached oligosaccharide to an oligosaccharide featuring at featuring least one cerebrosidesialic acid (N with-acetylneuraminic one Glc or Gal resi aciddue, Neu5Ac or ganglioside or N-glycosylneuraminic when attached to acid an oligosaccharide Neu 5Gc). featuring at least one sialic acid (N-acetylneuraminic-acetylneuraminic acidacid Neu5AcNeu5Ac oror N-glycosylneuraminic-glycosylneuraminic acidacid NeuNeu 5Gc).5Gc). Table 2. Examples of sphingolipids with α-Lac Cer, α-Gb3 and α-iGb3. Table 2. ExamplesExamples ofof sphingolipidssphingolipids withwith α-Lac-Lac Cer,Cer, α-Gb3-Gb3 andand α-iGb3.-iGb3.

Recently, the saccharide moiety 8 of isoglobotriaosyl ceramide (iGb3) was synthesized following Recently, the saccharide moiety 8 of isoglobotriaosyl ceramide (iGb3) was synthesized synthesized following the emergent concept of step-economy [31–34] avoiding multiple protection/deprotection steps and the emergent concept of step-economystep-economy [[31–34]31–34] avoidingavoiding multiplemultiple protection/deprotectionprotection/deprotection steps and is therefore especially promising in glycoconjugate chemistry. In this context, the regioselective silyl is therefore therefore especially especially promising promising in in glycoconjugate glycoconjugate chemistry. chemistry. In this In thiscontext, context, the regioselective the regioselective silyl exchange technology (ReSET) gives partially acetylated and silylated carbohydrates easily exchangesilyl exchange technology technology (ReSET) (ReSET) gives gives partially partially acetylated acetylated and and silylated silylated carbohydrates carbohydrates easily transformed in either glycosyl donors or acceptors [35], which greatly simplifies complex GLs transformed inin either either glycosyl glycosyl donors donors or acceptorsor acceptors [35], which[35], which greatly greatly simplifies simplifies complex complex GLs synthesis GLs synthesis (Scheme 1) [36]. synthesis(Scheme1 )[(Scheme36]. 1) [36]. Basically, per-O-silylated lactose undergoes selective exchange of TMS ethers for acetate Basically, per-per-OO-silylated-silylated lactose lactose undergoes undergoes selective selective exchange exchange of TMS of ethers TMS for ethers acetate for protecting acetate protecting groups in pyridine with acetic anhydride, depending on the amount of excess AcOH groupsadded and in pyridine the microwave with acetic reaction anhydride, time. Compound depending 3 on was the thus amount obtained of excess in two AcOH steps added and selective and the added and the microwave reaction time.3 Compound 3 was thus obtained in two steps and selective microwavedeprotection reaction of the silyl time. ethers Compound yielded thewas acceptor thus obtained 6. Glycosidation in two steps with and in selective situ prepared deprotection per-OBn of deprotection of the silyl ethers yielded6 the acceptor 6. Glycosidation with in situ prepared per-OBn thegalactosyl silyl ethers iodide yielded with thesilver acceptor triflate afforded. Glycosidation the trisaccharide with in situ 7 preparedfurther acetylated per-OBn galactosylto give the iodide iGb3 galactosyl iodide with silver triflate afforded7 the trisaccharide 7 further acetylatediGb3 to give the iGb3 withtrisaccharide silver triflate scaffold afforded 8. This the new trisaccharide strategy, givingfurther better acetylated yields to and give stereoselectivity the trisaccharide in fewer scaffold steps, trisaccharide8. This new strategy,scaffold 8 giving. This betternew strategy, yields and giving stereoselectivity better yields and in fewer stereoselectivity steps, should in representfewer steps, an should represent an attractive alternative to more conventional methods. attractiveComplex alternative glycosyl to ceramides, more conventional namely gangliosides, methods. which are present in the nerve cells [37], are Complex glycosyl glycosyl ceramides, ceramides, namely namely gangliosides, gangliosides, which which are are present present in the in thenerve nerve cells cells [37], [ 37are], mainly enzymatically synthesized with the help of glycosyl transferase. For example, the starfish areganglioside mainly enzymatically LLG-3 featuring synthesized a tetrasaccharide with the sphingolipid help of glycosyl has transferase. been bioenzymatically For example, prepared the starfish by ganglioside LLG-3LLG-3 featuring a tetrasaccharide sphingolipid has been bioenzymatically prepared by gangliosidean engineered endoglycoceramidasefeaturing a tetrasaccharide II glycosynthase sphingolipid (Figure has 1). been bioenzymatically prepared by an anengineered engineered endoglycoceramidase endoglycoceramidase II glycosynthase II glycosynthase (Figure (Figure1). 1).

Molecules 2018, 23, 89 4 of 25 Molecules 2018, 23, 89 4 of 25 Molecules 2018, 23, 89 4 of 25

SchemeScheme 1. 1. Synthesis SynthesisSynthesis of ofof the thethe saccharide saccharide moiety moiety 8 8 of isoglobotriaosylisoglobotriaosyllobotriaosyl ceramide ceramideceramide (iGb3). (iGb3).(iGb3). Reagents Reagents and and Conditions: (i) Ac2O, Py, 3 eq. AcOH, MW, 125 °C,◦ 1.25 h; (ii) excess Ac2O, Py, 3 eq. AcOH, MW, 125 °C,◦ Conditions:Conditions: (i) (i) Ac Ac22O,2O,O, Py, Py,Py, 3 33 eq. eq.eq. AcOH, AcOH,AcOH, MW, MW, 125 125 °C,C, 1.25 1.25 h; h; (ii) (ii) excess excess AcAc Ac22O,2O,O, Py, Py, Py, 3 3 3eq. eq. eq. AcOH, AcOH, AcOH, MW, MW, MW, 125 125 125 °C, °C,C, 1.25 h; (iii) Pd(OH)2/C, H2 1 atm, MeOH, 0.5 h, 91%; (iv) 1-acetyl-2,3,4,6-benzyloxy- 1.251.25 h; h; (iii)h; (iii) Pd(OH)(iii) Pd(OH)Pd(OH)2/C, H2/C,22/C,1 atm, HH2 2 MeOH,11 atm,atm, 0.5 h,MeOH,MeOH, 91%; (iv) 0.5 1-acetyl-2,3,4,6-benzyloxy- h,h, 91%;91%; (iv)(iv) 1-acetyl-2,3,4,6-benzyloxy-1-acetyl-2,3,4,6-benzyloxy-β-D-galatopyranoside, β-D-galatopyranoside,◦ TMSI, DCM, 0 °C, 0.5 h then AgOTf, 4A ◦MS, DCM, −78 to −30 °C, 4 h, 44%; (v) βTMSI,-βD--galatopyranoside,D-galatopyranoside, DCM, 0 C, 0.5 hTMSI, TMSI, then AgOTf,DCM, DCM, 004A °C,°C, MS, 0.50.5 DCM,hh thenthen −AgOTf,78 to − 4A4A30 MS,MS,C, 4 DCM,DCM, h, 44%; −−7878 (v) to to Pd(OH) − −3030 °C, °C, 24/C, 4 h, h, 44%; H 44%;2 1 (v) atm, (v) Pd(OH)2/C, H2 1 atm, MeOH, 1 h then Ac2O, TEA, cat DMAP, DCM, 3 h, 85%. Pd(OH)MeOH,Pd(OH)2 1/C,2 h/C, thenH H2 21 1 Acatm, atm,2O, MeOH, MeOH, TEA,cat 1 1 h h DMAP, then then AcAc DCM,22O,O, TEA,TEA, 3 h, cat 85%. DMAP, DCM, 33 h,h, 85%.85%.

Figure 1. LLG-3 ganglioside structure. Figure 1. LLG-3LLG-3 ganglioside ganglioside structure. Likewise, Globo-H (Figure 2), a tumor-associated antigen, has induced the development of a Likewise, Globo-H Globo-H (Figure (Figure 22),), a tumor-associated antigen, antigen, has has induced induced the the development development of of a therapeutic vaccine based on this synthetic hexasaccharide chemically [38] or enzymatically therapeutica therapeutic vaccine vaccine based based on on this this synthetic synthetic he hexasaccharidexasaccharide chemically chemically [38] [38] or or enzymatically synthesized [39]. synthesized [39]. [39].

Figure 2. Globo-H. Figure 2. Globo-H. Glycosphingolipids featuring various mono- and trisaccharide moieties were synthesized by a combinedGlycosphingolipids multicomponent/click featuring approach various [40].mono- The and ceramide trisaccharide skeleton moieties synthesis were involves synthesized a fatty acid, by a combineda lipidic isocyanide,multicomponent/click para formaldehyde approach and [40]. an The amine ceramide (either skeleton alkynyl synthesisor azido-amine) involves in aa fatty one-pot acid, a lipidic isocyanide, para formaldehyde and an amine (either alkynyl or azido-amine) in a one-pot

Molecules 2018, 23, 89 5 of 25

Glycosphingolipids featuring various mono- and trisaccharide moieties were synthesized by a combinedMolecules 2018 multicomponent/click, 23, 89 approach [40]. The ceramide skeleton synthesis involves a fatty5 acid,of 25 a lipidic isocyanide, para formaldehyde and an amine (either alkynyl or azido-amine) in a one-pot Ugi-four component reaction. The resulting ceramide mimic is then conjugated with a glycosyl azide (or alkyne) throughthrough CuAACCuAAC “click”“click” chemistrychemistry asas illustratedillustrated belowbelow (Scheme(Scheme2 2).).

