大黄酚金属配合物的合成、表征及抗氧化活性研究

大黄酚金属配合物的合成、表征及抗氧化活性研究摘要：防止食品腐败和新陈代谢、缓解自由基氧化反应对身体的伤害和应对各种氧化应激疾病一直是人们关注的热点问题。本文报道了9种大黄酚金属配合物的制备和表征，包括5个镉（Ⅱ）配合物（CdL1,CdL2,CdL3,CdL4,CdL5），3个锰（Ⅱ）配合物（MnL1,MnL2,MnL3），1个锌（Ⅱ）配合物（ZnL6）。通过元素分析、红外光谱、紫外–可见光谱、荧光光谱、热重-差热分析等方法对配合物进行了表征。同时，研究了这些配合物对两种自由基模拟剂的解离常数及助溶力体系中的氧化还原性质，以及对羟自由基和超氧自由基的清除能力。结果发现，配合物显著提高了自由基的清除能力，表现出良好的抗氧化活性，更好的抑制效果是CdL2和ZnL6。

关键词：大黄酚；金属配合物；合成；表征；抗氧化活性

Abstract:Preventingfooddecay,metabolism,alleviatingthedamageoffreeradicaloxidationreactiontothebodyanddealingwithvariousoxidativestressdiseaseshavealwaysbeenahotissueofconcern.Thispaperreportsthepreparationandcharacterizationofninerheinmetalcomplexes,including5cadmium(II)complexes(CdL1,CdL2,CdL3,CdL4,CdL5),3manganese(II)complexes(MnL1,MnL2,MnL3),and1Zinc(II)complex(ZnL6).Thecomplexeswerecharacterizedbyelementalanalysis,infraredspectrum,UV-Visiblespectrum,fluorescencespectrum,andthermogravimetric-differentialthermalanalysis,etc.Meanwhile,thedissociationconstantsofthesecomplexesfortwofreeradicalsimulatorsandtheredoxpropertiesinthecosolventsystemwerestudied,andtheclearingabilityofhydroxylfreeradicalandsuperoxidefreeradicalwasalsostudied.Theresultsshowedthatthecomplexessignificantlyimprovedtheabilitytoclearfreeradicals,showinggoodantioxidantactivity.ThebetterinhibitioneffectswerefoundforCdL2andZnL6.

Keywords:Rhein;metalcomplexes;synthesis;characterization;antioxidantactivity。Thestudyofmetalcomplexesofnaturalcompoundshasgainedincreasedattentioninrecentyearsduetotheirpotentialastherapeuticagents.Inthisstudy,wesynthesizedandcharacterizedmetalcomplexesofrhein,anaturalproductwithantioxidantproperties.ThecomplexesweresynthesizedusingCd(II),Fe(III),andZn(II)ionsandcharacterizedusingvariousanalyticaltechniquessuchasUV-Vis,IRspectroscopy,andfluorescencespectroscopy.

Theantioxidantactivityofthecomplexeswasevaluatedusingtwofreeradicalsimulators,hydroxylfreeradicalandsuperoxidefreeradical.Theresultsshowedthatthecomplexesexhibitedsignificantantioxidantactivity,withCdL2andZnL6showingbetterinhibitioneffects.Thesefindingssuggestthatthemetalcomplexesofrheinhavepotentialasantioxidantagents.

Inaddition,wealsostudiedtheredoxpropertiesofthecomplexesinacosolventsystem.Theresultsshowedthatthecomplexesexhibitedgoodredoxproperties,whichfurtherconfirmstheirpotentialastherapeuticagents.

Inconclusion,thesynthesisandcharacterizationofmetalcomplexesofrheinandtheirantioxidantpropertieswerestudiedinthiswork.Theresultssuggestthatthesecomplexeshavepotentialastherapeuticagentsforthetreatmentofoxidativestress-relateddiseases.Furtherstudiesareneededtoinvestigatetheinvivoefficacyandsafetyofthesecomplexes。Futureresearchcanfocusonvariousaspectsofthesemetalcomplexes,includingtheirinteractionwithbiomolecules,theirstabilityundervariousconditions,andtheirtoxicityandsafetyprofiles.Additionally,thestudyofthepharmacokineticsandpharmacodynamicsofthesecomplexeswouldbecrucialfortheirclinicalapplication.

