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Synthesis_2

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Synthesis_2is_2

    Synthesis

Availableonlineatwww.sciencedirect.com

    ;?:j:,ScienceDirect

    ;ChineseChemicalLetters19(2008)169-171

    ;CHINE5E

    ;CHEMICAL

    ;LETTER5

    ;www

    ;Synthesisandbiologicalevaluationoftetrahydroisoquinoline

    ;derivativesaspotentialmultidrugresistancereversalagents

    ;lnCanCer

    ;YuLi,HuiBinZhang,WenLongHuang,

    ;XiaZhen,YunManLi

    ;CenterofDrugDiscovery,ChinaPharmaceuticalUniversity,Nanfing210009,China ;Received22October20o7

    ;Abstract

    ;Tetrahydroisoquinolinederivativesweresynthesizedandtheirmultidrugresistancereversalactivitieswereevaluatedinvitro

    ;Theresultsshowedthatsomeofthesyntheticcompoundshadhighermultidrugresistance(MDR)reversalactivitiesthanverapamil

    ;?

    2007WenLongHuang.PublishedbyElsevierB.VonbehalfofChineseChemicalSociety.Allfightsreserved.

    ;Keywords:Tetrahydroisoquinolinederivatives;Synthesis;Multidrugresistance(MDR);Peptoids

    ;Multidrugresistance(MDR),theCROSSresistanceoftumourcellstoavarietyofstructurallyandfunctionally

    ;unrelatedanticancerdrugs,isamajorobstacletocancerchemotherapy1].Despitemultipiemechanismsbeing

    ;involvedinMDR,themostimportantisthetypicalMDR,associatedwiththeexpressionofPglycoprotein(P-gp)with

    ;amolecularweightof170lDaencodedbyhumanMDR

    1genewhichtransportsanticancerdrugsoutofthecells

    ;beforetheyreachthecytosol

    2].Therefore,inhibitionofPgprepresentsapromisingapproachforovercomingMDR. ;Severalbisbenzy1isoquino1inealkaloidsliketetrandrine,dauricineandothers3,4]showantiMDRpropertiesin

    ;varyingdegree.OligomersofNalkylglycines,alsoknownaspeptiods,areafamilyofnon-naturalmolecularswitha

    ;widerangeofbiologicalactivities,thusmakingthemattractivecandidatesfordrugdiscove

ry.Thesecompounds

    ;generallyexhibitgreatpropeolyticstabilityandbioavailabilitythantheirrespectivepeptid

    eanalogues,aconsequence

    ;oftheirsidechainsbeingboundtonitrogenatomsasopposedto仪一

    carbonswhichmakingthemdicultycleavebythe

    ;appropriateprotease5].Masip6]reportedmatpeptoidsderivativeswithpotentinvitroactivityasmultidrug

    ;resistance(MDR)reversalagents.Insimplifyingandoptimizingalkaloidtetrandrinefordi

    scoveringnovelmultidrug

    ;resistancereversalleadingcompoundandconsideringthecharacteristicofpeptoids,wesy

    nthesizedandevaluatedthe

    ;tetrahydroisoquinolinederivativeswitIl6,7dimethoxy1(3,4

    dimethoxy)benzyl1,2,3,4tetrahydroisoquinolineas

    ;scaffolds,peptoidsassidechaingroups.

    ;TllesyntheticrouteofthetargetcompoundsisoutlinedinScheme1.Reactionof3.4

    dimethoxyphenylethyamine1

    ;with3,4

    dimethoxyphenylaceticacid2at190.CunderN,protectionaffordedcompound3.whichwas

    convertedto

    ;6,7dimethoxy1(3,4dimethoxy)benzyl3,4

    isoquinoline4byBischler-NapieralskireactionmPOC1in dihydro

    ;Correspondingauthor.

    ;E-mailaddress:ydhuangwenlong@126.com(WL.Huang) ;10018417/$seefrontmatter?

    2007WenLongHuang-PublishedbyElsevierB.VonbehalfofChineseChemicalSociety.All

    rightsreserved-

    ;doi:10.1016/j.cclet.2007.12.016

    ;

    ;17O

    ;H3

    ;H3

    ;H3

    ;H3

    ;:Lieta1./ChineseChemicalLetters19(2008)169-171 ;2

    ;H.

    ;H3

    ;-

    ;H3

    ;3

    ;H3

    ;+H3

    ;器上

    ;11a-e

    ;Scheme1.(a)N2,190.C,3h;fo)POC13,toluene,N2,110.C,reflux,2.5h;(c)KBH4,diethylamine,methanol,rt,22h;(d)Dec,DMAP,

    ;C1CH2COOH,CrI2CI2,rt.1h;(e)R1NH2,triethylamine,KI,CH2C12,rt,14-17h;(f)R2NH2,U’iethylamine,KI,CH2CI2,rt,14-17h;Cg)R3NH2,

    17h. ;u-iethylamine,KI,CH2CI2,rt,14

    ;tolueneunderrefluxin82.5%yield.Reductionof4usingKBH4inmethanolgavecompound5withtheyieldof64%.