O COOH + + N m H H C n m= 3, 9 n= 3, 7, 9

Ugi-4CR or NH2 NH2 N3

O X= CCH m O or CH N 2 3 X N N H n

CuAAC Sugar or Sugar N O 3

Sugar-Triazol-Ceramide Scheme 2. Synthetic pathway of sugar-triazol-ceramides. Scheme 2. Synthetic pathway of sugar-triazol-ceramides. This novel approach to complex GLs turned out to be very efficient with average yields of nearly 80% Thisfor both novel sequential approach steps, to complex facilitating GLs the turned rapid out creation to be veryof libraries efficient for with this averageclass of yieldsUgi/click of nearlyglycolipids. 80% for both sequential steps, facilitating the rapid creation of libraries for this class of Ugi/click glycolipids. 3. Functionalized Carbohydrate Scaffolds 3. Functionalized Carbohydrate Scaffolds Functionalized carbohydrate scaffolds are often related to the concept of multivalency. Functionalized carbohydrate scaffolds are often related to the concept of multivalency. Multivalency can be defined as the “ability of a particle (or molecule) to bind another particle (or Multivalency can be defined as the “ability of a particle (or molecule) to bind another particle molecule) via multiple and simultaneous non-covalent interactions” [41]. Knowing that: (1) (or molecule) via multiple and simultaneous non-covalent interactions” [41]. Knowing that: carbohydrates are involved in a wide range of biological processes via non covalent interactions with (1) carbohydrates are involved in a wide range of biological processes via non covalent interactions lectins (which are specific carbohydrate proteins found inside and outside cells in animals, plants and with lectins (which are specific carbohydrate proteins found inside and outside cells in animals, microorganisms) [42–45]; (2) the binding affinity between carbohydrates and proteins is very weak, plants and microorganisms) [42–45]; (2) the binding affinity between carbohydrates and proteins is then, the multivalency concept a.k.a. “cluster effect” becomes perfectly obvious: multiple and very weak, then, the multivalency concept a.k.a. “cluster effect” becomes perfectly obvious: multiple simultaneous interactions occurring between lectins and their sugar ligands will result in a and simultaneous interactions occurring between lectins and their sugar ligands will result in a considerably stronger binding [46,47]. In this regard, functionalized carbohydrate scaffolds are well considerably stronger binding [46,47]. In this regard, functionalized carbohydrate scaffolds are well suited for ligand presentation as multivalent glycoconjugates. Recent reviews have described such suited for ligand presentation as multivalent glycoconjugates. Recent reviews have described such multivalent glycoconjugates and their therapeutic efficiency [48,49]. Cyclodextrins and calixarenes, multivalent glycoconjugates and their therapeutic efficiency [48,49]. Cyclodextrins and calixarenes, for example, offer intrinsic scaffolds for this purpose, owing to their numerous functionalization for example, offer intrinsic scaffolds for this purpose, owing to their numerous functionalization opportunities, whereas dendrimers can be tailored to the desired generation and functionality. opportunities, whereas dendrimers can be tailored to the desired generation and functionality. 3.1. Glycocyclodextrins 3.1. Glycocyclodextrins Cyclodextrins (CDs) are torus-like cyclic oligosaccharides, α-, β- and γ-CD being the most well- Cyclodextrins (CDs) are torus-like cyclic oligosaccharides, α-, β- and γ-CD being the most known of them. Thus, α-CD is composed of six glucopyranose units linked via an α-1,4 glycosidic well-known of them. Thus, α-CD is composed of six glucopyranose units linked via an α-1,4 glycosidic bond, β-CD is the most often used and comprises seven Glc units compared to eight units for the larger γ-CD [50]. Their internal cavity is hydrophobic and CDs can form inclusion complexes with guest molecules. A β-cyclodextrin scaffold has been used to synthesize a multivalent polycationic glyco-amphiphile cyclodextrin (pGaCD) as a gene delivery system [51,52]. The upper rim of the CD is functionalized with a glyco-cationic moiety while the lower rim exhibits lipophilic tails (Scheme 3).

Molecules 2018, 23, 89 6 of 25 bond, β-CD is the most often used and comprises seven Glc units compared to eight units for the larger γ-CD [50]. Their internal cavity is hydrophobic and CDs can form inclusion complexes with guest molecules. A β-cyclodextrin scaffold has been used to synthesize a multivalent polycationic glyco-amphiphile cyclodextrin (pGaCD) as a gene delivery system [51,52]. The upper rim of the CD is functionalized with a glyco-cationic moiety while the lower rim exhibits lipophilic tails (Scheme3). Molecules 2018, 23, 89 6 of 25

SchemeScheme 3.3. SyntheticSynthetic pathwaypathway of a multivalent polycation polycationicic glyco-amphiphile glyco-amphiphile cyclodextrin. cyclodextrin. Reagents Reagents and Conditions: (i) DCM, TEA, 98%; (ii) NaOMe/MeOH, 97%; (iii) 2% TFA, 99%; (iv) SCN(CH2)6NCS, and Conditions: (i) DCM, TEA, 98%; (ii) NaOMe/MeOH, 97%; (iii) 2% TFA, 99%; (iv) SCN(CH2)6NCS, acetone-H2O, 52%; (v) DMF, TEA, 40 °C,◦ 48 h, 84%; (vi) TFA-DCM, r.t., 3 h, freeze-drying from diluted acetone-H2O, 52%; (v) DMF, TEA, 40 C, 48 h, 84%; (vi) TFA-DCM, r.t., 3 h, freeze-drying from diluted HCl,HCl, 99%.99%.

StartingStarting from from the the known known 2-azidoethyl 2-azidoethyl peracetylated- peracetylated-α-D-mannopyranosideα-D-mannopyranoside and bis(2- and bis(2-aminoethyl)-(2-aminoethyl)-(2-N-BOC-ethyl)amineN-BOC-ethyl)amine respectively, respectively, the isocyanato the isocyanato sugar sugarderivative derivative 9 and9 theand theorthogonally orthogonally protected protected 10 were10 were readily readily obtained. obtained. They were They reacted were reactedwith TEA with to afford TEA to the afford adduct the adduct11 in almost11 in almost quantitative quantitative yield. yield. Acetyl Acetyl and andthen then trityl trityl cleavage cleavage were were conducted conducted with with the the same same efﬁciencyefficiency toto givegive thethe amineamine 1313 subsequentlysubsequently reacted with with the the spac spacerer 1,6-hexamethylene 1,6-hexamethylene diisocyanate diisocyanate toto afford afford the the glyco-cationicglyco-cationic moietymoiety 1414.. A thiourea linkage linkage between between the the known known ββ-CD-CD derivative derivative 1515 andand compoundcompound14 14was was formed formed under under TEA TEA catalysis, catalysis, and and carbamate carbamate deprotection deprotection gave gave the the ﬁnal final pGaCD pGaCD17 in17 excellent in excellent yield. yield. Here, Here, the chemistry the chemistry involved involved in this in synthesis this synthesis uses an uses amine-isothiocyanate an amine-isothiocyanate reaction forreaction the high for yieldsthe high it deliversyields it anddelivers to provide and to a prov thioureaide a belt,thiourea which belt, is expectedwhich is expected to interact to favorably interact withfavorably the phosphate with the groupsphosphate of the grou plasmidps of the chain. plasmid This pGaCD chain. This was indeedpGaCD able was to indeed self-assemble able to inself- the presenceassemble of in plasmid the presence DNA of leading plasmid to DNA stable leading nanoparticles to stable ranging nanoparticles from 70 ranging to 150 nm from in 70 size. to 150 nm in size. 3.2. Glycocalixarenes 3.2. Glycocalixarenes Calix[n]arenes are macrocyclic compounds composed of n phenolic units connected by methylene bridgesCalix[ [53].n]arenes They possess are macrocyclic a vase shape compounds with a cylindrical composed hydrophobic of n phenolic cavity units able connected to accomodate by inclusionmethylene compounds bridges [53]. much They like possess CDs. a vase Both shape sides with of the a cylindrical calixarene (upperhydrophobic and lowercavity rim)able canto beaccomodate easily derivatized—for inclusion compounds what much we are like concerned CDs. Both here—withsides of the calixarene saccharide (upper units and giving lower rise rim) to glycocalixarenescan be easily derivatized—for [54]. what we are concerned here—with saccharide units giving rise to glycocalixarenes [54]. A typical example is the synthesis of galactosyl- and lactosylcalix[4]arenes from tetraamino calixarenes with a CuAAC coupling as the key-step (Scheme 4) [55].

Molecules 2018, 23, 89 7 of 25

A typical example is the synthesis of galactosyl- and lactosylcalix[4]arenes from tetraamino Moleculescalixarenes 2018, with 23, 89 a CuAAC coupling as the key-step (Scheme4)[55]. 7 of 25

Scheme 4. SynthesisSynthesis of of glycosyl glycosyl calix[4]arenes calix[4]arenes from from te tetraaminotraamino calixarenes. calixarenes. Reag Reagentsents and and Conditions: Conditions: (i) ClC(O)CH2Cl, DIPEA, DCM, room temperature, 6 h (55%); (ii) NaN3, MeOH/DMF, reflux, 1 h (i) ClC(O)CH2Cl, DIPEA, DCM, room temperature, 6 h (55%); (ii) NaN3, MeOH/DMF, reﬂux, 1 h (75%); (75%); (iii) CuSO4.5H2O, Na-ascorbate, DMF/H2O, MW (150◦ W), 80 °C, 20 min (81%); (iv) (iii) CuSO4.5H2O, Na-ascorbate, DMF/H2O, MW (150 W), 80 C, 20 min (81%); (iv) NaOMe/MeOH, NaOMe/MeOH,room temperature, room 1 h temperature, (quantitative). 1 h (quantitative).

Calixarene derivative 18 was first first treated with chloroacetylchloride and then with sodium azide to give the tetraazido calixarene 20. Peracetylated Peracetylated galactopyranose galactopyranose was reacted with monopropargyl triethylene glycol glycol in in the the presence presence of of BF BF3·OEt3·OEt2 to2 yieldto yield the theazidosugar azidosugar derivative derivative 21. Coupling21. Coupling the later the compoundlater compound with with20 under20 under click-chemistry click-chemistry conditions conditions yielded yielded 2222 furtherfurther deacetylated deacetylated to to the the final final calixarene 23. The The lactosyl lactosyl cluster cluster deriva derivativetive was similarly prepared. An An interesting feature with calixarenes is their relative mobility from a conformational viewpoint. Depending on the size of the alkyl substituents on the phenolic OH lower rim, th theyey can actually exist in four main conformations (the so-called cone, partial cone, 1,2-alternate and 1,3-alternate) [56]. [56]. In this regard, the 1,3-alternate conformation was also prepared with both saccharides by thethe authors.authors. Surface plasmon resonance (SPR) experiments experiments were were then then carried carried out out on on surface surface immobilized immobilized His-tagged His-tagged Galectin-3 Galectin-3 showing showing that athat better a better affinity affinity was wasobserved observed with withthe lactosyl the lactosyl cluster cluster and andthe cone the coneconformation conformation over overthe 1,3- the 1,3-alternatealternate one. one.

