一氧化氮供体型抗耐药肿瘤药物的研究进展-白成锋

527ProgPharmSciJul.2016Vol.40No.72016,40407:527-534PROGRESSINPHARMACEUTICALSCIENCESProgressintheResearchofNitricOxide-DonatingDrugsagainstDrug-ResistantCancerBAIChengfeng,HUANGZhangjian,ZHANGYihua(CenterofDrugDiscovery,ChinaPharmaceuticalUniversity,Nanjing210009,China)Asamessengerand/oreffector,nitricoxide(NO)playsimportantrolesincardiovascular,nervous,respiratory,gastrointestinalandimmunesystems.Abnormalityinitsgenerationand/orsignaltransductionisassociatedwithvariousdiseases(includingcancer).Multidrug-resistance(MDR)isoneofthemainreasonsforintractabletreatmentandeasyrelapseofcancer.Inrecentyears,sufficientevidencehasshownthatNOdonordrugsareadvantageousinthetreatmentofdrug-resistanttumors.Basedonliteraturestudyandinconnectionwithourownresearch,theeffectandmechanismofNOondrug-resistanttumor(nitrationrelatedtransportproteins,aswellasinterferewithNF-κB/Snail/YY1/RKIP/PTENpathway)werereviewedandtheresearchprospectofNOdonordrugsagainstdrug-resistanttumorwasforecasted.nitricoxide;multidrugresistance;mechanism;nitrationp53p53p53528ProgPharmSciJul.2016Vol.40No.7NOONNONO2O2NNNOOONHONO2O2NONNNOHOHHOOHHOOOOOOOHOHOOHOHORHHH328OHHOOHOHOHOOHOHONNNO2O2NONNONR1R2NNOOPhSO2R1NR2NHONHONNOOOOHHOOHOHNOHOHOOHOHR1NR2R=R=R===NNOOPhSO2RNNOOOOHHOOHOHNOHOOHOHHOHOHOOHOHHONHONHORNR21RNR21529ProgPharmSciJul.2016Vol.40No.7O2O2NOONOOCO2OHHNOONOOCO2OHHNONO2530ProgPharmSciJul.2016Vol.40No.7NNNNNNNOO1245R1R23SRNR1R2O+NOONONRSOR1R2+NOONORSRSNONOPTENRKIPDNAABCRNOSONOO,NO2P-gpMRP1SnailNF-κBYY1·O2531ProgPharmSciJul.2016Vol.40No.7NHHOONCOOHHHONCOHOHNNONSO2PhOOOOOHOOOHOOHOOHOOHONH2OHOOOHOOHOOOOHONH2OONONSO2PhOHOOOHOOHOOOOHONH2OONO2ONO2OHOOOHOOHOOOOHONH2OOOONNONOHOOOHOOHOOOOHONH2OO2NOHClHClHClHClHCl+532ProgPharmSciJul.2016Vol.40No.7WangC,Kemp-HarperBK,KocanM,etal.Theanti-fibroticactionsofrelaxinaremediatedthroughaNO-sGC-cGMP-dependentpathwayinrenalmyofibroblastsinvitroandenhancedbytheNOdonor,diethylamineNONOate[J].FrontPharmacol,2016,7:91.MokhtarSS,VanhouttePM,LeungSWS,etal.Reducednitricoxide-mediatedrelaxationandendothelialnitricoxidesynthaseexpressioninthetailarteriesofstreptozotocin-induceddiabeticrats[J].EurJPharmacol,2016,773:78-84.YongsanguanchaiN,PongrakhananonV,MutiranguraA,etal.Nitricoxideinducescancerstemcell-likephenotypesinhumanlungcancercells[J].AmJPhysiolCellPhysiol,2015,308(2):89-100.ChangCF,DiersAR,HoggN.Cancercellmetabolismandthemodulatingeffectsofnitricoxide[J].FreeRadicBiolMed,2015,79:324-336.BianK,MuradF.Whatisnextinnitricoxideresearch?Fromcardiovascularsystemtocancerbiology[J].NitricOxide,2014,43:3-7.ChengH,WangL,MollicaM,etal.Nitricoxideincancermetastasis[J].CancerLett,2014,353(1):1-7.[1][2][3][4][5][6]''''NR2=CH3CHR2=CH3CHR1=O(CH2)4R1=O(CH2)2O(CH2)2OOOOOOOOOOOOOOOOCONHR2COR1ONONSO2PhOHOO533ProgPharmSciJul.2016Vol.40No.7WangC,XiaG,LiuX,etal.SynthesisandantitumoractivityofATB-429derivativescontaininganitricoxide-releasingmoiety[J].BioorgMedChem,2016,9(26):2355-2359.WangL,LiY,ZhuL,etal.Antitumoractivitiesandimmunomodulatoryofricebranpolysaccharidesanditssulfatesinvitro[J].IntJBiolMacromol,2016,88:424-432.HibbsJB,TaintorRR,VavrinZ.Macrophagecytotoxicity:roleforL-argininedeiminaseandiminonitrogenoxidationtonitrite[J].Science,1987,235(4787):473-476.SomasundaramV,NadhanR,HemalathaSK,etal.Nitricoxideandreactiveoxygenspecies:cluestotargetoxidativedamagerepairdefectivebreastcancers[J].CritRevOncolHematol,2016,101:184-192.BurkeAJ,SullivanFJ,GilesFJ,etal.Theyinandyangofnitricoxideincancerprogression[J].Carcinogenesis,2013,34(3):503-512.VahoraH,KhanMA,AlalamiU,etal.Thepotentialroleofnitricoxideinhaltingcancerprogressionthroughchemoprevention[J].JCancerPrev,2016,21(1):1-12.BirgitZ,RomanK,vonKnethenA,etal.NitricoxidedonorsinhibitformationoftheApaf-1/caspase-9apoptosomeandactivationofcaspases[J].BiochemJ,2003,371(3):1055-1064.DuanW,LiJ,InksES,etal.Design,synthesis,andantitumorevaluationofnovelhistonedeacetylaseinhibitorsequippedwithaphenylsulfonylfuroxanmoduleasanitricoxidedonor[J].JMedChem,2015,58(10):4325-4338.TreuerAV,GonzalezDR.Nitricoxidesynthases,S-nitrosylationandcardiovascularhealth:frommolecularmechanismstotherapeuticopportunities(review)[J].MolMedRep,2015,11(3):1555-1565.QuJ,LiuGH,HuangB,etal.NitricoxidecontrolsnuclearexportofAPE1/Ref-1throughS-nitrosationofcysteines93and310[J].NucleicAcidsRes,2007,35(8):2522-2532.ShamiPJ,SaavedraJE,WangLY,etal.JS-K,aglutathione/glutathioneS-transferase-activatednitricoxidedonorofthediazeniumdiolateclasswithpotentantineoplasticactivity[J].MolCancerTher,2003,2(4):409-417.FindlayVJ,TownsendDM,SaavedraJE,etal.TumorcellresponsestoanovelglutathioneS-transferase-activatednitricoxide-releasingprodrug[J].MolPharmacol,2004,65(5):1070-1079.ChenL,ZhangY,KongX,etal.Design,synthesis,andantihepatocellularcarcinomaactivityofnitricoxidereleasingderivativesofoleanolicacid[J].JMedChem,2008,51(15):4834-4838.HuangZ,ZhangY,ZhaoL,etal.Synthesisandanti-humanhepatocellularcarcinomaactivityofnewnitricoxide-releasingglycosylderivativesofoleanolicacid[J].OrgBiomolChem,2010,8(3):632-639.HuangZ,