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MildandEfficientSynthesisofω,ω-HeterodifunctionalizedPolymersandPolymerBioconjugates

C.AdrianFigg,AshtonN.Bartley,TomohiroKubo,BryanS.Tucker,RonaldK.Castellano,*and

BrentS.Sumerlin*George&JosephineButlerPolymerResearchLaboratory,CenterforMacromolecularScience&Engineering,DepartmentofChemistry,UniversityofFlorida,POBox117200,Gainesville,FL

32611-7200TableofContentsMaterialsCharacterizationMethods Benzotrifuranonesynthesis

mPEG-aminesynthesisBenzotrifuranonefunctionalizationsandpolymerconjugationsCopper-mediatedazide-alkynecycloadditionThiol-enereactionAvidinconjugations

SpectraandAdditionalFiguresReferences

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S2S4S4S7S7S7S9S15

Electronic Supplementary Material (ESI) for Polymer Chemistry.This journal is © The Royal Society of Chemistry 2017

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Materials Monomethyl ether poly(ethylene glycol) (mPEG, 2000 g/mol, Sigma Aldrich, trans-2-[3-(4-tert-butylphenyl)-2-methyl-2-propenylidene]malononitrile (DCTB, Santa Cruz Biotechnology, ≥99%), anthralin (AKScientific, 98%), trifluoroacetic acid (TFA, Fisher Scientific, 97%), sodium trifluoroacetate (NaTFA, Aldrich, 98%),andPierceavidinagarose(ThermoScientific)wereusedasreceived.AllotherreagentswerepurchasedfromVWRInternationalandusedasreceived.mPEG-aminewassynthesizedaccordingtotheprocedureoutlinebelow.Oct-7-ene-amine,1 the azide derivative of coumarin 1,2 and 2-mercaptoethylbiotin3 were synthesized according topreviousreports.AllsolventswerepurchasedfromFisherScientificandusedasreceived.DMFwaspurifiedusingaGlassContoursolventsystem(GlassContour,Inc.,nowPureProcessTechnology),degassedin20Ldrums,andpassedthroughtwocolumnsofmolecularsievesunderanargonatmosphere. ThinLayerChromatography(TLC)wasperformedusingaluminum-backedsilicagelplates.TheplatesweredevelopedusingUVlightandninhydrinstaining.FlashcolumnchromatographywasperformedusingSiO2-60230-400meshsilicagel.Characterization 1HNMRspectroscopywasconductedonanInova500MHz,2RFchannelinstrumentat25°C.Chloroform-d(CambridgeIsotopesLaboratories,Inc.,99.8%)solventwasusedasreceived. Matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF/TOF)was performed on a BrukerMicroflexLRFMALDITOF (Billerica,MA)massspectrometer in reflectron,positive ionmodeusinganN2on-axislaser.Spectrawerecollected in flexControl (BrukerDaltronics Inc.,Billerica,MA)andanalyzedusing flexAnalysis(BrukerDaltronicsInc.,Billerica,MA)andPolymerixVersion3software(SierraAnalytics,Modesto,CA).AnalysisofmPEG-aminewasperformedbymixingdithranolmatrix(20.0mg/mLinDCM)andpolymersolution(2.0mg/mLinDCMwith2drops trifluoroaceticacid)atav:v ratioof5:2matrix:polymerand3µLwerespottedonastainlesssteelBrukerMSP96targetpolishedsteelBCplateandairdried.AnalysisofmPEG-BTFconjugateswasperformedbymixing solutionsofDCTBmatrix (10.0mg/mL in THF) andpolymer (2.00mg/mL in THF) at a v:v ratioof 5:2matrix:polymerand2.00μLwerespotted,thendriedunderN2,onastainlesssteelABSciexPlate.Subsequently,1.00μLofaNaTFAsolution(1.00mg/mLinTHF)wasspottedontopofthepolymer-matrixspotanddriedunderN2.