3.3. Glycodendrimers Glycodendrimers are are currently emerging as an area of growing activity as multivalent glycoclusters asas evidencedevidenced byby the the numerous numerous surveys surveys recently recently dedicated dedicated to thisto this ﬁeld field (see (see reference reference [49] [49]for the for mostthe most recent recent review). review). In a recent contribution [[57],57], a library of 12 amphiphilicamphiphilic Janus glycodendrimers [58] [58] composed of variable variable carbohydrate carbohydrate head head groups groups and and hydrophobic hydrophobic tail tailgroups groups linked linked to an to azobenzene an azobenzene core have core beenhave synthesized been synthesized using usingsuccessive successive Steglich Steglich esterifi esteriﬁcationcation and Hüisgen and Hüisgen cycloaddition cycloaddition reactions. reactions. The generalThe general synthesis synthesis is outlined is outlined below below for forone one of ofthe the dendrimers dendrimers 3131 bearingbearing branched branched alkyl alkyl chains chains on one side and a D-mannose derivative on the opposite side (Scheme5 5).).

Molecules 2018, 23, 89 8 of 25 Molecules 2018, 23, 89 8 of 25

Scheme 5. Synthesis of a D-mannose dendrimer amphiphile Reagents and Conditions: (i) 4- Scheme 5. Synthesis of a D-mannose dendrimer amphiphile Reagents and Conditions: (dimethylamino)pyridinium p-toluenesulfonate, DCC, DCM, 56–61%; (ii) pentaerythritol, PTSA, (i) 4-(dimethylamino)pyridinium p-toluenesulfonate, DCC, DCM, 56–61%; (ii) pentaerythritol, PTSA, DMF, 50 °C, 46–61%; (iii) 4-(dimethylamino)pyridinium p-toluenesulfonate, DCC, DCM, 46–67%; (iv) DMF, 50 ◦C, 46–61%; (iii) 4-(dimethylamino)pyridinium p-toluenesulfonate, DCC, DCM, 46–67%; CuSO4, sodium ascorbate, THF/water (2:1 v/v), 40 °C, 31–54%.◦ (iv) CuSO4, sodium ascorbate, THF/water (2:1 v/v), 40 C, 31–54%.

TheThe resulting resulting glycodendrimersglycodendrimers self-assembledself-assembled in water to give uniform cylindrical cylindrical micelles micelles of of variousvarious size size asas evidencedevidenced byby differentialdifferential lightlight scattering (DLS) and and small small angle angle neutron neutron scattering. scattering. TheThe azo-benzene azo-benzene corecore exhibitingexhibiting trans-cistrans-cis isomerismisomerism under UV-light, UV-light, was was used used here here to to make make the the glycodendrimerglycodendrimer micellesmicelles phototunable,phototunable, allowingallowing to evaluateevaluate their potency as as inhibitors inhibitors of of LecA LecA and and LecBLecB bacterial bacterial lectins. lectins. OnlyOnly aa moderatemoderate activityactivity waswas recorded, though, a a result result imputed imputed to to a a low low light light penetrationpenetration inside inside the the micelle micelle toto reachreach itsits core.core. Chevolot, Morvan et al. targeted the same Lectin A with a family of 32 glycodendrimers of Chevolot, Morvan et al. targeted the same Lectin A with a family of 32 glycodendrimers generation 0 and 1 constructed by CuAAC coupling with azido-functionalized glycosides [59]. High of generation 0 and 1 constructed by CuAAC coupling with azido-functionalized glycosides [59]. affinity values were obtained when aromatic aglycones were used with the carbohydrate motif, High afﬁnity values were obtained when aromatic aglycones were used with the carbohydrate motif, confirming that the topology of the glycocluster is equally important as multivalency itself. conﬁrming that the topology of the glycocluster is equally important as multivalency itself. Interestingly, multivalency of small saccharide units can also be used to mimic the effect of larger Interestingly, multivalency of small saccharide units can also be used to mimic the effect of larger polysaccharides. Chondroitin sulfate (CS) for example, is a heterogeneous polysaccharide involved polysaccharides. Chondroitin sulfate (CS) for example, is a heterogeneous polysaccharide involved in several diseases. CS binds to many proteins via the disaccharide GlcA-GalNAc (4,6-di-OSO3) unit. in several diseases. CS binds to many proteins via the disaccharide GlcA-GalNAc (4,6-di-OSO ) unit. The need for homogeneous synthetic CS is thus clear but its synthesis is challenging. Therefore,3 The need for homogeneous synthetic CS is thus clear but its synthesis is challenging. Therefore, glycodendrimers featuring the sulfated disaccharide group may be a good alternative for this glycodendrimers featuring the sulfated disaccharide group may be a good alternative for this purpose. purpose. The dissacharide unit synthesis begins with the trichloroacetimidate 32 treated with 3- The dissacharide unit synthesis begins with the trichloroacetimidate 32 treated with 3-azidopropanol azidopropanol and TMSOTf as promoter (Scheme 6). Compound 6 was then protected in two steps and TMSOTf as promoter (Scheme6). Compound 6 was then protected in two steps with a with a 4,6-O-di-tert-butylsilylene group leaving the 3-OH free for glycosidation with the donor 36. O tert 4,6- -di-The disaccharide-butylsilylene 37 was group then leaving selectively the 3-OH deprotected free for on glycosidation its 4- and 6-OH with positions the donor to36 allow. their subsequentThe disaccharide sulfonation37 usingwas then a large selectively excess of deprotected sulfur trioxide on its trimethylamine, 4- and 6-OH positions to eventually to allow afford their subsequentthe desired sulfonation compound using 40 after a large basic excess hydrolysis of sulfur and trioxide deacetylation. trimethylamine, Tri-, totetra- eventually and hexavalent afford the desireddendritic compound cores were40 thenafter reacted basic hydrolysis with the disaccharide and deacetylation. units under Tri-, tetra-CuAAC and conditions hexavalent illustrated dendritic coresbelow were for thenthe hexavalent reacted with glycodendrimer the disaccharide 41 (Scheme units under 7). CuAAC conditions illustrated below for the hexavalent glycodendrimer 41 (Scheme7).

Molecules 2018, 23, 89 9 of 25

Scheme 6. Synthesis of a dissacharide unit starting from trichloroacetimidate 32. Reagents and Scheme 6. Synthesis of a dissacharide unit starting from trichloroacetimidate 32. Reagents and Conditions: (i) 3-Azidopropanol, TMSOTf, DCM,◦ 0 °C, 81%; (ii) NaOMe, MeOH, 96%; (iii) Conditions: (i) 3-Azidopropanol, TMSOTf, DCM, 0 C, 81%; (ii) NaOMe, MeOH, 96%; (iii) tBu2Si(OTf)2, SchemetBu2Si(OTf) 6. 2Synthesis, Py, 94%; of(iv) a TMSOTf,dissacharide DCM, unit 0 °C,starting 80%; (v)from (HF)n·Py, trichloroacetimidate THF, 0 °C, 95%; 32. (vi)Reagents SO3·Me and3N, Py, 94%; (iv) TMSOTf, DCM, 0 ◦C, 80%; (v) (HF)n·Py, THF, 0 ◦C, 95%; (vi) SO ·Me N, DMF, 100 ◦C, Conditions:DMF, 100 °C, (i) MW, 3-Azidopropanol, 85%; (vi) LiOH, HTMSOTf,2O2, THF; DCM, NaOH, 0 MeOH/H °C, 81%;2O; (ii) Ac 2O,NaOMe, Et3N, MeOH/H3MeOH,3 2O,96%; 73%. (iii) MW, 85%; (vi) LiOH, H O , THF; NaOH, MeOH/H O; Ac O, Et N, MeOH/H O, 73%. tBu2Si(OTf)2, Py, 94%;2 (iv)2 TMSOTf, DCM, 0 °C, 80%;2 (v) (HF)n·Py,2 3 THF, 0 °C, 95%;2 (vi) SO3·Me3N, DMF, 100 °C, MW, 85%; (vi) LiOH, H2O2, THF; NaOH, MeOH/H2O; Ac2O, Et3N, MeOH/H2O, 73%.

Scheme 7. Synthesis of a hexavalent glycodendrimer via CuAAC coupling Reagents and Conditions:

CuSO4·5H2O, sodium ascorbate, TBTA, DMSO/PBS buffer, room temperature, overnight, Schemequantitative. 7. Synthesis of a hexavalent glycodendrimer via CuAAC coupling Reagents and Conditions: Scheme 7. Synthesis of a hexavalent glycodendrimer via CuAAC coupling Reagents and Conditions: CuSO4·5H2O, sodium ascorbate, TBTA, DMSO/PBS buffer, room temperature, overnight, CuSO ·5H O, sodium ascorbate, TBTA, DMSO/PBS buffer, room temperature, overnight, quantitative. quantitative.All4 glycodendrimers2 were then successfully investigated for their multivalent properties against Allmidkine glycodendrimers (an heparin-binding were thengrowth successfully factor) to give investigated IC50 up to 1.2 for µM their for multivalent the hexavalent properties compound against 42. OnAll the glycodendrimers other hand, the were disaccharide then successfully itself exhi investbitedigated a very for theirlow affinitymultivalent for midkine properties (250 against µM) midkine (an heparin-binding growth factor) to give IC50 up to 1.2 µM for the hexavalent compound 42. midkineconfirming (an the heparin-binding value of the glucomimetics growth factor) approach to give IC developped50 up to 1.2 in µM this for work. the hexavalent compound On the other hand, the disaccharide itself exhibited a very low affinity for midkine (250 µM) confirming 42. OnMany the glucodendrimerother hand, the syntheses disaccharide take itselfadvantage exhibited of the a CuAACvery low coupling affinity [60–62], for midkine and not (250 only µM) for the valueconfirmingconnecting of the the glucomimetics valuesaccharide of the moiety. glucomimetics approach Thus, developped Das approach and Mukhopadhyay developped in this work. in this[63] work.for example, synthesized a Manypropargyl-functionalizedMany glucodendrimer glucodendrimer synthesesZn syntheses-porphyrin, take take furtheradvantage advantage conjugated of of the the CuAAC CuAACwith the coupling couplingseparately [60–62], [60 constructed– 62and], andnot only notazido- onlyfor for connectingconnectingfunctionalized the the saccharide mannose saccharide dendritic moiety. moiety. building Thus,Thus, Dasblocks. Das and and Synt Mukhopadhyay Mukhopadhyayhesis of the 1st and[63] [2nd63for] generationexample, for example, synthesized carbohydrate synthesized a a propargyl-functionalizedpropargyl-functionalizeddendrimers involved a click Zn Zn-porphyrin,reaction,-porphyrin, as well further as further the conjugated coupling conjugated step with with the the with separately porphyrin the separately constructedcore. constructed azido- azido-functionalizedfunctionalizedFinally, thiol-yne mannose mannose dendriticcoupling dendritic building(TYC) buildingor blocks. thiol- Syntene blocks. hesiscoupling of Synthesisthe (TEC)1st and are of2nd themild generation 1st and and high-yielding carbohydrate 2nd generation carbohydratedendrimersreactions dendrimerswhich involved proved a click involved especially reaction, a clickuseful as well reaction, in as glycos the coupling asidation well asstepsynthesis the with coupling the and porphyrin this step topic with core. has the recently porphyrin been core. Finally,reviewedFinally, thiol-yne[64]. thiol-yne coupling coupling (TYC) (TYC) oror thiol-enethiol-ene coupling coupling (TEC) (TEC) are are mild mild and and high-yielding high-yielding reactions which proved especially useful in glycosidation synthesis and this topic has recently been reactions which proved especially useful in glycosidation synthesis and this topic has recently been reviewed4. Vesicles, [64]. Liposomes reviewed [64]. It is known that the overall shape of an aggregate is driven by the shape of the amphiphilic 4. Vesicles, Liposomes 4. Vesicles,molecule Liposomes that produced it. When the amphiphiles are wedge-shape (cross section of the polar head is greaterIt is knownthan that that of the the overallside chain—a shape oftypical an aggregate situation is for driven a single by thelipidic shape chain of surfactant)the amphiphilic their Itmoleculeself-association is known that thatproduced produces the overall it. a sphericalWhen shape the micellar amphiphiles of an struct aggregate ure.are wedge-shape For is truncated-cone driven (cross by the shapes,section shape aggregationof of the the polar amphiphilic giveshead moleculeiscylindrical greater that than produced micelles. that of Finally,it. the When side for chain—a the cylindrical amphiphiles typical amphiphiles situation are wedge-shape for(cross-section a single lipidic (cross of the chain section polar surfactant) head of the roughly polar their head is greaterself-associationequals than that thatof the produces of side-chain, the side a spherical chain—a usually micellar when typical astruct doub situationure.le fatty For truncated-cone foracid a chain single islipidic involved) shapes, chain aggregation a planar surfactant) bilayer gives their self-associationcylindrical micelles. produces Finally, a spherical for cylindrical micellar structure.amphiphiles For (cross-section truncated-cone of the shapes, polar aggregationhead roughly gives cylindricalequals micelles.that of the Finally, side-chain, for cylindrical usually when amphiphiles a double fatty (cross-section acid chain ofis theinvolved) polar heada planar roughly bilayer equals that of the side-chain, usually when a double fatty acid chain is involved) a planar bilayer sheet Molecules 2018, 23, 89 10 of 25 Molecules 2018, 23, 89 10 of 25 issheet formed. is formed. Then, closure Then, ofclosure the bilayer of the sheet bilayer yields sheet spherical yields structuresspherical structures called vesicles, called entrapping vesicles, anentrapping aqueous domainan aqueous isolated domain from isolated the outer from aqueous the outer medium. aqueous Artificially medium. Artificially constructed constructed vesicles are calledvesicles liposomes. are called Depending liposomes. Depending on experimental on experimental conditions, conditions, several types several of liposomestypes of liposomes are obtained: are Molecules 2018, 23, 89 10 of 25 multilamellarobtained: multilamellar vesicles (MLV), vesicles small (MLV), unilamellar small unilame vesiclesllar (SUV), vesicles large (SUV), unilamellar large unilamellar vesicles vesicles (LUV) or giant(LUV) unilamellar sheetor giant is formed.unilamellar vesicles Then, (GUV) vesicles closure [65 (GUV)–of67 the]. [65–67].bilayer sh eet yields spherical structures called vesicles, SphericalSphericalentrapping micellesmicelles an aqueous havehave domain beenbeen isolated obtained from fromthe from outer the the aqueous self-assembly self-assembly medium. Artificiallyin in water water constructedof of a aseries series of of macromolecularmacromolecularvesicles are glycosylatedcalled liposomes. amphiphiles. amphiphiles. Depending onThey experimental They have have been conditions, been prepared prepared several by CuAACtypes by CuAACof liposomes coupling coupling are of 1-O- of 1-propargylO-propargylobtained: saccharides saccharides multilamellar (N-acetyl (N vesicles-acetyl glucosamine (MLV), glucosamine small and unilame lactose) and lactose)llar and vesicles various and (SUV), various azido-terminated large azido-terminated unilamellar PEG900 vesicles PEG900 esters (LUV) or giant unilamellar vesicles (GUV) [65–67]. esters[68–71]. [68 –In71 a]. representative In a representative work, work,C18PEG C90018GlcNAcPEG900GlcNAc 46 and 46C18andPEG900 C18LacPEG 47900 wereLac obtained47 were obtainedfrom a Spherical micelles have been obtained from the self-assembly in water of a series of 45 fromcommon a commonmacromolecular intermediate intermediate glycosylated 45 (Scheme(Scheme amphiphiles.8). This8 stearate). This They stearate derivative have been derivative wasprepared prepared was by CuAAC prepared in a few coupling steps in a few from of 1- steps OPEG900- from PEG900by monotosylationpropargyl by monotosylation saccharides followed (N followed -acetylby substitution glucosamine by substitution of andthe lactose)tosyl of group the andtosyl various with group sodium azido-terminated with azide. sodium PEG900 azide. esters [68–71]. In a representative work, C18PEG900GlcNAc 46 and C18PEG900Lac 47 were obtained from a common intermediate 45 (Scheme 8). This stearate derivative was prepared in a few steps from PEG900 by monotosylation followed by substitution of the tosyl group with sodium azide.

SchemeScheme 8.8. Synthesis of of stearoyl stearoyl amphiphiles, amphiphiles, GlcNAc GlcNAc 4646 andand Lac Lac 47.47 Reagents. Reagents and andConditions: Conditions: (i) TsCl, AgScheme2O, KI, 8. SynthesisDCM, 55%; of stearoyl (ii) NaN amphiphiles,3, DMF, 85%; GlcNAc (iii) 46 DCC, and LacDMAP, 47. Reagents stearic and acid, Conditions: DCM, 82%; (i) (iv) (i) TsCl, Ag2O, KI, DCM, 55%; (ii) NaN3, DMF, 85%; (iii) DCC, DMAP, stearic acid, DCM, 82%; CuSO4,TsCl, sodium Ag2O, ascorbate, KI, DCM, propargyl-2-55%; (ii) NaNN3, -acetamido-2-deoxy-DMF, 85%; (iii) DCC, DMAP,β-D-glucopyranoside, stearic acid, DCM, THF/H 82%; (iv)2O, 72%; (iv) CuSO4, sodium ascorbate, propargyl-2-N-acetamido-2-deoxy-β-D-glucopyranoside, THF/H2O, CuSO4, sodium ascorbate, propargyl-2-N-acetamido-2-deoxy-β-D-glucopyranoside, THF/H2O, 72%; 72%;(v) CuSO (v) CuSO4, sodium, sodium ascorbate, ascorbate, propargyl- propargyl-β-lactopyranoside,β-lactopyranoside, THF/H THF/H2O, 67%.O, 67%. (v) CuSO4 4, sodium ascorbate, propargyl-β-lactopyranoside, THF/H2O, 67%. 2

BothBoth glycoconjugates glycoconjugatesBoth glycoconjugates 4646 and and46 and 4747 47spontaneouslyspontaneously spontaneously self-assembled in inwater in water water into into intospherical spherical spherical micelles micelles micelles withwith a a mean withmean a diameter meandiameter diameter of of 1010 of nmnm 10 nm (Figure(Figure (Figure3 3).). 3).

. Figure 3. Transmission electronic microscopy (TEM) images for the self-assemblies of 46 (a) and 47 (b) Figure 3. Transmission electronic microscopy (TEM) images for the self-assemblies of 46 (a) and . 47 (taken with(b) (taken permission with permission from reference from reference [69]). [69]). Figure 3. Transmission electronic microscopy (TEM) images for the self-assemblies of 46 (a) and 47 Speciﬁc interactions of both 46 and 47 with lectins (Wheat Germ Agglutinin and Peanut (b) (takenSpecific with interactionspermission fromof both reference 46 and [69]). 47 with lectins (Wheat Germ Agglutinin and Peanut Agglutinin)Agglutinin) proved proved the presence the presence of theof the sugar sugar residues residues at at the the surface surface of the of themicelles micelles demonstrating demonstrating their potentialSpecifictheir potential interactions application application inof drug bothin drug delivery46 delivery and mediated47 mediated with lectinsby carbohydrate-protein carbohydrate-protein (Wheat Germ interactions.Agglutinin interactions. and Peanut To efﬁciently link a sugar derivative to a lipidic tail, thiol-yne/ene click-chemistry already quoted Agglutinin) proved the presence of the sugar residues at the surface of the micelles demonstrating intheir Section potential 3.3) can application be considered in drug as delivery a complementary mediated toolby carbohydrate-protein to the Hüisgen (CuAAC) interactions. reaction [72]. In a

MoleculesMolecules2018, 23 2018, 89, 23, 89 11 of 25 11 of 25

To efficiently link a sugar derivative to a lipidic tail, thiol-yne/ene click-chemistry already quoted in Section 3.3) can be considered as a complementary tool to the Hüisgen (CuAAC) reaction [72]. In a recent publication, Goyard et al. [24] reacted 1-propargyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside recent publication, Goyard et al. [24] reacted 1-propargyl-2,3,4,6-tetra-O-acetyl-β-D-glucopyranoside 49 49 withwith dodecane-, dodecane-, tetradecane- tetradecane- and and hexadecanethiols hexadecanethiols in the in presence the presence of AIBN of to AIBN give the to expected give the GL expected Molecules 2018, 23, 89 11 of 25 GL derivativesderivatives (as (as 1:1 1:1 diastereoisomer diastereoisomer mixtures) mixtures) in very in very high highyields yields (Scheme (Scheme 9). 9). Molecules 2018, 23, 89 11 of 25 To efficiently link a sugar derivative to a lipidic tail, thiol-yne/ene click-chemistry already quoted in SectionTo efficiently 3.3) can linkbe considered a sugar derivative as a complementar to a lipidic ytail, tool thiol-yne/ene to the Hüisgen click-chemistry (CuAAC) reaction already [72]. quoted In a inrecent Section publication, 3.3) can beGoyard considered et al. [24] as areacted complementar 1-propargyl-2,3,4,6-tetra-y tool to the HüisgenO-acetyl- (CuAAC)β-D-glucopyranoside reaction [72]. In 49 a recentwith dodecane-, publication, tetradecane- Goyard et al. and [24] hexadecanethiols reacted 1-propargyl-2,3,4,6-tetra- in the presence ofO-acetyl- AIBN toβ- Dgive-glucopyranoside the expected GL 49 withderivatives dodecane-, (as 1:1 tetradecane- diastereoisomer and hexadecanethiols mixtures) in very in high the yieldspresence (Scheme of AIBN 9). to give the expected GL derivatives (as 1:1 diastereoisomer mixtures) in very high yields (Scheme 9).