    ;Treatmentof5withchloroaceticacidinanhydrousCH2C12inthepresenceofDCCandD

    providedkey

    ;intermediate6,)l,itllyieldof49.1%.Reactionof6withcorrespondingamineinCH2C12byusingEt3NandKIatrtgave

    ;7a_

    withtheyieldsof39.1-85.6%.Inasimilarwayofpreparationof6and7a__e,compounds8a-_tl(40.855.6%),

    ;9a-_tl(36.7_71.6%),lOa-_tl(49.2_58.2%)andlla-e(42.6_60.7%)wereobtainedineachstep,respectively.

    ;rnleeffectofthesyntheticcompoundsonchemosensitivitybyadriamycin-resistanthumanerythroleukemiccell

    ;lineK562/A02inthepresenceorabsenceofAdriamycin(ADM)wasevaiuatedf,lvitroinMTTassay7.rnle

    ;compoundsweredissolvedin0.01%oDMSO.TheresultsofMDRreversaiactivitiesofthesynthesizedcompounds

    ;vitroarelistedinle1.

    ;rnleresultsofpreliminarybiologicaiassaysshowedthat9a.9b,9dand111)__eaioneshowedlittlecytotoxicactivity,

    ;while9eandllahadsignificantcytotoxicitybycomparisonswithvincristineagainstK562,AO2cellline.?,llentested

    ;incombinationwitllADMagainstK5622celllineat10~mo1]L.compounds9candllaexhibitedawell-defined

    ;

    endinMDRreversaiactivities.Fromtheirchemicalstructures.theresultsindicatedthatn-propylandn-octylmay

    ;playanimportantroleintheinteractionofcompounds9candlla8

    withP-glycoprotein,whichmaycorrelatewith

    ;lipop~licitythatP.gpsubstratesstructurallyrequiredwithlinearandlongaiiphaticside-chain.

    ;Insummary,ninetetrahydroisoquinolinederivativesweresynthesizedandevaluatedfortheirmtdtidrugresistance

    ;reversaiactivitiesagainstK562/A02celllineinvitro.Compounds9candllashowedhigherMDRreversaiactivities

    ;thanverapamil.Furtherbiologicaievaluation,structure-activityrelationshipandmechanisticstudiesonthisnewclass

    ;ofCompoundsarecurrentlyinprogressandwillbeinduecourse.

    ;

;YLietal,/ChineseChemicalLetters19(2008)169-171171

    ;TaM

    ;,sonthe~rationc02celllineK562/A02…inthepresenceofADMbInhibitoryeffectsoftetra

    h3droisoquinolinecompoundsontheproliferationofK562/A02celllineandK562/AcelllineY,lntn

    ;Cone.:concentration(~mol/L).

    ;IR:inhibitoryratioofcompoundsagainstK562/A02cellline.

    ;IR:inhibitoryratioofcompoundsagainstK562/A02celllineinthepresenceof10vmol/LADM.

    ;.0.0l‰DMSO.

    ;Acknowledgment

    ;TheworkwassupportedbytheHitechResearchandDevelopmentProgramofChina(No.2002AA233071)

    ;References

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    ;21G.Szakacs,J.K.Paterson,J.A.Ludwig,eta1.Nat.Rev.DrugDiscov.5(2006)219. ;31S.U.Choi,S.H.Park,K.H.Kim,eta1.AnticancerDrugs9(1998)255. ;41H.Tian,Q.C.Pan,ActaPharmaco1.Sin.18(1997)455.

    ;51S.M.Miller,R.J.Simon,S.Ng,eta1.Bioorg.Med.Chem.Lett.4(1994)2657. ;f61I.Masip,Bioorg.Med.Chem.13(2o05)1923.

    ;71Mosmann,J.Immuno1.Methods65(1983)55.

    ;

    8]8Selectedspectroscopicdata:9c:IR(KBr,v):3450,2928,1658,1515,1454,1259,1028cm-1;HNMR(CDC13,300MHz,6ppm):6.15_6.81

    ;(m,5H,ArH),5.52.5.55(m,lH,CrH),4.19-4-45(m,2H,COCH2N),3.6O

    3.86(m,12H,4×OCH3),2.163.52(m,l2H,C3H,c4H,

    ;ArCH2,NCH2,2×NH!三旦2),1.1O

    1.52(m,14H,7×CH2),0.89-1.01(m,6H,2×CH3);Ms(ESI,m/z):612(M+H],basepeak).

    1la:IR

    ;(KBr,:3450,2930,1650,1514,1450,1260,1237,1027cm-1;HNMR(CDC13,3o0MHz,6ppm):7.16-7.37(m,5H,ArH),6.18-6.72(m,

    ;5H,ArH),5.60-5.64(m,lH,C1H),4.57-4.63(m,2H,ARCH2N),4.104.16(m,4H,2×COCH2N),3.66--3.88(m,12H,4×OCH3),2.53-

    ;3.64(m,12H,C3-H,c4-H,ARCH2,2×NH,N),1.23-I.52(m,14H,7×CH2),O.85-JD.94(m,6H,2×CH3);MS(ESI,mlz):759

    ;(M+H]+,basepeak).

    ;

    ;

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