Sizeexclusionchromatography(SEC)wasperformedinN,N-dimethylacetamide(DMAc)with50mMLiClat50°Canda flowrateof1.0mLmin-1 (Agilent isocraticpump,degasser,andautosampler,colums:Plgel5μmguard+twoViscoGelI-seriesG3078mixedbedcolumns:molecularweightrange0-20×103and1-100×104gmol-1). Detection consisted of a Wyatt Optilab T-rEX refractive index detector operating at 658 nm and a WyattminiDAWNTreos lightscatteringdetectoroperatingat659nm.AbsolutemolecularweightsandpolydispersitieswerecalculatedusingtheWyattASTRAsoftwareand100%massrecoverymethods.MethodsSynthesisofBenzotrifuranone(BTF)

1,3,5-Tris(bromomethyl)-2,4,6-trimethoxybenzene. To a 350 mL sealed pressure vessel was added 1,3,5-trimethoxybenzene (15 g, 89 mmol), paraformaldehyde (10 g, 33 mmol), and glacial acetic acid (35 mL). Thesolutionwasallowedtostirforonehouratroomtemperature.HBr(33%inAcOH,75mL)wasaddedtotheflaskandthesolutionwasstirredfor3hoursat70°C.Theresultingorangesolutionwascooledtoroomtemperatureandallowedtostirfor16hours.Thereactionmixturewaspouredintowater(700mL),andCH2Cl2wasaddeduntilallsolidsweredissolved. Theorganic layerwasseparatedandtheaqueouslayerwasextractedwithCH2Cl2. All

OO

O

OO

O

BrBr

Br

ParaformaldehydeAcOHHBr24 h

70 °C

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organicswerecombinedandwashedsuccessivelywithsaturatedNaHCO3,brine,andwater.TheorganiclayerwasdriedoverNa2SO4,filtered,andconcentratedunderreducedpressuretoaffordabrownoil.Theoilwaspurifiedvia column chromatography (2:1 hexanes:CH2Cl2) to yield 1,3,5-tris(bromomethyl)-2,4,6-trimethoxybenzene as awhitesolid(12g,29%).

1HNMR(CDCl3)δ4.15(s,9H),4.63(s,6H).13CNMR(CDCl3)δ22.6,62.8,123.4,160.2.HRMS(DART)calculatedforC12H15O3Br3[M+NH4]

+463.8889,found463.8903.

2,2ʹ,2�-(2,4,6-Trimethoxybenzene-1,3,5-triyl)triacetonitrile.Presentedhereisamodifiedandimprovedsyntheticproceduretotheoneweoriginallypublishedin2005.4Toasolutionof1,3,5-tris(bromomethyl)-2,4,6-trimethoxybenzene(17g,37mmol)inacetonitrile(250mL)andwater(33mL)wasaddedKI(0.37g,1.5mmol),KCN(12g,12mmol)and18-crown-6(2.5g,6.2mmol).Theresultingsolutionwasallowedtostirovernightatroomtemperature.Thesolutionwaspouredintoicewater(700mL)andsuctionfilteredassoonastheicemelted.Thefilteredsolidwasdriedunderreducedpressuretoafford2,2ʹ,2�-(2,4,6-trimethoxybenzene-1,3,5-triyl)triacetonitrileasawhitesolid(11g,100%).1HNMR(CDCl3)δ3.72(s,6H),4.02(s,9H).13CNMR(CDCl3)δ13.0,62.9,116.2,117.7,158.6.HRMS(DART)calculatedforC15H15N3O3[M+NH4]

+303.1452,found303.1462.

2,2ʹ,2�-(2,4,6-Trimethoxybenzene-1,3,5-triyl)triaceticacid.Presentedhereisanupdatedsyntheticproceduretotheonesweoriginallypublishedin20054and2009.5Asolutionof2,2',2''-(2,4,6-trimethoxybenzene-1,3,5-triyl)triacetonitrile(8.5g,28mmol)inHBr(48%,95mL)washeatedtorefluxovernight.Thesolutionwascooledtoroomtemperatureatwhichaprecipitateformed.Water(200mL)wasaddedtotheflaskandthemixturewasextractedwithethylacetate.Theorganiclayerswerecombined,driedoverMgSO4,andconcentratedunderreducedpressure.ThesolidwasthenhydrolyzedwithNaOH(22gNaOHin100mLwater)at60°Cfor3hours.Theresultantsolutionwascooledonanicebath,acidifiedwithconcentratedHCl,andextractedwithethylacetate.Theorganicswerecombined,driedoverMgSO4,andconcentratedunderreducedpressureyielding2,2ʹ,2�-(2,4,6-trihydroxybenzene-1,3,5-triyl)triaceticacid(8.8g,95%).1HNMR(DMSO-d6)δ3.46(s,6H),8.23(s,3H),11.95(s,3H).13CNMR(DMSO-d6)δ29.7,103.0,153.0,173.5.HRMS(ESI)calculatedforC12H12O9[M=Na]+323.0374,found323.0380.