SchemeScheme 9. Thiol-yne/ene 9. Thiol-yne/ene chemistry chemistry for for the the synthesissynthesis of of GLs. GLs. Reagents Reagents and andCond Conditions:itions: (i) Propargyl (i) Propargyl ◦ alcohol,alcohol, BF3·OEt BF32·OEt, DCM,2, DCM, 0 0C °C to to room room temperature, temperature, 2 2 h, h, 91%; 91%; (ii) (ii) CH CH3CH3CH2(CH22(CHCH2)2nSH,CH 2AIBN,)nSH, AIBN, dioxane,dioxane, 100 ◦C, 100 1 °C, h, 95%;1 h, 95%; (iii) (iii) MeONa, MeONa, MeOH, MeOH, room temperature, temperature, 1 h, 1 96%. h, 96%. The Gal (56), Man (57) and Lac (58) derivatives have been prepared similarly. The GLs were The Gal (56), Man (57) and Lac (58) derivatives have been prepared similarly. The GLs were capableScheme of self-assembling 9. Thiol-yne/ene into chemistry vesicles for. theAmong synthesis them, of GLs. vesicles Reagents prepared and Cond fromitions: 53 (i) andPropargyl 57 formed capable of self-assembling into vesicles. Among them, vesicles prepared from 53 and 57 formed multivalentSchemealcohol, interactions 9.BF Thiol-yne/ene3·OEt2, DCM, with chemistry 0concanavalin °C to room for the temperature, Asynthesis (ConA) of used2GLs. h, 91%;Reagents as a (ii) model CHand3CH Condlectin.2(CHitions: 2Furthermore,CH 2(i))nSH, Propargyl AIBN, 57 was multivalentable to interactions alcohol,dioxane,bind to BF100 murin3·OEt °C, with 21, dendritich,DCM, 95%; concanavalin 0(iii) °C cellsMeONa, to roomand MeOH, A totemperature, (ConA) en capsulateroom temperature, used 2 h, hydrophobic 91%; as a (ii) model1 h, CH 96%.3 CHcomp lectin.2(CHounds2CH Furthermore,2)n SH,like AIBN, Taxol, thus57 was able paving dioxane,the way 100 to °C,the 1 vectorization h, 95%; (iii) MeONa, of active MeOH, substances room temperature, to specific 1 h, cells. 96%. to bind to murinThe Gal dendritic (56), Man cells (57) and and toLac encapsulate (58) derivatives hydrophobic have been prepared compounds similarly. like The Taxol, GLs were thus paving A method of choice for the surface functionalization of liposomes calls on the Staudinger ligation the way tocapable theThe vectorization ofGal self-assembling (56), Man of(57 active )into and vesicles.Lac substances (58) Amongderivatives to them, speciﬁc have vesicles been cells. preparedprepared similarly.from 53 and The 57GLs formed were [73] named after the well-known Staudinger reaction between a phosphine and an azide giving an A methodcapablemultivalent of self-assembling choiceinteractions for with the into concanavalin surface vesicles. functionalizationAmong A (ConA) them, used vesicles as a of modelprepared liposomes lectin. from Furthermore, 53 calls and on57 formed the57 was Staudinger iminophosphoranemultivalent interactions which with hydrolizes concanavalin into anA (ConA)amine used[74]. asHere, a model to avoid lectin. the Furthermore, iminophosphorane 57 was ligation [73able] named to bind afterto murin the well-knowndendritic cells and Staudinger to encapsulate reaction hydrophobic between comp a phosphineounds like andTaxol, an thus azide giving hydrolysis,ablepaving to thebind the way tophosphine murinto the vectorizationdendritic features cells an of andelectrophilic active to substancesencapsulate trap tosuch hydrophobic specific as a methylcells. comp esterounds producing like Taxol, an thusamide an iminophosphoranebondpaving (TableA methodthe 3) way [75,76]. of to which choice the vectorization for hydrolizes the surface of active functionalizatio into substances an aminen toof [ 74specificliposomes]. Here, cells. calls to on avoid the Staudinger the iminophosphorane ligation hydrolysis,[73] the namedA method phosphine after of thechoice well-known features for the surface an Staudinger electrophilic functionalizatio reaction trap betweenn of suchliposomes a asphosphine a calls methyl on and the ester Staudingeran azide producing giving ligation an an amide bond (Table[73]iminophosphoraneTable3 )[named75 3.,76 Mechanisms after]. the which well-known for thehydrolizes Staudinger Staudinger into reaction an reaction am ineand between [74].ligation Here, ina phosphine water.to avoid Note andthe that iminophosphoranean the azide Staudinger giving an iminophosphoranehydrolysis,ligation leaves the phosphine a diphenylphosphinewhich featureshydrolizes an residueelectrophilicinto an in am thine etrap molecule. [74]. such Here, as The a methyl to“traceless” avoid ester the Staudinger producing iminophosphorane ligation an amide hydrolysis,(especially the useful phosphine in peptide features synthesis) an electrophilic [77] is not depicted trap such here. as a methyl ester producing an amide Tablebond 3. Mechanisms (Table 3) [75,76]. for the Staudinger reaction and ligation in water. Note that the Staudinger bond (Table 3) [75,76]. Staudinger reduction ligation leavesTable 3. a Mechanisms diphenylphosphine for the Staudinger residue reaction in the and molecule. ligation in water. The “traceless” Note that the Staudinger Staudinger ligation (especiallyTableligation useful 3. leavesMechanisms in peptide a diphenylphosphine for synthesis) the Staudinger [77 residue] isreaction not in depictedth ande molecule. ligation here. Thein water. “traceless” Note thatStaudinger the Staudinger ligation ligation(especially leaves useful a diphenylphosphinein peptide synthesis) residue [77] is notin thdepictede molecule. here. The “traceless” Staudinger ligation (especially useful in peptide synthesis)Staudinger [77] is not depicted reduction here. Staudinger reduction Staudinger reduction

Staudinger ligation

Staudinger ligation Staudinger ligation Staudinger ligation

The chemically-selective surface glyco-functionalization of liposomes through Staudinger ligation was popularized by Sun and co-workers [78–80]. They recently evaluated this reaction with a lactosyl azide and different ratios of two types of anchoring lipids in DPPC liposomes [81]. Lipids were Molecules 2018, 23, 89 12 of 25

MoleculesThe2018 chemically-selective, 23, 89 surface glyco-functionalization of liposomes through Staudinger12 of 25 ligation was popularized by Sun and co-workers [78–80]. They recently evaluated this reaction with a lactosyl azide and different ratios of two types of anchoring lipids in DPPC liposomes [81]. Lipids synthesized from cholesterol-PEG -NH and commercially available DSPE-PEG -NH with were synthesized from cholesterol-PEG2000 2000-NH2 2 and commercially available DSPE-PEG20002000-NH2 2with 3-diphenylphosphino-4-methoxycarbonylbenzoic3-diphenylphosphino-4-methoxycarbonylbenzoic acid acid active active ester ester (Scheme (Scheme 10) 10 )to to give give functional functional vesiclesvesicles withwith respect respect to to their their stability, stability, encapsulation encapsulation and release and release capacity, capacity, and their and lectin their binding lectin bindingefficiency. efﬁciency.

Scheme 10. Chemically-selective glycol-functionalization of liposomes by Staudinger ligation. Scheme 10. Chemically-selective glycol-functionalization of liposomes by Staudinger ligation. Reagents and Conditions: (i) DCM, TEA (50% Chol-PEG2000-TP, 30% DSPE-PEG2000-TP); (ii) Liposome Reagents and Conditions: (i) DCM, TEA (50% Chol-PEG2000-TP, 30% DSPE-PEG2000-TP); (ii) Liposome formulation then Staudinger ligation with 1-(2-azido)ethyl lactopyranoside. formulation then Staudinger ligation with 1-(2-azido)ethyl lactopyranoside.