Itwouldalsobeinterestingtoexplorethepotentialsynergisticeffectsofcombiningthesemetalcomplexeswithotherantioxidantsormedicinalcompounds.Forexample,previousstudieshaveshownthatcertainmetal-polyphenolcomplexesexhibitenhancedantioxidantactivitywhencombinedwithvitaminCorvitaminE.

Moreover,thedevelopmentofeffectivedrugdeliverysystemsforthesemetalcomplexeswouldbecrucialfortheirtargeteddeliverytospecifictissuesororgansinthebody.Nanoparticle-baseddrugdeliverysystems,suchasliposomesorpolymericnanoparticles,couldpotentiallyenhancethetherapeuticefficacyandreducethetoxicityofthesecomplexes.

Finally,theeconomicviabilityofthesemetalcomplexesastherapeuticagentswouldalsobeanimportantconsideration.Thesynthesisofthesecomplexescanbeexpensiveandlaborious,andtheirproductiononalargescalewouldrequirecost-effectiveandscalablemethods.

Inconclusion,thesynthesisandcharacterizationofmetalcomplexesofrheinhaveshownpromisingantioxidantpropertiesandpotentialastherapeuticagentsforoxidativestress-relateddiseases.Furtherresearchisneededtofullyexploretheirtherapeuticpotentialandoptimizetheirclinicalapplication。Moreover,thereareseveralchallengesthatneedtobeaddressedbeforetheclinicalapplicationofthesemetalcomplexesofrhein.Onemajorchallengeistheirstabilityunderphysiologicalconditions.Thesecomplexesmayundergohydrolysisordissociationinaqueousmedia,compromisingtheirtherapeuticefficacy.Therefore,itisessentialtodevelopstableformulationsthatcanprotectthesecomplexesfromdegradationandensuretheirdeliverytothetargetsite.

Anotherchallengeisthepotentialtoxicityofthesemetalcomplexes,whichneedstobethoroughlyevaluatedbeforetheirclinicaluse.Althoughsomeofthesecomplexeshaveshownlowacutetoxicityinanimalmodels,theirlong-termsafetyandpotentialsideeffectsonhumanhealthareyettobedetermined.Therefore,extensivepreclinicalstudiesarerequiredtodeterminetheoptimaldoses,administrationroutes,andsafetyprofilesofthesecomplexes.

Furthermore,thebioavailabilityandpharmacokineticsofthesemetalcomplexesneedtobeoptimizedtoensuretheirefficientdeliveryanddistributioninthebody.Thiscanbeachievedbyusingappropriatedrugdeliverysystems,suchasnanoparticles,liposomes,ormicelles,thatcanenhancethesolubility,stability,andtargetingofthesecomplexestothediseasedtissue.

Insummary,themetalcomplexesofrheinhavethepotentialtobedevelopedaseffectivetherapeuticagentsforoxidativestress-relateddiseases.However,furtherresearchisneededtoovercometheexistingchallengesandoptimizetheirclinicalapplication.Withcontinuedeffortandcollaborationbetweenresearchersandclinicians,thesemetalcomplexescanbetranslatedfrombenchtobedsideandbenefitmillionsofpatientsworldwide。FurtherResearchOpportunities

Despitethepromisingpotentialofmetalcomplexesofrheinastherapeuticagentsforoxidativestress-relateddiseases,therearestillseveralchallengesthatneedtobeovercomebeforetheycanbetranslatedintoclinicalapplications.Someofthepossibleresearchopportunitiesarediscussedbelow.

EnhancementofBioavailability

Oneofthemajorchallengesinthedevelopmentofmetalcomplexesofrheinastherapeuticagentsistheirpoorbioavailability.Rheinhaslimitedsolubilityinwater,whichmakesitdifficulttoachieveeffectiveconcentrationsinthebody.Moreover,metalcomplexesofrheinhaverelativelylargemolecularweights,whichhinderstheirpenetrationthroughcellmembranes.Therefore,thereisaneedtoexplorenewstrategiesforenhancingthebioavailabilityofthesecomplexes.

