Tetrahedron Letters xxx (2013) xxx–xxx

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Tetrahedron Letters

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Crosslinking of polysaccharides with activated dimethylsulfoxide

Zivomir Petronijevic a,⇑, Biljana Maluckov a,b, Andrija Smelcerovic c,d

a Faculty of Technology, University of Nis, Bulevar oslobo -denja 124, 16000 Leskovac, Serbiab Technical Faculty in Bor, University of Belgrade, Vojske Jugoslavije 12, 19210 Bor, Serbiac Institute of Environmental Research, Technical University of Dortmund, Otto-Hahn-Str. 6, 44221 Dortmund, Germanyd Department of Chemistry, Faculty of Medicine, University of Nis, Bulevar Dr Zorana Djindjica 81, 18000 Nis, Serbia

a r t i c l e i n f o a b s t r a c t

Article history:Received 17 December 2012Revised 12 February 2013Accepted 12 April 2013Available online xxxx

Keywords:PolysaccharidesCrosslinkingDimethylsulfoxideDextranStarch

0040-4039/$ - see front matter � 2013 Published byhttp://dx.doi.org/10.1016/j.tetlet.2013.04.050

⇑ Corresponding author. Tel.: +381 16247203; fax:E-mail address: zpetronijevic@yahoo.com (Z. Petro

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A simple method for the crosslinking of dextran, starch, and several other polysaccharides is described.The crosslinking of polysaccharides is performed with dimethylsulfoxide (DMSO) activated with organicor inorganic acid halogenides or phosphorus pentoxide. The crosslinking level increases with an increasein the acid chloride concentration, the temperature, and the reaction time. A possible crosslinking mech-anism is proposed.

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The use of natural or synthetic macromolecular matrices for thechromatographic separation of biological compounds in the aque-ous phase is a technique developed about 50 years ago. The poros-ity of these supports, which are insoluble but swell in water, isutilized for the separation of molecules as a function of theirmolecular weight by simple elution from a column.1 Porath andFlodin were the first to develop this principle, by using the naturalpolysaccharide dextran crosslinked by a bifunctional reagent suchas epichlorohydrin in a basic medium.2

A variety of materials have been used to modulate drug delivery;in this respect polysaccharides and their derivatives represent agroup of polymers commonly present in pharmaceuticalformulations. Among these, starch and cellulose, with appropriatechemical or physical modifications, are the most frequentlyemployed. Nevertheless, numerous other polysaccharides (algi-nates, carrageenans, gellan, etc.) have been used for the preparationof controlled release dosage forms.3 Biocompatible three-dimensional porous scaffolds are also of significant interest fortissue engineering applications4 as well as for enzymes and cellimmobilization.5,6

Different chemical and physical methods are available forcrosslinking polysaccharides. Crosslinking agents such as epichlo-rohydrin,7 alkane dihalides,3 poly(ethyleneglycol)-diamines,8 dial-dehydes, dihydrazides,9,10 etc., lead to covalent chain crosslinking.Covalent crosslinking of polysaccharides can also be accomplished

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by radical polymerization with acrylate monomers in the presenceof a crosslinking agent.11,12 From the reactions of DMSO withpolysaccharides, oxidation has been described,13,14 where theactivation of DMSO was carried out with electrophiles such asdicyclohexylcarbodiimide, acetic anhydride, phosphorus pentox-ide,15 or sulfur trioxide-pyridine.13 Hirano et al.16 have describedthe polysaccharide synthesis from mono- and oligosaccharides bythe action of phosphorus pentoxide in DMSO. Herein, we reportthe crosslinking of dextran, starch, and several other polysaccha-rides with activated DMSO. A possible crosslinking mechanism isproposed.