Benzo[1,2-b:3,4-bʹ:5,6-b�]trifuranone(BTF).Presentedhereisanupdatedsyntheticproceduretotheoneweoriginallypublishedin2009.5Asolutionof2,2ʹ,2�-(2,4,6-trihydroxybenzene-1,3,5-triyl)triaceticacid(4.4g,15mmol)andpolyphosphoricacid(PPA,50g)wereheatedto110°Covernight.Thesolutionwascooledto0°Cand800mLicewaterwasaddedwithstirring.TheaqueoussolutionwasextractedwithCH2Cl2(emulsion).The

OO

O

BrBr

Br

KIKCN

18-crown-6ACN

rt, 16 h OO

O

CNNC

CN

OO

O

CNNC

CN

1. HBr, reflux, 16 h2. NaOH, 60 °C, 3 h

OHHO

OHOH

OH

HO

O

OO

OHHO

OHOH

OH

HO

O

OO

Polyphosphoric acid

OO

O

O

O

O

100 °C, 16 h

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organicswerecombined,washedwithwater,brine,anddriedoverNa2SO4.Thesolutionwasfilteredandthenclarifiedwithactivatedcarbon.ThesolutionwasconcentratedunderreducedpressuretoyieldBTF(1.1g,30%).Thesolidwaspurifiedbycolumnchromatography(98%CH2Cl2/acetone)andobtainedwasalighttanproduct.1HNMR(CDCl3)δ3.80(s,6H).13CNMR(CDCl3)δ30.3,101.4,150.3,171.9.HRMS(GC-CI-MS)calculatedforC12H6O6[M+H]+247.0243,found247.0243.SynthesisofmPEG-amine(1)

Thesynthesiswasadaptedfromapreviousreport.6First,mPEG(50g,25mmol)wasdissolvedintoluene(300mL) anddriedduring the azeotropic distillationof approximately 150mL toluene. The flaskwasbackfilledwithN2,cooledto0°C,andTEA(13g,13mmol)wasadded.Subsequently,p-toluenesulfonylchloride(24g,130mmol)wasdissolvedindryDCMandcannulatedintothecooledflask.Thereactionwasheldat0°Cfor2hthenallowedtowarmtoroomtemperatureandstirovernight.Thesaltswerefilteredoff, thesolutionconcentrated,andthepolymerprecipitated2×intocolddiethyletheryielding49gofmPEG-TS.Theaminationwasperformedintwobatches.Oneofthebatchesproceededasfollows:mPEG-TS(20g,10mmol)wasdissolvedin30%ammoniumhydroxide solution (300 mL) in a plastic Nalgene bottle, wrapped in Parafilm, and left to stir for 7 days. Thereactionwasopenedandplacedinthebackofthehoodtoallowtheammoniatoevaporateover7days.ThepHwasthenadjustedto13using1.0MNaOHandtheaqueoussolutionwaswashed4×withDCM.Theorganiclayerswere combined, concentrated, and the polymer precipitated 2× into cold diethyl ether yielding the PEG-amineproduct1(38.8gtotalyieldacrossbothbatches).SynthesisofmPEG-BTFconjugatesmPEG-amineconjugationtoBTF

1(40mg,2.0×10-2mmol)andBTF(6.2mg,2.5×10-2mmol)weredissolvedinTHF(1.6mL)andlefttostir

at room temperature for 16 h. The polymer was then precipitated from cold diethyl ether yielding thefunctionalizedmPEG2.

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One-potmPEG-amineconjugationtoBTFfollowedbydiallyl-amineadditionconjugate

mPEG-amine(100mg,5.0×10-2mmol)andBTF(15mg,6.3×10-2mmol)weredissolvedinTHF(2.0mL)and left tostirat roomtemperature for16h.Subsequently,allylamine(13mg,0.23mmol)wasaddedandthereactionlefttostirforanadditional24h.ThepolymerwasthenprecipitatedfromcolddiethyletheryieldingthefunctionalizedmPEG3.