5.5. Gels Gels HydrogelsHydrogels areare foundfound inin ourour everydayeveryday lifelife inin aa varietyvariety of forms and products. For For example example hydratedhydrated gel gel materials materials can can bebe usedused asas cosmeticscosmetics (shampoo, hair hair gel, gel, soaps soaps etc.). etc.). Importantly Importantly most most of of the gels, if not all, are derived from polymers. This type of gels has been known for many years with the gels, if not all, are derived from polymers. This type of gels has been known for many years with different applications in the fields of materials science, medicine, cosmetics, etc. Low molecular different applications in the fields of materials science, medicine, cosmetics, etc. Low molecular weight gels (LMWGs), which were developed more recently, offer an interesting alternative to weight gels (LMWGs), which were developed more recently, offer an interesting alternative to polymer-based gels. Indeed, thanks to their supramolecular nature LMWGs are thermoreversible and polymer-based gels. Indeed, thanks to their supramolecular nature LMWGs are thermoreversible allow a rapid response to external stimuli. Also, LMWGs can be used as biodegradable systems and allow a rapid response to external stimuli. Also, LMWGs can be used as biodegradable systems because of an easier clearance and/or elimination from the body compared to regular polymeric gels. because of an easier clearance and/or elimination from the body compared to regular polymeric Nevertheless, the supramolecular assemblies obtained using LMWGs are still poorly controlled and gels. Nevertheless, the supramolecular assemblies obtained using LMWGs are still poorly controlled it is still difficult to properly predict the gel behaviours depending on the molecular structure of the and it is still difficult to properly predict the gel behaviours depending on the molecular structure of components. In this regard, several LMWG based bioconjugates have been investigated recently for thetheir components. supramolecular In this gel regard, properties, several including LMWG basedlipids, bioconjugates carbohydrates, have nucleosides, been investigated amino acids recently or forpeptide their supramolecularderivatives. Among gel properties, them, glycoconjugates including lipids, have carbohydrates,been discovered nucleosides, to be interesting amino gelators acids or peptidefor biomedical derivatives. applications. Among them,In this glycoconjugates section, we present have several been discovered examples of to synthetic be interesting sugar gelatorsbased foramphiphiles biomedical forming applications. LMWGs. In this section, we present several examples of synthetic sugar based amphiphilesA gel can forming be defined LMWGs. as a molecular network able to immobilize a fluid (organic solvent or water) in aA very gel large can amount be defined (up to as more a molecular than 99% networkw/w) giving able rise to to immobilizea soft, jelly-like a fluidmaterial (organic [82,83]. solvent Such ormaterial water) can in abe very made large of polymeric amount chains (up to or more from than the self-assembly 99% w/w) giving of small rise molecules to a soft, (a.k.a. jelly-like low materialmolecular [82 ,weight83]. Such gelators) material a process can be madedriven of by polymeric weak molecular chains orinteractions from the self-assembly[84]. It is commonly of small moleculesbelieved now(a.k.a. that low gelation molecular is a stepwise weight gelators) process, astarting process from driven the bymolecular weak molecular level to the interactions macroscopic [84 ]. Itstructure. is commonly First, believed non-covale nownt that interactions gelation is (H-bonding, a stepwise process, π-π stacking, starting hydrophobic from the molecular forces) must level take to the macroscopicplace between structure. gelling First,molecules, non-covalent leading interactions to their nanostructuration (H-bonding, π- πinstacking, a one-dimensional hydrophobic fashion forces) must(fibers take formation). place between Then, gellingthe growing molecules, fibers form leading a continuous to their nanostructuration three-dimensional in entangled a one-dimensional network fashionin the solvent (fibers formation).under the same Then, non-covalent the growing set fibers of forc formes, to a eventually continuous give three-dimensional rise to a macroscopic entangled soft networkmaterial, in i.e., the a solventgel. The underexact mechanism the same non-covalent of self-organization set of forces,of the gelling to eventually agents is give still risepoorly to a macroscopicunderstood softespecially material, in i.e.,water. a gel. Nevertheless, The exact mechanisma simple packing of self-organization model to mimic of the fiber gelling formation agents isduring still poorly self-assembly understood was especiallyrecently developed in water. [85]. Nevertheless, The fiber is a considered simple packing as the model stacking to mimicof discrete fiber formationprisms exhibiting during self-assembly various hydrophobic was recently and developed hydrophilic [85 ].faces The fibercorrected is considered with several as the weighting stacking of discrete prisms exhibiting various hydrophobic and hydrophilic faces corrected with several weighting Molecules 2018, 23, 89 13 of 25 Molecules 2018, 23, 89 13 of 25 coefficientsMolecules 2018 representing, 23, 89 free energy penalties. Use of this model demonstrated that for 13selected of 25 coefficientsclasses of LMWGs, representing the fiber free structure energy penalties. represents Use the of thisthermodynamic model demonstrated minimum. that for selected classes of LMWGs,coefficients the representing fiber structure free represents energy penalties. the thermodynamic Use of this model minimum. demonstrated that for selected 5.1.classes Glycoconjugate of LMWGs, Based the Gelsfiber structure represents the thermodynamic minimum. 5.1. Glycoconjugate Based Gels 5.1.Hydrogels Glycoconjugate possess Based many Gels applications in tissue engineering [86,87], biosensing, drug or gene deliveryHydrogels [88–90], possess water manydepollution applications [91], etc. in tissueThe most engineering relevant [86 gelling,87], biosensing, agents for drug biomedical or gene deliveryapplicationsHydrogels [88 –90are], biologically-inspiredpossess water depollutionmany applications [ 91molecules], etc.in tissue The such engineering most as relevantpeptide-amphiphiles, [86,87], gelling biosensing, agents oligonucleotide- drug for biomedical or gene delivery [88–90], water depollution [91], etc. The most relevant gelling agents for biomedical applicationsamphiphiles or are glycosylated-amphiphiles. biologically-inspired molecules In the context such of as this peptide-amphiphiles, survey, only low molecular oligonucleotide- weight applications are biologically-inspired molecules such as peptide-amphiphiles, oligonucleotide- amphiphilesglycosylated-amphiphiles or glycosylated-amphiphiles. will be addressed In the with context a ofparticular this survey, interest only lowin molecularglyconucleolipid weight amphiphiles or glycosylated-amphiphiles. In the context of this survey, only low molecular weight glycosylated-amphiphilesamphiphiles. will be addressed with a particular interest in glyconucleolipid amphiphiles. glycosylated-amphiphiles will be addressed with a particular interest in glyconucleolipid For example, monolipidic disaccharides have b beeneen prepared by CuAAC cycloaddition of the amphiphiles. corresponding sugar azides with N-propargylpalmytoyl amide (Scheme 11)[92,93]. correspondingFor example, sugar monolipidic azides with disaccharides N-propargylpalmytoyl have been amidpreparede (Scheme by CuAAC 11) [92,93]. cycloaddition of the corresponding sugar azides with N-propargylpalmytoyl amide (Scheme 11) [92,93].

Scheme 11. SynthesisSynthesis of of lipidic lipidic disaccharides disaccharides by by CuAA CuAACC cycloaddition cycloaddition Reagents Reagents and and Conditions: Conditions: (i) C15SchemeH31CO2 H,11. THF, Synthesis DCC/HOBt, of lipidic room disaccharides temperature, by CuAA 2 days,C cycloaddition75%; (ii) Malt(OAc) Reagents7-N 3and or Cell(OAc)Conditions:7-N (i)3 or (i) C15H31CO2H, THF, DCC/HOBt, room temperature, 2 days, 75%; (ii) Malt(OAc)7-N3 or Lact(OAc)C15H31CO7-N2H,3, THF,CuBr, DCC/HOBt, PMDETA, room87%, 80%temperature, and 81% 2 resp. days, then 75%; MeONa, (ii) Malt(OAc) MeOH,7-N 385–90%, or Cell(OAc) 77% 7and-N3 or80% Cell(OAc)7-N3 or Lact(OAc)7-N3, CuBr, PMDETA, 87%, 80% and 81% resp. then MeONa, MeOH, Lact(OAc)7-N3, CuBr, PMDETA, 87%, 80% and 81% resp. then MeONa, MeOH, 85–90%, 77% and 80% 85–90%,resp. 77% and 80% resp. resp. The resulting disaccharidic GLs were efficientefficient hydrogelatorshydrogelators (0.5(0.5 toto 1 wt %). The contribution of The resulting disaccharidic GLs were efficient hydrogelators (0.5 to 1 wt %). The contribution of the triazole ring (giving π--π stacking)stacking) andand thethe amide-NHamide-NH moietymoiety (H-bonding)(H-bonding) in the hydrogelation the triazole ring (giving π-π stacking) and the amide-NH moiety (H-bonding) in the hydrogelation process was evidenced by nuclear magnetic resonanc resonancee (NMR). Furthermore, field field emission scanning process was evidenced by nuclear magnetic resonance (NMR). Furthermore, field emission scanning electron microscopy (FESEM) images ofof aa singlesingle ribbonribbon ofof Cell-Tz-CCell-Tz-C1616 exhibited a right-handed twist electron microscopy (FESEM) images of a single ribbon of Cell-Tz-C16 exhibited a right-handed twist whereas Lact-Tz-C 16 showedshowed a a left-handed left-handed twist twist suggesting suggesting that the nature of the disaccharide polar whereas Lact-Tz-C1616 showed a left-handed twist suggesting that the nature of the disaccharide polar headhead influencesinfluences influences the the supramolecular supramolecular chirality chirality (Figure(Figure4 4).).

FigureFigure 4. 4.FESEM FESEM images images of of a asingle single ribbon ribbon ofof Cell-Tz-C16 Cell-Tz-C16 (0.5(0.5 wtwt % % water) water) xerogel xerogel on on the the left left and and of of Lact-Tz-C16 on the right (1 wt % water) (taken with permission from reference [93]). Lact-Tz-C16 on the right (1 wt % water) (taken(taken with permission fromfrom referencereference [[93]).93]). Another aspect of GLs is their ability to self-aggregate with a long-range molecular ordering Another aspectaspect of of GLs GLs is is their their ability ability to self-aggregateto self-aggregate with with a long-range a long-range molecular molecular ordering ordering giving giving rise to a crystal-like structure while retaining a liquid behaviour. This state of matter is the risegiving to arise crystal-like to a crystal-like structure structure while retaining while retaining a liquid behaviour.a liquid behaviour. This state This of matter state isof the matter distinctive is the distinctive feature of liquid crystals (LCs). Thus, simple GLs regarded as rod-like molecules self- featuredistinctive of liquid feature crystals of liquid (LCs). crystals Thus, (LCs). simple Thus, GLs regardedsimple GLs as rod-likeregarded molecules as rod-like self-aggregate molecules self- into aggregate into lamellar assemblies with a tendancy to form columnar or spherical structures lamellar assemblies with a tendancy to form columnar or spherical structures according to their tail to aggregateaccording into to their lamellar tail to assemblieshead volume with ratio a[94]. tendan This cyphase to changeform columnar can be induced or spherical by an increase structures in head volume ratio [94]. This phase change can be induced by an increase in temperature (thermotropic accordingtemperature to their (thermotropic tail to head LCs) volume but also ratio if [94].their Thisconcentration phase change is varied can inbe ainduced solvent (lyotropicby an increase LCs) in temperature (thermotropic LCs) but also if their concentration is varied in a solvent (lyotropic LCs)

Molecules 2018, 23, 89 14 of 25

Molecules 2018, 23, 89 14 of 25 LCs) but also if their concentration is varied in a solvent (lyotropic LCs) resulting in more mobile ◦ structuresresulting giving in more rise mobile to additional structures phase giving changes. rise to additional At temperatures phase changes. above 90At temperaturesC, Malt-Tz-C above16 in the previous90 °C, Malt-Tz-C example16 exhibits in the previous a LC behaviour. example exhibits For Cell-Tz-C a LC behaviour.16 and Lact-Tz-C For Cell-Tz-C16 the16 and liquid Lact-Tz-C crystalline16 phasesthe liquid (mesophases) crystalline appeared phases (mesophases) above 150 ◦C, appear and Smecticed above A phase150 °C, (molecules and Smectic are A directionally phase (molecules ordered intoare layers) directionally for the ordered latter compounds into layers) wasfor the evidenced latter compounds by X-ray was diffraction. evidenced Of by course, X-ray diffraction. dealing with LCOf properties course, dealing of GLs with is beyond LC properties the scope of GLs of thisis beyond account the andscope further of this readingaccount and and further examples reading can be and examples can be found elsewhere [95–97]. Note, however, that thermotropic LC phases were found elsewhere [95–97]. Note, however, that thermotropic LC phases were much less studied than much less studied than LC structures formed in water, and other biomolecules can form such LC structures formed in water, and other biomolecules can form such materials [98]. materials [98]. Original asymmetric glyco bola-amphiphiles were obtained by Ochi et al. [99] by reacting Original asymmetric glyco bola-amphiphiles were obtained by Ochi et al. [99] by reacting 4- 4-aminophenylgluco-,aminophenylgluco-, galacto- galacto- and and manno- manno- pyranosides pyranosides with with an an am aminododecanoicinododecanoic acid acid derivative derivative (Scheme(Scheme 12 12).). Despite the the presence presence of an of activated an activated ester at ester one end at one of the end hydrocarbon of the hydrocarbon chain, chlorine chain, chlorinedisplacement displacement on the maleimide on the maleimide moiety unexpectedly moiety unexpectedly occurred with occurred good with yields. good yields.