Crosslinking of polysaccharides

The crosslinking of dextran, starch, or other polysaccharides isperformed by the addition of an acid chloride or phosphorus pent-oxide as a solution with the polysaccharide in DMSO, or by theaddition of activated DMSO (obtained by the reaction of acid chlo-rides and DMSO) in a solution of the polysaccharide in DMSO (seeSupplementary data and Tables 1 and 2). The gelation kineticsdepended on the ratio of the reactants. The gelation time wasbetween 2 and 45 min. A very vigorous crosslinking reaction (witha short gelation time) occurred using the acid chlorides: benzoylchloride, acetyl chloride, thionyl chloride, phosphorus oxychloride,as well as phosphorus pentoxide. Moreover, the crosslinking ofpolysaccharides could be accomplished with the chlorides ofaromatic acids containing electron-withdrawing groups (e.g., with4-nitrobenzoyl chloride), but the vigor of the reaction was reduced

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Table 2Relevant data on starch crosslinking with DMSO activated with an acid chloride, phosphorus pentoxide, or acetic anhydride

Productcodea

Starch(g)

DMSO(ml)

Electrophile Method ofsynthesis

Heating Standing at roomtemperature (h)

Appearance of thepurified product

Yield[g (%)]

(�C) Time (h)

StS-1.85 6 40 + 20 5 ml of Sa 1b, 6b 50 2 20 White particles 4.0 (67)StS-1.48 6b 40 + 20 4 ml of Sa 1b, 6b 50 1 20 White particles 5.2 (87)StS-4.00 5 50 + 20 9 ml of Sa 1b, 6b 45 1 40 White particles + orange liquid 3.72 (75)StPc-1.74 6 40 + 20 6 ml of Pca 1b, 6b 40 2 20 White particles 3.02 (50)StN-1.50 7 40 + 20 12 g of Na 1b, 8 40 1 20 Yellowish particles 4.55 (65)StA-3.43 5 40 10 ml of Aa 2, 7 40 2.5 20 White amorphous water-soluble particles 4.05 (81)StA-6.43 4 30 15 ml of Aa 2, 7 40 2 40 Yellow water-soluble paste 14.9 (75)StP-1.63 7 40 + 20 10 g of Pa 4a, 6b 50 3 20 Yellowish particles 3.2 (46)StP-2.93 7 40 18 g of Pa 4b, 6b 70 3 20 White particles 5.2 (74)StB-3.35 5 25c 12 ml of Ba 5, 6c 55 1.5 20 Off-white beads 4.2 (84)

All experiments were performed in triplicate and averaged.a The first letter(s) in the product code indicates the polysaccharide used (St—starch). The second letter(s) indicate the electrophile: A—acetic anhydride, Ac—acetyl

chloride, B—benzoyl chloride, N—4-nitrobenzoyl chloride, P—phosphorus pentoxide, Pc—phosphoryl chloride, and S—thionyl chloride. The number in the product codeindicates the ratio of moles of chloride (or anhydride) and glucosyl residues.

b The reaction was performed with starch, which was dissolved in DMSO with 2 g of tris(hydroxymethyl)aminomethane.c After dissolution of starch, 20 ml of n-hexane was added. With benzoyl chloride as the electrophile 15 ml of n-hexane was added.

Table 1Relevant data on dextran crosslinking with DMSO activated with an acid chloride or acetic anhydride

Productcodea

Dextran(g)

DMSO(ml)

Electrophile CaCO3

(g)Method ofsynthesis

Heating Standing at roomtemperature (h)

Appearance of thepurified product

Yield[g (%)]

(�C) Time (h)

NBC-2.20 5 70 7.9 ml of Ba 9.6 1a, 6a — — 20 Off-white particles 4.35 (87)NSC-2.76 3 70 3.72 ml of Sa 10.77 1a, 6a — — 20 Off-white particles 2.49 (83)NAcC-2.78 3 70 3.66 ml of Aca 5.38 1a, 6a — — 20 Off-white particles 2.52 (84)NS-2.78 7.5 100 + 40b 9.4 ml of Sa 0 1b, 6b 50–65 1.5 20 Snow-white particles 5.47 (73)KS-2.40 5.0 40 + 20b 5.4 ml of Sa 0 1b, 6b 40 1 120 Off-white particles 3.90 (78)KS-6.00 5.0 40 + 60b 13.5 ml of Sa 0 1b, 6b 50–65 1.5 20 Liquid white amorphous 2.70 (54)KA-3.41 5.0 40 21.55 ml of Aa 0 2, 7 40 3 50 Water-soluble particles 3.95 (79)N_C-0.0 3 70 None 2.0 3 — — 20 No products —NChC-0.97 3 70 2.0 g of Cha 2.0 3 — — 20 No products —

All experiments were performed in triplicate and averaged.a The first letter in the product code indicates the type of dextran: N—native, K—clinical (Mr = 40000). The second letter(s) indicate the electrophile: A—acetic anhydride,

Ac—acetyl chloride, B—benzoyl chloride, Ch—calcium chloride, and S—thionyl chloride. A dash indicates that no electrophile was used. The third letter indicates whethercalcium carbonate (letter C) was used in the synthesis. The number in the product code indicates the ratio of moles of chloride (or anhydride) and glucosyl residues.

b The first and second numbers represent the volume of DMSO in which the dextran and the acid chloride were dissolved, respectively.