2-(4,6-Dihydroxy-2-oxo-5-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2,3-dihydrobenzofuran-7-yl)-N-heptylacetamide(4).ToasolutionofBTF(50mg,0.20mmol)indryDMF(2.0mL)cooledto-41°Cwasaddedpropargylamine(11mg,0.20mmol,0.40mLof0.50MsolutioninDMF).Thereactionstirredfor1handthenheptylamine(23mg,0.20mmol,0.81mLof0.25MsolutioninDMF)wasadded.Theresultingreactionmixturestirredat-41°Cfor8handwasthenpouredintoEtOAc(75mL).Theorganicsolutionwaswashedwithwater(5×25mL)andwater(1×25mL),driedoverNa2SO4, filtered,andconcentrated. Theresiduewaspurifiedbycolumnchromatography (40:60EtOAc:Hex)toyieldproduct4(0.42g,49%)asamixtureofregioisomers(43%and57%).

1HNMR(DMSO-d6)δ0.85(t,6H,J=6.9Hz),1.24(s,6H),1.40(m,4H),3.04(dq,4HJ=5.5Hz),3.09(t,1H,J=2.6Hz),3.11(t,1H,J=2.5Hz),3.43(s,2H),3.46(s,4H),3.50(s,2H),3.70(s,4H),3.86(ddd,4H,J=2.52and5.31Hz),8.26(t,1H,J=5.5Hz),8.37(t,1H,J=5.5Hz),8.50(t,1H,J=5.5Hz),8.63(t,1H,J=5.4Hz),9.71(s,1H),9.92(s,1H),10.7(s,1H)10.9(s,1H).

13CNMR(DMSO-d6)δ13.9,22.0,26.3,28.1,28.2,28.3,28.4,28.7,28.8,30.4,30.7,30.8,31.2,31.2,31.3,31.6,3.1.7,39.0,73.0,73.2,80.8,81.1,98.1,98.5,100.5,100.7,106.4,106.6,150.5,150.7,151.7,152.1,155.4,155.5,170.8,171.4,171.9,172.6,172.6,174.6.

HRMS(ESI)calculatedforC22H28N2O6[M+H]+417.2020,found417.2039.mPEG-amineconjugationtoBTFconjugate4

1(37mg,1.8×10-2mmol)andBTFconjugate4(9.5mg,2.3×10-2mmol)weredissolvedinTHF(0.73mL)andlefttostiratroomtemperaturefor16h.ThepolymerwasthenprecipitatedfromcolddiethyletheryieldingthefunctionalizedmPEG5.

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N-Allyl-2-(5-(2-(heptylamino)-2-oxoethyl)-4,6-dihydroxy-2-oxo-2,3-dihydrobenzofuran-7-yl)acetamide(6).ToasolutionofBTF(40mg,0.16mmol)indryDMF(2.0mL)cooledto-41°Cwasaddedallylamine(9.1mg,0.16mmol,0.33mLof0.5MsolutioninDMF).Theresultingsolutionwasallowedtostirfor1hbeforetheadditionofheptylamine(18mg,0.16mmol,0.65mLof0.25MsolutioninDMF).Thesolutionthenstirredforanadditional6hat-41°CbeforebeingpouredintoEtOAc(75mL).Theorganicsolutionwaswashedwithwater(5×25mL)andbrine(1×25mL),driedoverNa2SO4,filtered,andconcentrated.Theresiduewaspurifiedbycolumnchromatography(1:1EtOAc:Hex)toyieldproduct6(0.38g,56%)asamixtureofregioisomers(43%and57%).

1HNMR(DMSO-d6)δ0.85(t,6H,J=6.5Hz),1.19–1.30(m,16H),1.34–1.45(m,4H),3.04(dq,4HJ=5.9

Hz),3.45(s,2H),3.46(s,2H),3.49(s,2H),3.50(s,2H),3.65–3.73(m,8H),5.01–5.08(m,2H),5.09–5.12(m,1H),5.15–5.18(m,1H),5.70–5.85(m,2H),8.20(dt,2HJ=5.0Hz),8.45(dt,2H,J=5.0Hz),9.87(s,1H),9.98(s,1H),10.9(s,1H),11.0(s,1H).

