杂环_flavones

lableatScienceDirectEuropeanJournalofMedicinalChemistry84(2014)206e239ContentslistsavaiEuropeanJournalofMedicinalChemistryjournalhomepage:http://www.elsevier.com/locate/ejmechInvitedreviewFlavones:AnimportantscaffoldformedicinalchemistryManjinderSingh,ManinderKaur,OmSilakari*MolecularModelingLab,DepartmentofPharmaceuticalSciencesandDrugResearch,PunjabiUniversity,Patiala,Punjab147002,IndiaarticleinfoArticlehistory:Received20May2014Receivedinrevisedform3July2014Accepted5July2014Availableonline5July2014Keywords:FlavonesFlavonoidsAntioxidantPoly-functionalMulti-factorialdiseases*Correspondingauthor.E-mailaddress:omsilakari@gmail.com(O.Silakarihttp://dx.doi.org/10.1016/j.ejmech.2014.07.0130223-5234/漏2014ElsevierMassonSAS.AllrightsreabstractFlavoneshaveantioxidant,anti-proliferative,anti-tumor,anti-microbial,estrogenic,acetylcholines-terase,anti-inflammatoryactivitiesandarealsousedincancer,cardiovasculardisease,neurodegener-ativedisorders,etc.Also,flavonoidsarefoundtohaveaneffectonseveralmammalianenzymeslikeproteinkinasesthatregulatemultiplecellsignalingpathwaysandalterationsinmultiplecellularsignalingpathwaysarefrequentlyfoundinmanydiseases.Flavoneshavebeenanindispensableanchorforthedevelopmentofnewtherapeuticagents.Themajorityofmetabolicdiseasesarespeculatedtooriginatefromoxidativestress,anditisthereforesignificantthatrecentstudieshaveshownthepositiveeffectofflavonesondiseasesrelatedtooxidativestress.Duetothewiderangeofbiologicalactivitiesofflavones,theirstructureeactivityrelationshipshavegeneratedinterestamongmedicinalchemists.Theoutstandingdevelopmentofflavonesderivativesindiversediseasesinveryshortspanoftimeprovesitsmagnitudeformedicinalchemistryresearch.Thepresentreviewgivesdetailaboutthestructuralrequirementofflavonederivativesforvariousphar-macologicalactivities.Thisinformationmayprovideanopportunitytoscientistsofmedicinalchemistrydisciplinetodesignselective,optimizeaswellaspoly-functionalflavonederivativesforthetreatmentofmulti-factorialdiseases.漏2014ElsevierMassonSAS.Allrightsreserved.1.IntroductionFlavonoidsarelowmolecularweightpolyphenolicphyto-chemicals,derivedfromsecondarymetabolismofplantsandplayimportantroleinvariousbiologicalprocesses.Theyexhibitdiversetypeofpropertiesthatarebeneficialforhumanhealthviainter-actingwithanumberofcellulartargetsinvolvedincriticalcellsignalingpathwaysinthebody.ResearchinthefieldofflavonoidshasincreasedsincetheFrenchparadoxconceptwasformulatedbyFrenchepidemiologistsinthe1980s,i.e.,lowercardiovascularmortalityrateobservedinMediterraneanpopulationsinassocia-tionwithredwineconsumptionandahighsaturatedfatintake[1,2].Flavonoidsarecomponentsofawidevarietyofedibleplants,fruit,vegetablesandofbeveragessuchastea,coffee,beer,andwine.So,in-vitroinhibitionofLDLoxidationbyflavonoidsderivedfromredwinewasdemonstrated.Severalotherbeneficialproper-tiesofflavonoidshavesincebeenascertainedasinformationaboutthemechanismsofflavonoidswasscarce,butwithtimethefla-vonoidswereexploredhastily.).served.Flavonoidscanbeclassifiedintovariousclassesi.e.Flavonols(Quercetin,Kaempferol,Myricetin,Fisetin),Flavones(Luteolin,Apigenin),Flavanones(Hesperetin,Naringenin),FlavonoidGlyco-sides(Astragalin,Rutin),Flavonolignans(silibinin),Flavans(Cate-chin,Epicatechin),Isoflavones(Genistein,Daidzein),Anthocyanidins(Cyanidin,Delphinidin),Aurones(Leptosidin,Aur