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(longer gelation time). After gel formation the mixing was stoppedand the reaction mixture was allowed to stand for 1–3 h at aslightly increased temperature (up to a maximum of 70 �C), andfor 20–120 h at room temperature. The acid formed during thecrosslinking-reaction can be bound by the addition of pulverizedcalcium carbonate (e.g., a 5% molar excess with respect to theamount of acid chloride), but calcium carbonate is not necessaryfor the crosslinking process. After completion of the reaction,washing with ether, ethanol, and/or hot water was performed inorder to remove the acid halide, DMSO, and other solublecomponents.

Besides the examples described in Tables 1 and 2, the crosslink-ing was also successfully performed with other polysaccharides:clinical dextranes T70 and T100, hydroxyethyl-cellulose, andpolyvinyl alcohol. On the other hand, the crosslinking of the acidicpolysaccharides, carboxymethyl-cellulose, and pectin was notsuccessful under these conditions.

There was no reaction in the control synthesis (N_C-0.0 andNChC-0.97, see Table 1) with native dextran, DMSO, and calciumcarbonate (with and without calcium chloride), but withoutaddition of an electrophilic agent which can activate DMSO. Thisconfirmed that activated DMSO was the active agent in the cross-linking reactions.

We found that the initial concentration of the polysaccharidewas of significant importance for the crosslinking process andthe properties of the final product. We used polysaccharideconcentrations in the range of 5–70% of the reaction mixture and

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obtained successful crosslinking. Lower concentrations resultedin products with a lower degree of crosslinking (i.e., with higherswellability). An increase of swellability can be achieved by reduc-tion of: (i) the molecular mass of the polysaccharide, (ii) theamount of acid halide in relation to the polysaccharide, and (iii)the temperature and/or duration of the reaction.

The crosslinking reaction can also be accomplished in a two-phase system (sample StB-3.35, Table 2). The size of the granulesproduced is mostly dependent on the stirring speed and less onthe ratio of the reactants and solvents used (data not shown).The extent of crosslinking increases with an increase in the acidchloride concentration, the reaction temperature, the reactiontime, and the stirring rate.

Properties of crosslinked products

All the crosslinked products were insoluble in water, DMSO, andother solvents (ethanol, acetone, diethyl ether, benzene, petroleumether, n-hexane, etc.). The swellability in water was inversely pro-portional to the number of reacted hydroxyl groups of the polysac-charide (i.e., the crosslinking-level), while the level of resistance tothe action of hydrolytic enzymes was directly proportional to thecrosslinking-level (Tables 3 and 4).

Crosslinking of native dextran gave a product (sample NBC-2.20) with a swelling degree of 18 ml/g, which was slowly butincompletely hydrolyzed with dextranase (in contrast with solubledextran which hydrolyzed quickly and completely). Based on the

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Table 3Properties of the products obtained by crosslinking dextran with activated DMSO

Product codea Swelling(ml/g)

Glc/C@O(mol/mol)

Glc/ester(mol/mol)

Glc/COOH(mol/mol)

Glc/reducing groups(mol/mol)

Glc/released formicacid (mol/mol)

Sensitivity todextranase action (%)

NBC-2.20 18 9.6 307 30 488 1.48 65NSC-2.76 12 11.9 432 nd 275 3.78 ndNAcC-2.78 14.5 5.7 498 nd 566 3.27 ndNS-2.78 2.5 14.3 476 7.6 207 14.6 0KS-2.40 3.1 11.8 394 P32.2 367 23.6 0KA-3.41 Soluble 2.9 4.1 nd nd nd ndClinical dextran Mr = 40000 — — — — 236 1.01 100Native dextran — — — — 787 1.02 100

All experiments were performed in triplicate and averaged.a See the product codes in Table 1.