13CNMR(DMSO-d6)δ13.9,22.1,26.3,28.3,28.4,28.7,28.8,30.7,30.8,31.0,31.2,31.2,31.3,31.6,31.7,38.9,39.0,41.1,41.2,98.3,98.5,100.6,100.7,106.5,106.7,115.2,115.4,134.8,134.9,150.6,150.7,151.7,151.9,155.4,155.5,171.2,171.7,171.9,172.4,174.6,174.6.HRMS(ESI)calculatedforC22H30N2O6[M+H]+419.2177,found419.2177.mPEG-amineconjugationtoBTFconjugate6

1(20mg,1.0×10-2mmol)andBTFconjugate6(5.0mg,1.2×10-2mmol)weredissolvedinTHF(0.20mL)andlefttostiratroomtemperaturefor16h.ThepolymerwasthenprecipitatedfromcolddiethyletheryieldingthefunctionalizedmPEG7.

2-(4,6-Dihydroxy-2-oxo-7-(2-oxo-2-(prop-2-yn-1-ylamino)ethyl)-2,3-dihydrobenzofuran-5-yl)-N-(oct-7-en-1-yl)acetamide(8).ToasolutionofBTF(50mg,0.20mmol)indryDMF(2.0mL)at-41°Cwasaddedpropargylamine(11mg,0.20mmol,0.40mLof0.50MsolutioninDMF).Theresultingsolutionwasallowedtostirfor1.5hbeforetheadditionofoct-7-en-1-amine(25mg,0.20mmol,0.81mLof0.25MinDMF)wasaddedandthesolutionstirredfor8hat-41°C.ThereactionmixturewasthenpouredintoEtOAc(75mL).Theorganicsolutionwaswashedwithwater(5×25mL)andbrine(1×25mL),driedoverNa2SO4,filtered,andconcentrated.Theresiduewaspurifiedbycolumnchromatography(1:1EtOAc:Hex)toyieldproduct8(29mg,34%)asapairofinseparableregioisomers(34%and66%).

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1HNMR(DMSO-d6)δ1.25–1.42(m,16H),2.00(q,4H,J=6.7Hz),3.04(dq,4HJ=5.6Hz),3.09(t,1H,J=2.5Hz),3.11(t,1H,J=2.4Hz),3.43(s,4H),3.46(s,2H),3.49(s,2H),3.70(s,4H),3.86(ddd,4H,J=2.49and5.30Hz),4.91–5.02(m,4H),5.72–5.85(m,2H),8.26(t,1H,J=5.3Hz),8.37(t,1H,J=5.5Hz),8.50(t,1H,J=5.5Hz),8.63(t,1H,J=5.5Hz),9.71(s,1H),9.92(s,1H),10.7(s,1H),10.9(s,1H).

13CNMR(DMSO-d6)δ26.2,28.2,28.2,28.6,28.7,30.4,30.7,30.9,31.3,31.7,31.7,33.1,38.9,38.9,72.9,73.2,80.8,81.1,98.1,98.5,100.5,100.7,106.4,106.6,114.6,138.8,150.4,150.7,151.7,152.1,155.4,155.5,170.8,171.5,171.8,172.6,174.5,174.6.

HRMS(ESI)calculatedforC23H28N2O6[M+H]+429.2020,found429.2033.mPEG-amineconjugationtoBTFconjugate8

1(35mg,1.8×10-2mmol)andBTFconjugate8(9.4mg,2.2×10-2mmol)weredissolvedinTHF(0.70mL)andlefttostiratroomtemperaturefor16h.ThepolymerwasthenprecipitatedfromcolddiethyletheryieldingthefunctionalizedmPEG9.Copper-mediatedazide-alkynecycloadditionofmPEG-BTFconjugate9andazidocoumarin

mPEG-BTFconjugate9(50mg,2.1×10-2mmol),azidocoumarin(6.2mg,2.3×10-2mmol),andN,N,Nʹ,Nʹʹ,Nʹʹ-pentamethyldiethylenetriamine(2.6mg,1.5×10-2mmol)weredissolved inDMF(0.75mL) inaSchlenkflaskandthesolutionwaspurgedwithargonfor20min.ThereactionwasplacedinliquidN2andCu(I)Br(1.5mg,1.0×10-2mmol)wasaddedontopthefrozensolution.Thehead-spacewaspurgedwithargonforanadditional20min,thesolutionthawed,andthereactionsettostirfor24hatroomtemperature.Thereactionwasquenchedbyexposuretoair,filteredthroughneutralalumina,andpolymer10wasprecipitatedfromcolddiethylether.Thiol-eneofpolymer10with2-mercaptoethylbiotin

