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Design,

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Design,Design

    Design,

Availableonlineatwww.sciencedirect.c0m

    ;?

    ;,

    ;ScienceDirect

    ;ChineseChemicalLetters19(2008)1395-1397

    ;CHINEE

    ;CHEMlCAL

    ;LETTERS

    ;www.elsevier.com/locate/cclet

    ;Design,synthesisandantitumoractivityof3-substituted

    ;quinolonederivatives(I)

    ;HuaWang,QiDongYou,ZhiYuLi,YiQuanZou

    ;DepartmentofMedicinalChemistry,ChinaPharmaceuticalUniversity,Nanjing210009,China

    ;Received12May2008

    ;Abstract

    ;Aseriesofquinolonederivativescontainingbenzimidazole,benzoxazoleorbenzothiazoleringweresynthesized.The

    ;cytotoxicityof12newcompoundswasevaluatedinKB,Be17402,A2780andHT-29celllines.Mostofsynthesizedcompounds

    ;showedmoderateinhibitoryactivityagainstcancercells.Theinhibitoryactivitiesof6k,againstKBandA2780tumorceilsare

    ;comparabletothatoftopotecan,oneoftopoisomeraseIinhibitors.

    ;?

    2008QiDongYou.PublishedbyElsevierB.VonbehalfofChineseChemicalSociety.Allrightsreserved.

    ;Keywords:Quinolonederivatives;Synthesis;Anfitumor

    ;DNAtopoisomerases(tope)areconsideredtoplayimportantrolesinreplication,recombination,transcription,

    ;chromosomecondensation.andthemaintenanceofgenomestabilitybycatalyzingthepassageofindividualDNA

    ;strands(topeI)ordoublehelices(topeII)throughoneanother.Inaccordance,topoisomeraseactivitiesareactivatedin

    ;cancercellproliferation,andsotopoisomerasesaregoodtargetsforantineoplasticdrugsl,2].Theanticancerdrugs

    ;camptothecin,doxorubicin,andetoposidearerepresentativesoftopeIortopoIIinhibitors31.

    ;Basedonthestructureanalysisofexistingtopoisomeraseinhibitors,wefoundthatseveralcoplanarringswere

    ;commonstructuralfeaturesinthosemolecules.W_especulatedthatthosecoplanarringswereessentialfortheir

    ;antitumoractivitiesascamptothecin4.

    ;Usingbenzimidazole.benzoxazoleorbenzothiazoleasreplacementoftheA_Bring.andquinoloneasreplacement

    ;ofD—EpartofCPT’wedesignedaseriesofcompounds.whichremainedcoplanarityando

    verlappedwithCPT

    ;relativelywel1.Benzimidazoles,benzoxazolesandbenzothiazoleswerereportedtobetopeIinhibitorsandquinolones

    ;tobetopeIIinhibitors

    57.Thestructureactivityrelationshipstudiesofquinolonederivativeshavedemonstrated

    ;matthehalogensonthequinolineringplayedanimportantroleintheirantitumoractivity,probablyinvolvedindrug/

    ;DNAbinding[8].Toinvestigatetheimpactofthesubstituentsontheactivityofthesecompounds,thehalogenswere

    ;alsoincorporatedintothe6.7.8.positionofquinolones.

    ;Hereinwereposedthesynthesisandcytotoxicityofaseriesof3.substitutedquinolonederivatives(Tablel1.

    ;Thecompoundswereobtainedbycondensationofquinolone.3.carboxylicacidswitho.phenylenediamine.

    ;o-aminophenoloroaminothiophenolathightemperature

    91.Reactionofethoxymethylenemalonicesterwith

    ;Correspondingauthor.

    ;E-mailaddress:youqidong@gmail.tom(Q.D.You)

    ;10018417/$-seefrontmatter?

    2008QiDongYou.PublishedbyElsevierB.VonbehalfofChineseChemicalSociety.Allfightsreserved.

    ;doi:10.10160.cclet.2008.09.034

    ;疆一

    ;Table1

    ;Thetargetcompounds

    ;H.Wangeta1./ChineseChemicalLetters19f2OO8)1395-1397

    ;Forspectraldata,seereference13

    ;aromaticanlinesat120.Cgaveanilinoacrylates2a_1.whichweredirectlycyclizedtogive3a.1uponheatingin

    ;diphenyletherat250.C.Thecorrespondingquinolone-3

    carboxylicacids5a_1werepreparedbyN-ethylationand

    ;subsequenthydrolysis[10-12].ThestructuresofthetargetcompoundswereconfirmedbyHN/VlR.MSspectraand

    ;elementalanalysis(Table2).

    ;R

    ;1

    ;C2Hs

;4

    ;2a1

    ;O

    ;R1

    ;5

    ;O

    ;COOH

    ;NH2

    ;XH

    ;o

    ;COOC2Hs

    ;R

    ;R1

    ;6a~l

    ;(a)EMlVlE,120.c;(b)Ph20,250.C;(c)EtBr,K2CO3;(d)NaOHthenHC1;(e)PPA ;Thecytotoxicityof12newcompoundswasevaluatedinKB,Be17402,A2780andHT-29celllinesinvitrobythe

    ;standardMTTassay(Table3).Theresultsshowedthatmostnewcompoundspossessedinhibitoryactivityagainst

    ;Ible2

    ;Physicochemicaldataof3-substitutedquinolonederivatives6a_l ;T{Ible3

    ;HWangeta1./ChineseChemicalLetters19(20o8)1395-1397

    ;ThecytotoxicityoftheriflecompoundsagainstKB,A2780,Be17402,HT-29(IC5o)(1~mol/mL)

    ;1397

    ;cancercens.Thetitlecompoundscontainingbenzoxazole6b,6e,6hand6kshowedmoderateantitumoractivityinKB

    ;cellline.Compounds6j-61,6-floro-3-substitutedquinolonederivativesdisplayedhighercytotoxocity.Theinhibitory

    ;activitiesof6kagainstKB(IC5o=1.31txmol/L)andA2780(IC5o=0.62p~mol/L1tumorcellsarecomparableto

    ;topotecan(ICso=O.57;2.14~mol/L).oneoftopoIinhibitors.