Scheme 12. Synthesis of asymmetric glycol bola-amphiphiles. Reagents and Conditions: (i) DIEA, Scheme 12. Synthesis of asymmetric glycol bola-amphiphiles. Reagents and Conditions: (i) DIEA, DMF, room temperature, 24 h, 64% βGlc-C11, αGlc-C11 and βGal-C11, 80% αMan-C11. DMF, room temperature, 24 h, 64% βGlc-C11, αGlc-C11 and βGal-C11, 80% αMan-C11.

AllAll bolaform bolaform GLs GLs turned turned out out toto bebe excellentexcellent hydr hydrogelatorsogelators with with a acritical critical gelation gelation concentration concentration (CGC) < 0.1 wt %. Interestingly, the π-conjugated 2-anilino-3-chloromaleimide is a known (CGC) < 0.1 wt %. Interestingly, the π-conjugated 2-anilino-3-chloromaleimide is a known chromophore chromophore with a λmax value appearing near 400 nm. As a result, the chloromaleimide GLs with a λmax value appearing near 400 nm. As a result, the chloromaleimide GLs exhibited color change exhibited color change upon gelation from warm orange (sol) to yellow (gel). Furthermore, the color upon gelation from warm orange (sol) to yellow (gel). Furthermore, the color change was also observed change was also observed upon gel incubation with the corresponding glycosidases, thanks to the upon gel incubation with the corresponding glycosidases, thanks to the proximity of the chromophore proximity of the chromophore with the glycoside moiety. The enzyme selectivity is therefore retained within thethe glycosidegel state and moiety. makes The these enzyme gels usable selectivity as sensing is therefore materials retained to detect in the an gel enzymatic state and activity makes by these gelsthe usable naked as eyes. sensing materials to detect an enzymatic activity by the naked eyes.

5.2.5.2. Mechanical Mechanical Characterization Characterization of of Gels Gels TheThe increasing increasing number number of of supramolecular supramolecular gels require require a a characterization characterization at atthe the microscopic microscopic and and thethe macroscopic macroscopic levels. levels. Speciﬁc Specific information information about the the structure structure and and dynamics dynamics of ofthe the self-assembling self-assembling willwill be be obtained. obtained. Gels Gels are are not not only only molecules molecules solvated solvated in in water, water,oil oil oror solvent,solvent, for hydrogels, oleogels oleogels or organogelsor organogels respectively, respectively, but but also also secondary secondary and and tertiary tertiary structures.structures. Thes Thesee structures structures responsible responsible of theof the gelation gelation phenomenom phenomenom need to to be be highlighted, highlighted, especially especially the number, the number, type and type strength and strength of the of theinteractions. interactions. One One way way to investigate to investigate the viscoelactic the viscoelactic behaviour behaviour of such of material such material is rheology. is rheology. This Thistechnique technique analyses analyses samples samples at their at their native native state state enabling enabling a better a better understanding understanding of the of thegel gel macroscopicmacroscopic organization. organization. DifferentDifferent types of setup setup are are availabl availablee for for rheological rheological studies, studies, cone cone and and plateplate systems, systems, parallel parallel plates plates and and concentricconcentric cylinders,cylinders, depending depending of of the the material material viscosity. viscosity. In each In each case,case, thin thin layer layer of of gel gel will will bebe spread between between the the movable movable and and the the stationary stationary plates. plates. The response The response of the supramolecular gels to applied oscillatory stress quantifies its viscoelastic properties by three of the supramolecular gels to applied oscillatory stress quantiﬁes its viscoelastic properties by three major variables: G* (complex modulus), G’ (storage or elastic modulus) and G” (loss or viscosity major variables: G* (complex modulus), G’ (storage or elastic modulus) and G” (loss or viscosity modulus). The evolution of theses variables function of the imposed stress, the frequency, the time modulus). The evolution of theses variables function of the imposed stress, the frequency, the time or or the temperature will contribute to the characterization of gelation key points (i.e., linear the temperature will contribute to the characterization of gelation key points (i.e., linear viscoelastic viscoelastic region (LVER), strength of the gel, thixotropic behaviour, Tgelsol, etc.) [82,83]. Almost all regionmechanical (LVER), properties strength are of thedetermined gel, thixotropic within the behaviour, LVER. In Tthisgelsol domain,, etc.) [ the82,83 evolution]. Almost of allmoduli mechanical will propertiesbe independent are determined of the magnitude within the of LVER. imposed In this stress domain, or strain the evolution [100]. So ofthe moduli macroscopic will be behaviour independent ofobserved the magnitude will only of be imposed due to the stress variant or strainfactors. [100 Wh].en Sothis the factor macroscopic is the temperature, behaviour the observedmost often will onlyreported be due parameter to the variant will be factors.determined: When temperature this factor of isgelation the temperature, (Tgelsol). During the the most experiment, often reported the

Molecules 2018, 23, 89 15 of 25

parameter will be determined: temperature of gelation (Tgelsol). During the experiment, the temperature increases and the macroscopic properties of the supramolecular gel evolve until a break of the tertiary structure. The point when the sample goes from a gel-like state to a liquid-like state is called Tgel or Tgelsol [82,83]. Another rheological property determines for supramolecular system, especially gel composed of glycolipids, is the thixotropic behaviour. This unique behaviour is investigated by a time Molecules 2018, 23, 89 15 of 25 dependent experiment. Supramolecular assembly undergoes a mechanically stimulus leading to a collapse oftemperature the tertiary increases structure and the and macroscopic to a gel-sol properties transition. of the supramolecular When the gel external evolve until force a break is withdrawn, the supramolecularof the tertiary gel structure. can rebuilt The point to itswhen initial the sample state (sol-gelgoes from transition). a gel-like state The to a reversibility liquid-like state of is the system called Tgel or Tgelsol [82,83]. Another rheological property determines for supramolecular system, is called thixotropy. This phenomenon is essentially due to modiﬁcations at the macroscopic level especially gel composed of glycolipids, is the thixotropic behaviour. This unique behaviour is without chemicalinvestigated alterations. by a time dependent Supramolecular experiment. assemblies Supramolecular are assembly essentially undergoes based a mechanically on weak interactions (π stacking,stimulus hydrophobic leading to effect,a collapse H of bonding) the tertiarywhich structure can and be to disrupteda gel-sol transition. and can When recover the external from external stress enablingforce is this withdrawn, thixotropic the supramolecular behaviour. gel can rebuilt to its initial state (sol-gel transition). The reversibility of the system is called thixotropy. This phenomenon is essentially due to modifications All these rheological parameters are crucial for the characterization of gels and is unambiguously at the macroscopic level without chemical alterations. Supramolecular assemblies are essentially required.based The strengthon weak interactions of gels could (π stacking, have anhydrophobic impact oneffect, its H application, bonding) which for can example be disrupted in the and biomedical ﬁeld allowingcan recover cell proliferationfrom external stress and enab differentiationling this thixotropic [101 behaviour.–103]. Supramolecular assemblies are often compared toAll polymeric these rheological gels on variousparameters criteria are crucial and especiallyfor the characterization mechanical strength.of gels and Mei is et al. [83] unambiguously required. The strength of gels could have an impact on its application, for example classify hydrogels in two categories: the polymeric and the supramolecular one. Among the in the biomedical field allowing cell proliferation and differentiation [101–103]. Supramolecular polymericassemblies classes, are they often distinguish compared to the polymeric polymeric gels on hydrogels various criteria based and on especially covalent mechanical crosslink (Type I) or on noncovalentstrength. Mei crosslink et al. [83] classify (Type hydrogels II). The in hydrogels two categori arees: the compared polymeric functionand the supramolecular of numerous criteria and especiallyone. Among the mechanical the polymeric strength. classes, they Polymeric distinguish hydrogels the polymeric arecharacterized hydrogels based by onstrong covalent mechanical crosslink (Type I) or on noncovalent crosslink (Type II). The hydrogels are compared function of strength (extremely strong for Type I/relatively strong for type II) and supramolecular systems by numerous criteria and especially the mechanical strength. Polymeric hydrogels are characterized by weak mechanicalstrong mechanical strength. strength (extremely strong for Type I/relatively strong for type II) and However,supramolecular the mechanical systems by weak properties mechanical of astrength. supramolecular system could be improved by the addition to theHowever, biomaterial the mechanical of a ligand. properties Zhang of et a al. supr [104amolecular] incorporated system could vancomycin be improved in a by supramolecular the addition to the biomaterial of a ligand. Zhang et al. [104] incorporated vancomycin in a hydrogel of self-assembled pyrene-D-Ala-D-Ala resulting in a 106 fold increase of the elastic modulus supramolecular hydrogel of self-assembled pyrene-D-Ala-D-Ala resulting in a 106 fold increase of the (Figure5).elastic modulus (Figure 5).

Figure 5. (A) Structure of the complex Vancomycin—pyrene D-Ala-D-Ala contained in the self-assemblingFigure 5. system; (A) Structure (B) Evolution of the complex of the Vancomycin—pyrene elastic modulus D (G’)-Ala-D function-Ala contained of the in frequencythe self- for the assembling system; (B) Evolution of the elastic modulus (G’) function of the frequency for the hydrogel with or without vancomycin (taken with permission from [86,104]). hydrogel with or without vancomycin (taken with permission from [86,104]).

AnotherAnother way to way improve to improve the the mechanical mechanical strength strength of supramolecular of supramolecular gels is the synthesis gels is theof new synthesis of new generationsgenerations of of low low molecular weight weight hydrogelator hydrogelatorss which present which high present elastic modulus high elastic up to 10 modulus4–105 up to 104–105 PaPa [ 105[105–108].–108]. The molecules used to obtain such results are glycolipids based. Full rheological data about The moleculessupramolecular used assemblies to obtain composed such of results glycoconjugates are glycolipids are not always based. found Fullbut is rheological very useful for data about supramolecularthe characterization assemblies of composedglycolipids based of glycoconjugates gels. The rheological are data not of alwaysself-assembled found glycoconjugate but is very useful for the characterizationbased gels are of summarized glycolipids in Table based 4. gels. The rheological data of self-assembled glycoconjugate based gels are summarized in Table4.

Molecules 2018, 23, 89 16 of 25

Molecules 2018, 23, x FOR PEER REVIEW 16 of 25 Molecules 2018,, 23,, xx FORFOR PEERPEER REVIEWREVIEW 16 of 25 Table 4. RheologicalTable 4. Rheological characterization characterization of low ofmolecular low molecular weight weighthydrogelators hydrogelators self self assembled assembled of glycolipids of glycolipids and their applications. and their applications. Table 4. RheologicalRheological characterizationcharacterization ofof lowlow molecularmolecular weightweight hydrogelhydrogelators self assembled of glycolipids and their applications. Concentration Morphological Solvent G’ (Pa) Thixotropic Behaviour Tgelsol (°C) Applications Ref. ConcentrationConcentration% (w %/w) MorphologicalMorphologicalStructure ◦ SolventSolvent G’ (Pa)G’ (Pa) Thixotropic Thixotropic Behaviour Behaviour TgelsolgelsolT (°C)(°C)gelsol ( C) ApplicationsApplications Ref. Ref. (w/w%) (w//w)) StructureStructure

Water 2 Wormlike micelles ≈500 Yes 29 Reduced biocompatibility [109] WaterWater 22 WormlikeWormlike micelles micelles ≈500≈500 Yes Yes 29 29 Reduced biocompatibility Reduced biocompatibility [109] [109]

Matrix for cell culture Water 1.5 Nanofibers 800 Yes 52 MatrixBiomaterial forMatrix cell culture for cell culture [101,102,110,111] Water 1.5 Nanoﬁbers 800 Yes 52 [101,102,110,111] Water 1.5 Nanofibers 800 Yes 52 DecontaminationBiomaterialBiomaterial Decontamination [101,102,110,111][101,102,110,111] Decontamination

3 Water 11.55 mM Nanoﬁbers 5 × 10 3 Yes 62Injection Injection in mice in mice Biomaterial [106] Water 11.55 mM Nanofibers 5 × 10 Yes 62 InjectionInjection inin micemice [106] Water 11.55 mM Nanofibers 5 × 1033 YesYes 62 62 Biomaterial [106][106] Biomaterial

Molecules 2018, 23, 89 17 of 25

Molecules 2018, 23, x FOR PEER REVIEW 17 of 25 Molecules 2018,, 23,, xx FORFOR PEERPEER REVIEWREVIEW 17 of 25 Table 4. Cont. Table 4. Cont. Table 4.. Cont..

InjectionInjection inin micemice 3 33 InjectionInjection in mice in mice No foreign WaterWater 11.55 mM 11.55 mM Nanoﬁbers Nanofibers 12 × 1210 × 103 YesYes 79 79 [106][106] [106] Water 11.55 mM Nanofibers 12 × 10 Yes 79 No foreign body reaction [106] No foreign bodybody reaction reaction

Water 2 Nanofibers 30 ×3 1033 Yes 46 Scaffold for stem cells [103] WaterWater 2 2 Nanoﬁbers Nanofibers 30 × 3010 × 103 YesYes 46 46 Scaffold for Scaffold stem cells for stem cells [103] [103]

No biomedical application for 33 No biomedical application for Water 4 Nanofibers 57 ×3 103 Yes 36 No biomedicalNo biomedical application application for for [105][105] WaterWater 4 4 Nanoﬁbers Nanofibers 57 × 5710 × 10 YesYes 36 36 the moment [105] [105] thethe momentmomentthe moment

Molecules 2018, 23, 89 18 of 25

Molecules 2018, 23, x FOR PEER REVIEW 18 of 25 Table 4. Cont. Table 4. Cont.

3 WaterWater 5 5 Nanoﬁbers Nanofibers 63 × 6310 ×3 103 --- - Enzyme/cellEnzyme/cell responsive responsive capsule capsule [108] [108]

Cyclohexane 0.6 Nanofibers 100 × 103 - 49 No application for the moment [107] CyclohexaneCyclohexane 0.6 0.6 Nanoﬁbers Nanofibers 100 × 10010 ×3 103 -- 49 49 No application No application for the moment for the moment [107] [107]

Molecules 2018, 23, 89 19 of 25

Except for the molecule developed by Prasad et al. [107], the glycolipids are solvated in water allowing potential applications in the medical field. They are all prepared with low concentrations of gelator molecules (<10% (w/w)) compared to the polymeric gels. Fitremann et al. [109] developed a weak hydrogel presenting a low biocompatibility for neural cell culture. It’s a first approach for this generation of glycolipids, which will need tuning to improve the biocompatibility but also the Tgelsol for biomedical applications. Barthélémy’s group found a way to design specific glycolipids allowing biomedical applications and personalization of the biomaterial with various mechanical strengths. The incorporation of a nucleoside in the glycolipid structure add a coding information and these inspired molecules present high cytocompatibility [101,102]. The glyconucleolipid is the basic structure and different generations were synthetized from this skeleton: Glycosyl-Nucleoside Fluorinated amphiphiles (GNF) [101,102,110,111] and also Glycosyl-Nucleoside Bola-Amphiphiles (GNBA) [103,105,106]. Each hydrogel obtained with this glyconucleolipid structure presents specific rheological parameters, which were used to tune the molecule design. This tuning was done to improve the mechanical strength essentially to widen the biomedical applications (scaffold for stem cells, osteoblastic cells, etc.) [102–104,107]. These modifications could also affect other parameters such as the Tgelsol. Indeed, for the GNBA carbamate, an increase of the mechanical strength was observed compared to the previously synthetized GNBA [105] but also a decrease of the Tgelsol (36.3 ◦C) preventing biomedical applications for the moment. That’s why the association of organic chemistry and physico-chemical characterization (rheology) is essential to guide the design of new glycolipid molecules able to self-assemble. The viscoelastic behaviour could also be analyzed by indentation and not only rheology. Ikeda et al. used atomic force microscopy (AFM) indentation to characterize the elastic modulus of their strong hydrogel for an application on prostate cancer cells [108]. Glycoconjugate are not only forming gel in water but also in various solvents and vegetal oils. The organogel obtain in cyclohexane exhibits a mechanical strength comparable to polymeric gels at very low concentrations (0.6% (w/w)) [107]. Even if no real applications are proposed for this new LMWG, it is a very promising new way to obtain glycolipids from renewable resources. The gelification of such molecules in vegetable oils open the way to new applications in the pharmaceutical and cosmetic fields for example. The rheological parameters of a gel are very important for the potential biological applications: scaffold for cell’s culture, drug delivery systems, and regenerative medicine. Moreover with the examples presented here, the impact of the chemical structure on the LMWGs is clearly identified. Rheological characterization need to be compulsory for supramolecular gels allowing molecular screening and fine-tuning to adapt the chemical structure to the application.

6. Conclusions Despite the substantial progress in the synthesis of soft materials, i.e., the formation of supramolecular gels with low molecular weight gelators, there is still a significant need to design, synthesize, and evaluate new glycoconjugate amphiphiles for an access to biomaterials possessing the required properties for different biomedical fields, including regenerative medicine, drug delivery or tissue engineering. Much of this activity is mainly driven by the current weak viscoelastic properties of the synthetic amphiphile gelators as well as the lack of biocompatibility for in vivo applications. With this in mind, polymer-free biomaterials that can overcome these two major hurdles are highly sought after. It is clear that the modulation of the elastic modulus (G’) and the thixotropy propreties are important limiting parameters of supramolecular biomaterials. Therefore, the design of glycoconjugate that self-assemble in a controlled manner would provide new biomaterials for constructing sophisticated supramolecular gels. Although the control of supramolecular gel properties is still under investigation, it is important to avoid inflammatory response once this type of bioinspired material is injected or implanted in vivo. Nevertheless the chemistry of glycoconjugate amphiphiles has much to offer to the vast Molecules 2018, 23, 89 20 of 25 domain of biomedicine. Indeed, playing with the chemical diversity of the sugar code can modulate and/or trigger biological responses. The role of synthetic carbohydrate chemistry for designing and synthesizing carbohydrate derivatives featuring biological properties can be illustrated in the context of vaccines with two recent reports. In a recent publication Gauthier et al. hypothesized that the chemical modification of lipopolysaccharide (LPS)-based vaccines antigen could have a strong impact on immune responses [112]. To validate this hypothesis they prepared several oligosaccharides with the aim of deciphering the immunogenic epitopes of surface polysaccharides. They demonstrated that synthetic chemistry and sugar modifications were crucial for recognition. In another recent report Guler et al. investigated the physico and biological properties of novel mannosylated glycopeptides. Interestingly, the nanofibers resulting from the self-assemblies of these amphiphiles were well adapted for the delivery of immunogenic mimetic antigens [113]. The future development of the glycoconjugate amphiphiles, in particular the synthetic access to a large diversity of molecular and supramolecular structures, will certainly witness exciting discoveries in different biomedical areas, including biomaterials, medicinal chemistry or vaccination.

Acknowledgments: This work, realized within the framework of the Laboratory of Excellence AMADEus with the reference ANR-10-LABX-0042-AMADEUS, has benefitted from aid by the “French National Research Program for Environmental and occupational Health of ANSES” (2015/1/072). Author Contributions: L.L., A.G. and P.B. wrote the paper. Conflicts of Interest: The authors declare no conflict of interest.

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