-eusidin),Leucoanthocyanidins(Teracacidin),Neoflavonoids(Cou-tareagenin,Dalbergin),Chalcones.Allclassesofflavonoidsexhibitsvarietyofbiologicalactivities,butamongthem,theflavoneshavebeenconsiderablyexplored.Variousnatural,semi-syntheticandsyntheticderivativesofflavoneshavebeensynthesizedandeval-uatedforseveraltherapeuticactivitieslikeanti-inflammatory,anti-oestrogenic,antimicrobial[3],anti-allergic,antioxidant[4],anti-tumorandcytotoxicactivities[5].Themajorityofmetabolicdis-easesarespeculatedtooriginatefromoxidativestress,anditisthereforesignificantthatrecentstudieshaveshownthepositiveeffectofflavonesondiseasesrelatedtooxidativestress,suchasatherosclerosis,diabetes,cancer,Alzheimer'sdisease,etc.SomeoftheflavonesofnaturaloriginlikeNaringenin(NaturalFemaleSupport),GingkoFlavoneglycosides(GingkoSmart),andsyntheticoriginlikeFlavopiridolarepresentlyavailableinthemarket.Flavonesarepresentinfruitsandvegetableswhichweconsumeinadvertentlyinourdailydietandtheyhaveapositiveimpactonourhealthwithoutanymajorsideeffects.InordertoexploreM.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239207diverserolesofflavones,investigatingvariousmethodsfortheirsynthesisandstructuralmodificationofflavoneringhavenowbecomeimportantgoalsofseveralresearchgroups.Thus,naturallyobtainedflavonemoietyhavingavarietyofbiologicalactivitiescanbetakenasleadcompoundforthesynthesisofsemi-andpurelysyntheticflavonederivativeswithdifferentfunctionalgroupsatdifferentpositionsofflavoneskelton.2.ChemistryFlavoneisaclassofflavonoidsbasedonthebackboneof2-phenylchromen-4-one(2-phenyl-1-benzopyran-4-one).Themo-lecularformulaofflavonemoleculeisC15H10O2.Ithasathree-ringskeletons,C6eC3eC6,andtheringsarereferredtoasA-,C-,andB-rings,respectively(Fig.1).Flavoneshavethreefunctionalgroups,includinghydroxy,carbonyl,andconjugateddoublebond;conse-quentlytheygivetypicalreactionsofallthreefunctionalgroups.Flavonesarecolorless-to-yellowcrystallinesubstances,solubleinwaterandethanol.Theygiveyellowcolorsolutionwhendissolveinalkali.Flavonesaremoderate-to-strongoxygenbases,andaresol-ubleinacidsduetotheformationofoxoniumsaltshavingpKavaluesrangingfrom0.8to2.45[6].FlavoneshaveaplanarstructurewithitsCeOeCbondangle120.9
.ItsbondlengthbetweenCeOis1.376脜anddihedralangleisaround179.2
.Synonymsofflavoneare2-phenyl-4H-chromen-4-one;2-phenyl-1-benzopyran-4-one.Flavonescanreactinseveralways,includingreductionreactions[7],degradationinthepresenceofbase[8],oxidation[9],rearrangement[10],substitution[11,12],addition[13e15],condensation[16],reactionwithorganometallicreagents[17].Severalsyntheticmethodshavebeendevelopedandmodifiedtogetproductsofhighyield,purityandofthedesiredquality.FlavonescanbesynthesizedbyvarioussyntheticschemeslikeClaiseneSchmidtcondensation[18],BakereVenkataraman-rear-rangement[19,20],IonicLiquidPromotedsynthesis[21],AllaneRobinson[22],VilsmeiereHaackreaction[23],Wittigreac-tion,FriesrearrangementandmodifiedSchotteneBaumannreac-tion.Nowaday,mostoftheflavonesaresynthesizedbasedontheBakereVenkataramanmethod.Itinvolvestheconversionofo-hydroxyacetophenoneintophenolicester,whichundergoesanintramolecularClaisencondensationinthepresenceofabasetoformb-diketone,whichiscyclizedtoflavonesbyanacid-catalyzedcyclodehydration(Schemes1and2).Traditionally,flavonesweresynthesizedwithBakereVenkataraman-rearrangementbutthesereactionsundergotheuseofstrongbases,acids,longreactiontimeandlowyieldsconsequentlySashidharaetal.reportedexpedient,simplisticandalternatesynthesisofmedicinallyimportantflavonesinwhich2-hydroxychalconesresultingfromcondensationbetweenaceto-phenonesandsalicylaldehyde,undergooxidativecyclizationonheatinginthepresenceofcatalyticiodineandgeneratingFig.1.Basicscaffoldofflavone.diversifiedflavonesundersolvent-freeenvironmentalfriendlyconditions[24](Scheme3).3.BiosyntheticpathwayforflavonesFlavonoidbiosynthesisstartswiththecondensationof1moleculeof4-coumaroyl-CoAandthreemoleculesofmalonyl-CoAyieldingnaringeninchalcone,carriedoutbytheenzymechalconesynthase(CHS).Thetwoimmediateprecursorsofthechalconeoriginatefromtwodifferentpathwaysofprimarymetabolism.Coumaroyl-CoAissynthesizedfromtheaminoacidphenylalaninebythreeenzymaticsteps,collectivelycalledthegeneralphenyl-propanoidpathway,Malonyl-CoAissynthesizedbycarboxylationofacetyl-CoA,acentralintermediateintheKrebstricarboxylicacidcycle.Thechalconeisconsequentlyisomerizedbytheenzymechalconeflavanoneisomerase(CHI)toyieldaflavanone.Fromthiscentralintermediatethepathwaydivergesintoseveraldifferentclassesofflavonoids[25](Scheme4).4.PharmacologicalactivitiesofflavonesFlavonesscaffoldcanbetermed鈥榮keletonkey鈥�asitisanimportantcoreinmanycompoundsactingatdifferenttargetstoelicitvariedpharmacologicalpropertieswithvarioussubstitutionpatterns(Fig.2).Itisthediversityofthisstructurethatgivesfla-voneswiderangeofbiologicalactivity.Duetothewiderangeofbiologicalactivitiesofflavones,theirstructureeactivityrelation-shipshavegeneratedinterestamongmedicinalchemists,andthishasculminatedinthediscoveryofseveralleadmoleculesinnumerousdiseaseconditions.ThisreviewgivesacomprehensiveaccountofSARorstructuralrequirementofflavonederivatives,necessaryforwidebiologicalactivityspectrum.4.1.Anti-oxidantThehighlevelsoffreeradicalsinlivingsystemsareabletooxidizebio-molecules,leadingtotissuedamage,celldeathorvariousdiseasessuchascancer,cardiovasculardiseases,arterio-sclerosis,neuraldisorders,skinirritationsandinflammations[26].Freeradicalsarehighlyreactiveandthereforecanattackmembranelipids,generatingcarbonradicalsandproduceperoxyradicalswhichcauselipidperoxidation.Therefore,asingleradicalmaydamagemanymoleculesbyinitiatinglipidperoxidationchainre-actions.Toopposetheviciouseffectoffreeradicals,thebodyhasanumberofantioxidantdefensemechanismsintheformofenzymessuchassuperoxidedismutaseandcatalase,copperandirontransportproteins,aswellaswater-solubleandlipid-solublean-tioxidants[27].Itwasstudiedthatimbalancebetweenfreeradicalsandtheantioxidantdefensemechanismisassociatedwithseveralhumandiseases.Antioxidantsmayactwithtwomechanisms:preventionofinitiationofoxidation,oraschainbreakingantioxidants.Preven-tionofinitiationofoxidationoccursbyinhibitingsuperoxideanionproduction,degradinghydrogenperoxideandchelatingorreducingmetalions,whilechainbreakingantioxidantsactbyscavengingradicals,mostlyhydroxylradicals,therebyinhibitingthechainofoxidativeeventsthatleadstodamageoflipidmem-branes,proteinsandDNA[28].Oxidativespeciesandfreeradicalinvolveinthepathophysiologyofnumerousdiseaseslikeinneu-rodegenerateddisorders,cardiovascular,cerebrovascular,autoim-munedisorderslikediabetes,rheumatoidarthritis,psoriasisetc.Therefore,variousnaturalaswellassyntheticantioxidantsareusedtoscavengingfreeradicals.Itwasreportedthatflavoneshavewellknownantioxidantac-tivity;andcanactbyseveralpathways.Therefore,flavonesareScheme1.Synthesisofflavonesviabetadiketoneintermediate.Scheme2.BakereVenkataramanrearrangementreaction.M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239208significantlyusedinpharmaceuticalandfoodindustries[29].Fla-voneslikechrysin(1),luteolin(2)andapigenin(3)whichcontaintwoorthreefreehydroxylgroupsinringsA/B,showantioxidantpropertiesatlowconcentrations[30,31](Table1).Hyunetal.generateaQSARmodelfordifferentflavoneshavinganumberofhydroxylgroupstoevaluatestructurerequirementforantioxidantactivityandconcludedthatasthenumberofhydroxylgroupsincreases,thescavengingeffectsalsoincreases.Inaddition,twohydroxylgroupsneighboringtoeachother,showbettereffectstoo.Theyfoundthatamongallflavoneanalogues6,7,30-trihy-droxyflavone(4),showedscavengingeffectupto87.8%[32].Itwasalsofoundthatsubstitutionof3,4-dihydroxybenzoylatpositionC-3(5)increasesscavengingactivityagainstfreeradicals[33].Variousconjugatedflavones,C60-Flavone(6)wereevaluatedforantioxidantactivityinwhichtheflavonesphenolicmoietyreactwithperoxylradicals,whiletheC60partofthemoleculeactsScheme3.ClaiseneSchmidtsynergicallybytrappingalkylradicalsunderreducedO2partialpressure.Thus,thismoleculeactsaspromisingleadforbroad-spectrumradicalscavengers.FullerenederivativesareusedasprotectivedrugsagainstdiseasesrelatedwithoxidativestressandPoly-hydroxylatedfullerenes[C60(OH)n]arealsoexcellentantioxi-dantsabletoreducethefreeradicaldamageofneuronaltissues[34,35]Gazaketal.evaluatedantioxidantactivityofseveralflavonesderivativesusingthreedifferentassays(DPPHscavenging,inhibi-tionoflipidperoxidation,andinhibitionofsuperoxide)andfoundthat2,3-dehydrosilybin(7)governedradical-scavengingactivity[36].A5,6,7-trioxygenatedflavone,baicalein(8)iscapableofattenuatingoxidativestressinvariousinvitromodels,thuspossesssignificantantioxidantactivity[37].Eupafolin,(9)causedareduc-tionofenzymaticactivitiesbetweencomplexesIandIIIoftherespiratorychain.Italsoprotectsculturedneuronsagainstglutamate-inducedoxidativestressandinhibitsxanthineoxidaseactivity[38].Anaturalflavone,Chrysoeriol,(10)extractedfromthetropicalplantCoronopusdidymusweretestedfortheirabilitytoinhibitlipidperoxidationinducedbyg-radiation,Fe(III)andFe(II)andshowedbetterprotectingeffectwithDPPHradicalsatmillimolarconcen-trations[39].5,7,30,40-tetrahydoxy-3-methoxyflavone(THMF),11wasinves-tigatedforantioxidanteffectsontheN-formyl-methionyl-leucyl-phenylalanine-induced(fMLP)superoxidegenerationandtyrosylphosphorylationofproteinsinhumanneutrophilsandfoundthatTHMFwasmoreeffectivethanluteolinandquercetinduetocondensationreaction.Scheme4.Biosyntheticpathwayofflavones.M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239209methoxygroupatposition-3[40].Variousdi-tert-butylhydrox-yphenyl(DBHP)substitutedflavonesderivativesweresynthesizedandevaluatedforradicalscavengingactivity,theseactssynergis-ticallywithbutylatedhydroxytoluene(BHT),awell-knownlipidperoxidationinhibitor[41].Twobutylatedflavones(12)and(13),werepowerfulscavengersofstablefreeradicalDPPH.Theyexhibithighantioxidantprotectiveactivityagainstperoxidationsinducedbymetalionsorperoxylradical[42].Cotelleetal.reportedthat20,30,40-trihydroxyflavone(14)exhibitinterestingantioxidantpropertiesexpressedeitherbythecapacitytoscavengefreeradicalsortocompetitivelyinhibitxanthineoxi-dase[43].ReportedSARstudiesofantioxidantactivitiesofflavonederivativesindicatethatthreestructuralfeaturesareessentialforantioxidantactivity(markedinbold)are:thecatecholgroup(30,40-OH)intheB-ring,theC2]C3doublebondintheC-ring,thaten-ablestheconjugationoftheB-ringtothe4-oxogroup,andthe3-and5-OHgroupstogetherwiththe4-oxogroup(Fig.3).A2,3-doublebondinconjugationwith4-ketofunctionalgroupprovideselectrondelocalizationfromtheringBandtheelectron-donatinggroupsontheringBreducetheOeHbonddissociationenergy,thustheseimportantgroupsorfeaturesimpartradicalscavengingpropertiestoflavones.HydroxylgroupontheringAappearstobeoflowerimportance.Flavonesalsohavethecapa-bilitytoformchelateswithoxidizingmetalionsandpreventvariousredoxreactions,thusimpartingantioxidanteffects(Fig.4).The5-hydroxylgroupinassociationwiththe4-ketoandcat-echolichydroxylgroupschelatescatalyticallyactivemetalionsinvolvedinredoxreactions,whichmaypreventtheformationofoxidizingspecies[44].Themostdetrimentalofthereactiveoxygenspeciesisthehydroxylradical,thatmayinducelipidperoxidationgeneratedintheFentonreaction(Fig.5)[45,46].HydroxylgroupsontheB-ringdonatehydrogenandanelectrontohydroxyl,per-oxyl,andperoxynitriteradicals,stabilizingthemandgivingrisetoarelativelystableflavoneradical[47](Fig.6).4.2.Anti-canceractivityCancerisoneofthemostdeath-defyinghealthhazardwhichisdistressingagreaterpartoftheworldpopulationthatconstrainstheprogressivetransformationofnormalcellstowardsmalignancy.Itinvolvesthecellproliferation,differentiation,angiogenesis,andapoptosisofthenormalcellwhichleadstotumorconditions.Variousanticanceragents(alsoreferredasantitumor,anti-proliferativeandanti-neoplastics)reportedfortreatmentofvar-iedkindsofcancersactthroughdifferentmechanisms.However,themajorsideeffectassociatedwiththeseagentsiscytotoxicitytowardsnormalcellsduetolackofselectivityfortheabnormalcells.Thus,asearchforanticanceragenthasbeenincontinuumsincemanyyears.In1960,Zutphenstudiedthatthemortalityorriskforalimentaryorrespiratorytractcancersisreducedwithdifferentflavonoidslikemyricetin,quercetin,kaempferol,luteolinandapigenin[48].In1967e1991,alargegroupstudywasorganizedtoexploretheprotectiveroleofflavonoidsagainstlungcancerandothermalignantneoplasmsandtheriskofovariancancer[49,50].Thestudyconfirmedthatapigenin,anaturallyoccurringflavonecanreducetherecurrencerateandriskofcertaincancers,pre-dominantlythebreast,digestivetract,skin,prostateandcertainhematologicalmalignancies[51].Fig.2.Therapeuticactivityprofileofflavones.M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239210Variouskinasessuchascyclin-dependentkinases(CDKs),glycogensynthasekinase-3(GSK3),dualspecificitytyrosine-phosphorylation-regulatedkinase1A(DYRK-1A)criticallypartici-pateincancer[52].Nowadays,around250smallmoleculekinaseinhibitorsareundergoingclinicaltrialsforthetreatmentofcancer,showingthatkinasesconstituteimportanttherapeutictargetsforitstreatment.Nguyenetal.developed8-substitutedregioisomer,amongallcompound(15)wasmoreactivethanits6-substitutedanalogueCapitavine(16)aswellaschrysinagainstvariouskinases[53].TheaminomoietyandthefreehydroxylgroupatC-5offlavonesnu-cleuswereessentialforinteractionwithseveralkinasesinvolvedincancer.Thestructuresofthesemoleculesarereminiscentoffla-vopiridol(17),thefirstsyntheticcCDKinhibitorenteredinclinicaltrialsasananticancerdrug.Similartoflavopiridol,anothernewsyntheticflavonoidalalkaloid,P276-00(18)enteredintoclinicalstudiesasasmall-moleculeCDKinhibitor[54,55].SelectivedualinhibitorsofRaf1andJNK1kinases,1-(3-chloro-4-(4-oxo-4H-chromen-2-yl)phenyl)-3-phenylureaderivatives,havebeendevelopedforantitumortreatment.TheRafproteininvolvedinRaseRafeERKmitogen-activatedproteinkinases(MAPKs)pathway,regulatescellularprocesseslikecellprolifera-tion,migrationandapoptosis.c-Jun-N-terminalKinase(JNK),anotherMAPKmember,isactivatedinsomecancersbyRastocooperativelypromotecancertogetherwiththeRaseRafeERKsignaling.DysregulationofbothRafeMAPKsandJNKpathwayshadbeenwellelucidatedinvarioushumancancers.SomecompoundstargetingeitherRaforJNKhadbeenapprovedorinpreclinicaltrialsforanti-cancertreatment,butnoneofmulti-targeteddrugshadenteredclinicaltrialstilldate.Compound(19)at50mMhasselec-tivityagainstp38-alphakinase,goodanti-proliferativeactivityagainstHepG2cell-lineandrelativelylowtoxicityagainstnormallivercell-linesQSG7701andHL7702.Duetolowtoxicity,20-chloro-40-aminoflavonesscaffoldmaybepotentiallyexploredforderivingmulti-targetRaf1andJNK1inhibitors[56,57].Inbreastcancer,tumorcellproliferationisstimulatedviaanomalousestrogenreceptorssignalingpathwayswhenestrogenbinds.Aromatase(CYP19)catalyzesthearomatizationreactionofandrogensubstratestoestrogens,thelastandrate-limitingstepinestrogenbiosynthesis.Therefore,aromatasetakemajorroletodevelophormone-dependentbreastcancer.Inhibitionofaroma-taseisanewandpromisingapproachtotreatbreastcancer[58].Variousaromataseinhibitorslikeletrozole,anastrozoleetcapprovedbyFDAandareusedasfirst-linetherapyinthetreatmentofbreastcancerinpostmenopausalwomen,butduetovarietyofsideeffects,naturallyoccurringflavonoidaromataseinhibitorsareattractingmoreandmoreattentionrecentlyfortheirfutureclinicaluses[59].Naturalflavonechrysin(1)andtheiranalogssynthesizedbyintroducingvariousfunctionalgroupslikehalides,nitroandaminohavebeenreportedtoshowinhibitoryeffectsagainstaro-mataseenzyme[60].Yaoetal.developednumberofflavonesscaffoldshavingvariousfunctionalgroups(carboxy,-fluoro,and-nitro)andevaluatedbyMTTassayfortheiranti-proliferativeactivityinbreastcancercellTable1Thestructuresofflavonederivatives.C.No.StructureC.No.Structure191292393494595696797898999(continuedonnextpage)M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239211Table1(continued)C.No.StructureC.No.Structure10100111011210213103141041510516106171071810819109M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239212Table1(continued)C.No.StructureC.No.Structure201102111122112231132411425115261162711728118(continuedonnextpage)M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239213Table1(continued)C.No.StructureC.No.Structure291193012031121321223312334124351253612637127M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239214Table1(continued)C.No.StructureC.No.Structure381283912940130411314213243133441344513546136(continuedonnextpage)M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239215Table1(continued)C.No.StructureC.No.Structure4713748138491395014051141521425314354144M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239216Table1(continued)C.No.StructureC.No.Structure5514556146571475814859149601506115162152(continuedonnextpage)M.Singhetal./EuropeanJournalofMedicinalChemistry84(2014)206e239217Table1(continued)C.No.Struc