Table 4Properties of the products obtained by crosslinking of starch with activated DMSO

Productcodea

Swelling(ml/g)

Glc/C@O(mol/mol)

Glc/ester(mol/mol)

Glc/reducinggroups(mol/mol)

Sensitivityto a-amylaseaction (%)

Induceractivity(%)

StS-1.48 4.0 11.5 242 64 0 ndStS-1.85 3.7 9.3 226 nd 5.0 70StS-4.00 3.1 4.4 96 78 4.5 7.5StPc-1.74 4.2 nd 212 83 0 ndStN-1.50 7.2 nd 237 97 0.9 12StP-2.93 6 18.9 121 89 7.1 42StA-3.43 Soluble 21.8 67 nd nd ndStA-6.85 Soluble nd 15 nd nd ndSoluble

starch— — — 96 100 100

All experiments were performed in triplicate and averaged.a See the product codes in Table 2.

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amount of formic acid released after 27 h of periodate oxidationfrom native dextran (which contains about 94% of a-1,6-glycosidicbonds), it can be concluded that complete periodate oxidation wasaccomplished. The amount of released formic acid from cross-linked dextran showed that about two thirds of the glycosidic unitswere not modified by crosslinking. Comparison of the mean valuesof periodate consumption of crosslinked dextran and native dex-tran showed that periodate consumption of crosslinked dextranwas about two thirds that of the periodate consumption of nativedextran.

Crosslinking of native dextran with DMSO activated with thionylchloride gives product (NS-2.78) with a swelling degree of 2.5 ml/g,which was completely resistant to the hydrolytic action of dextran-ase. The amount of released formic acid (Table 3) showed that only6–8% of the glucosyl residues were not modified. A similar result al-lowed comparison of periodate consumption of crosslinked dextranand native dextran, because the mean value of periodate consump-tion of crosslinked dextran was very low. So, for sample NS-2.78,the periodate consumption amounted to 0.077 mol periodate/molGlc or �26.0 mol Glc/periodate, which indicates that periodate oxi-dized every 26th glucose residue of the crosslinked dextran. Due tothe low content of various groups per glycoside residue of the cross-linking products, the reciprocal values, which show the number ofglycosidic residues on which one of those groups is present, are gi-ven in Tables 3 and 4. The main conclusion from the above-men-tioned data is that a correlation exists between the degree ofswelling and periodate oxidation, and that both indicate a high levelof crosslinking of the polysaccharide samples.

Based on the amount of released formic acid, it can be concludedthat in sample NAcC 2.78 about one third of the glucosyl residuesremained unmodified, while in sample KS-2.40, only about 3–6%of the glucosyl residues were not modified. Sample KS-2.40 has ahigher swelling degree than NS-2.78, which can be attributed to

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the lower thionyl chloride:dextran ratio as well as to the lowermolecular weight of the initial dextran.

Crosslinking of starch gave a product (sample StPc-1.74) with aswelling degree of 4.2 ml/g, which was completely resistant to thehydrolytic action of a-amylase. On the other hand, the crosslinkingof hydroxyethyl-cellulose gave a product with a swelling degree of14 ml/g, which was slowly and incompletely hydrolyzed with cel-lulase from Trichoderma reesei.

The reactions with thionyl chloride led to the formation of avery small number of keto groups (below 0.09 keto groups permodified glycosidic residue, that is approximately one keto groupper 11 glycosidic residues). The reaction with acetyl chlorideyielded approximately two times more keto groups, while reac-tions with acetic anhydride led to products with 0.31–0.38 ketogroups per modified glycosidic residue (Table 3), which is in accor-dance with the results obtained by de Belder et al.17

The results shown in Table 3 indicate a low quantity of –COOHgroups in the modified insoluble dextrans. All the modifieddextrans contain a small number of reducing groups, the amountoften not being significantly less than the initial dextran used inthe synthesis. This indicates that during synthesis with an acidchloride in DMSO, significant hydrolysis of the glycosidic linkagesand degradation of the polysaccharides do not take place.

Some of the modified starches were tested as inducers of a-amylase from Bacillus mycoides 57. The induction effect of thecrosslinked starches decreased with an increased degree ofcrosslinking. The above-described decrease in the induction effectwas less than the reduction of sensitivity to the action of a-amylase (Table 4).