10 (30 mg, 1.1 × 10-2 mmol), 2-mercaptoethylbiotin (17 mg, 5.5 × 10-2 mmol), and 2,2-dimethoxy-2-phenylacetophenone(14mg,×10-2mmol)weredissolvedinDMF(0.50mL)inaSchlenkflask,wrappedinfoil,andpurgedwithargonfor20min.TheflaskwasthenplacedunderUVirradiationfor2h.Thereactionwasquenched

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by exposure to air and polymer 11 was purified via dialysis against DI water (1000 MCWO tubing) andlyophilization.AvidinconjugationsPurificationof11usingavidinagarosegelbeads 11(1.5mg,0.5mLofa3.0mg/mLPBSsolution)wasaddedtoasuspensionofavidinagarosegelbeads(0.50mL)ina centrifuge tube. The mixture was agitated for 2 h at room temperature. Subsequently, the solution wascentrifuged, the supernatantwas removed, PBSwas added (0.50mL), and the solutionwas agitated for 1 h atroomtemperature.Thiscyclewasrepeated5×untilthesupernatantappearedcolorless,whilethegelretainedalightyellowcoloration.Theavidin-agarosegelbeadswereaddedtoabiotinsolutioninPBS(1.0mL,ca.1.00×10-2M)andstirredfor48hatroomtemperature.Isolationofthepolymerwasconductedvia4cyclesofcentrifugation,supernatantcollection,andadditionofPBS.Thecollectedsupernatantwascombined,dialyzedagainstDIwater(1000MWCOtubing),andlyophilizedyieldingthepolymerproduct11.PolymerconjugationtoAvidinBiotin-containingpolymerconjugate11 (1.5mg,4.97×10-4mmol)andavidin (0.60mg,9.95×10-6mmol)weredissolved in PBS (1.2mL) and stirred at room temperature for 16h. Sodiumdodecyl sulfate-polyacrylamide gelelectrophoresiswasperformedusingaliquotstakendirectlyfromthissolution.

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SpectraandAdditionalFigures

FigureS1.1HNMRspectrumofcompound1.

FigureS2.1HNMRspectrumofcompound2.

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FigureS3.1HNMRspectrumofcompound3.

FigureS4.1HNMRspectrumofcompound4.

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FigureS5.1HNMRspectrumofcompound5.

FigureS6.1HNMRspectrumofcompound6.

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FigureS7.1HNMRspectrumofcompound7.

FigureS8.1HNMRspectrumofcompound8.

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FigureS9.1HNMRspectrumofcompound9.

Figure S10. Matrix-assisted laser desorption-ionization time-of-flight mass spectrum of compounds 5, 7, and 9confirmingquantitativeend-groupfunctionalization.

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FigureS11.1HNMRspectrumofcompound10.

FigureS12.Matrix-assisted laserdesorption-ionization time-of-flightmass spectrumof compounds1,9, and10,confirmingthepresenceofthedye-containingω,ω-heterodifunctionalizedadduct.

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FigureS13.1HNMRspectrumofcompound11.References

1. Tamaru,Y.;Hojo,M.;Higashimura,H.;Yoshida,Z-i.J.Am.Chem.Soc.1988,110,3994-4002.2. Bourbon,P.;Peng,Q.;Ferraudi,G.;Stauffacher,C.;Wiest,O.;Helquist,P.J.Org.Chem.2012,77,2756-

2762.3. Fu,J.;Yu,C.;Li,L.;Yao,S.Q.J.Am.Chem.Soc.2015,137,12153-12160.4. Lampkins,A.J.;Abdul-Rahim,O.;Li,H.;Castellano,R.K.Org.Lett.2005,7,4471-4474.5. Li,Y.; Lampkins,A. J.;Baker,M.B.;Sumpter,B.G.;Huang, J.;Abboud,K.A.;Castellano,R.K.Org.Lett.

2009,11,4314-4317.6. Elbert,D.L.;Hubbell,J.A.Biomacromolecules2001,2,430-441.