    ;Acknowledgment

    ;TheworkwassupportedbyNationalNaturalScienceFoundationofChina(No.30271543) ;L.FLiu.Annu.Rev.Biochem.58(1989)351.

    ;B.K.Sinha,Drugs49(1)(1995)l1.

    ;H.J.Park,YS.Kim,J.S.Kiln,eta1.Bioorg.Med.Chem.Lett.14(15)(2O04)3385. ;M.R.Redinbo,J.J.Champoux,G.J.Wim,Biochemistry39(23)(2O0o)6832. ;M.Rangarajan,J.S.Kirn,S.ESim,eta1.Bioorg.Med.Chem.8(12)(2000)2591. ;J.S.Kim,Q.Sun,B.Gatto,eta1.Bioorg.Med.Chem.4(4)(1996)621.

    ;VE.Anderson,R.PZaniewski,FS.Kaczmarek,eta1.J.Bio1.Chem.274(5O)(1999)35927. ;M.J.Robinson,B.A.Martin,D.Gootz,eta1.Antimicrob.AgentsChemoth36(4)(1992)751.

    ;D.WHein,R.J.Alheim,J.J.Leavitt,J.Am.Chem.Soc.79(1)(1957)427. ;H.Koga,A.Itoh,S.Murayarna,eta1.J.Med.Chem.23(12)(198O)1358.

    ;L.A.Mitscher’H.E.Gracey,G.WClark,eta1.J.Med.Chem.21(5)(1978)485.

    ;I.Mozk,B.Sket,J.Heterocyc1.Chem.31(5)(1994)1293.

    ;6a:HNMR(CD3OD,8p1):7.47(t,1H,J=8.1Hz),7.66(dd,1H,J=8.4,1.8Hz),7.79(m,IH),7.86(dd,1H,J=8.1,1.8Hz),7.97(m,1H),

    ;8.17(m,1H),8.40(dd,1H,J=8.4,1.8Hz),9.05(s,1H);6b:H(DMSO-

    ,pm):7.38(m,2H),7.47(t,1H,J=7.8Hz),7.75(m,2H),

    ;7.94(d,1H,J=7.8Hz),8.22(d,1H,J=7.8Hz),8.71(s,1H);6c:HN(DMSO

    ,6ppIn):7.39(t,1H,J=7.2Hz),7.51(m,2H),7.97(m,2H),

    ;8.10(d,1H,J=7.2Hz),8.3l(dd,1H,J=8.1,1.5Hz),9.08(s,1H);6d:H

    (DMSOd6,6ppm):1.43(t,3H,J=7.1Hz),4.57(q,2H,

    ;J=7.1Hz),7.15(m,2H),7.62(m,2H),7.86(dd,1H,J=9.0,2.4Hz),7.98(d,1H,J=9.0Hz),8.34(s,1H),9.25(s,1H);6e:HNMR(DMSO

    ;d6,6ppm):1.42(t,3H,J=7.2Hz),4.51(q,2H,J=7.2Hz),7.38(m,2H),7.74(m,2H),7.86(dd,1H,J=9.1,2.5Hz),7.95(d,1H,J=9.1Hz),

    ;8.26(s,1H),9.04(s,1H);H

    (DMsO?,pm):1.46(t,3H,J=7.1Hz),4.63(q,2H,J=7.1Hz),7.40(m,1H),7.52(m,1H),7.90(dd,

    ;1H,J=7.9,2.5Hz),8.00(m,2H),8.12(d,1H,J=7.9Hz),8.34(d,1H,J=2.5Hz),9.35(s,lH):6g:H?(DMSO’t6,‰?):1.43(t,3H,

    ;J=7.1Hz),4.55(q,2H,J=7.1Hz),7.16(m,2H),7.42(m,1H),7.59(m,1H),7.67(m,1H),7.81(dd,1H,J=11.4,2.2Hz),8.49(m,1H),9.24(s,

    ;1H),12.65(s,1H);6h:HNM

    (DMSOd,6pp):1.41(t,3H,J=7.1Hz),4.48(q,2H,J=7.1Hz),7.367.42(m,3H),7.727.81

    (m,3H),

    ;8.39(m,1H),9.01(s,lH);6i:HNMR(DMSo-

    ,6pp):1.47(t,3H,J=7.1Hz),4.58(q,2H,J=7.1Hz),7-367.45(m,2H).7.50(m,1H), ;7.82(dd,1H,J=l1.3,2.2Hz),7.97(d,1H,J=8.0Hz),8.10(d,1H,J=7.8I-Iz),8.47(m,1H),9.30(s,1H);6j:HNMR(DMSOd6,8pr.m):

    ;1.43(t,3H,J=7.1Hz),4.54(q,2H,J=7.0Hz),7.39(m,2H),8.0o(m,2H058.13(m,3H),9.3

    6.(s,1H).

    ;旧互.

    ;

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