A possible crosslinking mechanism

On the basis of previous work18–20 on the reactions of activatedDMSO with alcohols, we propose a possible mechanism for thecrosslinking of polysaccharides with activated DMSO (Scheme 1).The reaction begins with the nucleophilic attack of DMSO on thecarbonyl carbon of the acid chloride with formation of a sulfoxoni-um intermediate I.18 This reacts with the hydroxy-group of thepolysaccharide leading to the formation of an alkoxydimethylsulfo-nium chloride intermediate II (Eq. 1). In the reaction of DMSO andthionyl chloride, after obtaining intermediate III, the chloride iondisplaces the oxygen-containing group in III by attacking the sulfurion to give the sulfonium compound IV (Eq. 2), which also reactedwith the hydroxy-group of the polysaccharide to form the samealkoxydimethylsulfonium intermediate II (Eq. 3). The proposedmechanism is consistent with that proposed for the Swern oxida-tion of alcohols to their respective carbonyl compounds.19,20

Hollinshead et al.21 and Tidwell22 reported that if excess alcoholwas present, this could react with the alkoxydimethylsulfoniumchloride to form an ether, and we think that formation of an etherlinkage is also a possible mechanism for the crosslinking of polysac-

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Scheme 1. Presumed mechanism of the crosslinking of polysaccharides with activated dimethylsulfoxide (R1R2CHOH = polysaccharide).

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charides using DMSO (Eq. 4). All the crosslinking reactions withactivated DMSO led to the release of dimethylsulfide. After comple-tion of the reactions, distillation of the mixtures containing samplesNS-2.78 and KS-6.00 yielded 20.6 ml and 18.8 ml of dimethylsul-fide, respectively. The presence of dimethylsulfide in the distillatewas confirmed by determination of its boiling point and via IRspectroscopy.

Another possible mechanism for polysaccharide crosslinkingwith DMSO involves reaction via an ylide, formed from intermedi-ates I and IV,23 or via covalent hemiacetal linkages,24 formed frompolysaccharide hydroxyl groups and the keto group obtained byoxidation of the polysaccharide with DMSO.13

It was found that samples obtained with thionyl chloride werepartially soluble in 1 M NaBH4, which indicates25 the possibilitythat a crosslinking mechanism with acetal bonds may be occurringto some degree (but not as the main mechanism). The use of thechloride or anhydride of polybasic acids (thionyl chloride, phos-phorus pentoxide, or phosphoryl chloride) as electrophilic agentsin reactions with the hydroxyl groups of polysaccharides resultsin the formation of ester bonds.26 However, crosslinking did notproceed by way of this mechanism because only a very low num-ber of ester groups were determined to be present (Tables 3 and 4).Also, there were no appropriate absorptions in the IR spectra, andelemental analysis indicated very low contents of sulfur (0.30–0.97%) and phosphorus (0.006–0.040%).

Possible application of crosslinked products

According to analogy with other crosslinked polymers, theproducts obtained by crosslinking of polysaccharides withactivated DMSO may be used, directly or after chemical modifica-tion, as carriers for chromatography. Another possible applicationof this crosslinking method is its use for immobilization of en-zymes and cells which are sufficiently stable under these reaction

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conditions. Our initial results on the immobilization of horseradishperoxidase in a biphasic system with starch and DMSO showedthat this enzyme could be immobilized while maintaining signifi-cant residual activity.

In conclusion, we have described a new method for crosslinkingdextrans, starch, hydroxyethyl-cellulose, and polyvinyl alcoholusing DMSO activated with halides of organic or inorganic acids.The obtained products are insoluble in water, DMSO, and other sol-vents (see the section on the properties of crosslinked products),but swell in water. Also, the results of periodate oxidation experi-ments and resistance to the action of hydrolytic enzymes con-firmed the crosslinking of the products. This method showspotential for crosslinking of other non-ionic polysaccharides andother substances containing hydroxyl groups. This crosslinkingmethod may be used for the production of carriers for chromatog-raphy as well as for the immobilization of enzymes and cells.

Acknowledgment

This work was supported by the Ministry of Science and Tech-nological Development of Serbia (project 172044).

Supplementary data

Supplementary data (materials and methods, description of thesynthesis of crosslinked polysaccharides and methods used forcharacterization of the crosslinked products) associated with thisarticle can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.04.050.

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