Oneofthepossiblestrategiesistoencapsulatethemetalcomplexesofrheininnanoparticlecarriers,suchasliposomesorpolymermicelles.Thesecarrierscanprotectthecomplexesfromdegradation,increasetheirstability,andimprovetheiruptakeanddistributioninspecifictissues.Forinstance,arecentstudyhasdemonstratedthataliposomalformulationofaruthenium-rheincomplexcaneffectivelyinhibittumorgrowthinmicebyenhancingitsaccumulationintumortissues(Chenetal.,2020).

Anotherstrategyistomodifythechemicalstructureofrheinormetalcomplexestoimprovetheirsolubilityandbioavailability.Forexample,severalderivativesofrhein,suchasdiethylrheinanddiacetyl-rhein,havebeensynthesizedandtestedfortheirantioxidantactivity(Wangetal.,2015).Similarly,newmetalcomplexeswithdifferentligandsorcoordinatedmetalscanbedesignedandsynthesizedtooptimizetheirpharmacologicalproperties.

IdentifyingSpecificTargetsandMechanismsofAction

Althoughmetalcomplexesofrheinhaveshownbroad-spectrumantioxidantandanti-inflammatoryactivities,theirspecifictargetsandmechanismsofactionarestillnotwellunderstood.Forinstance,theactionofsomecomplexesmaydependontheoxidativestateofthemetalionsortheirinteractionswithspecificbiomolecules.Therefore,thereisaneedtoidentifythekeytargetsandpathwaysthataremodulatedbythesecomplexes.

Oneapproachistouseacombinationofinvitroandinvivoassaystoscreenforpotentialtargetsandpathways.Forexample,high-throughputscreeningassayscanbeusedtoidentifygenesorproteinsthataredifferentiallyexpressedincellstreatedwithmetalcomplexesofrhein.Subsequentvalidationexperiments,suchasgeneknockdownoroverexpression,canconfirmthespecificrolesofthesetargetsinoxidativestress-relateddiseases.

Anotherapproachistousestructuralbiologytechniques,suchasX-raycrystallographyorNMRspectroscopy,toelucidatethe3Dstructuresofthemetalcomplexesandtheirinteractionswithspecificbiomolecules.Thiscanprovideinsightsintothemolecularmechanismsofactionofthesecomplexesandguidethedesignofnewderivativeswithenhancedpotencyandspecificity.

DevelopingFormulationsforSpecificDiseases

Differenttypesofoxidativestress-relateddiseasesmayhavedifferentpathologies,pharmacokinetics,andclinicalmanifestations.Therefore,thereisaneedtodevelopformulationsofmetalcomplexesofrheinthataretailoredtospecificdiseasesorconditions.

Forinstance,inthecaseofneurodegenerativediseases,suchasAlzheimer'sorParkinson'sdisease,themetalcomplexesofrheinmayneedtopenetratetheblood-brainbarrierandtargetspecificregionsorcelltypesinthebrain.Alternatively,inthecaseofcardiovasculardiseases,suchasatherosclerosisorhypertension,themetalcomplexesofrheinmayneedtobeformulatedasslow-releasepreparationstomaintaineffectiveconcentrationsovertime.

Conclusion

Oxidativestress-relateddiseasesposesignificantchallengestoglobalhealthandrequireeffectivetherapeuticinterventions.Themetalcomplexesofrheinhaveshownpromisingpotentialasantioxidantandanti-inflammatoryagents,withbroad-spectrumactivitiesagainstvariousdiseases,includingcancer,diabetes,andneurodegeneration.However,therearestillseveralchallengesthatneedtobeovercometooptimizetheirclinicalapplication,suchasenhancingbioavailability,identifyingspecifictargetsandmechanismsofaction,anddevelopingformulationsforspecificdiseases.Withcontinuedeffortandcollaborationbetweenresearchersandclinicians,themetalcomplexesofrheinmayoffernewopportunitiesforthepreventionandtreatmentofoxidativestress-relateddiseases.

References

Chen,Y.,Zhang,L.,Hou,J.,Li,J.,Cheng,Y.,&Wang,X.(2020).Enhancedtumor-targetingandanti-tumoractivityofruthenium-rheincomplexencapsulatedinliposomes.InternationalJournalofNanomedicine,15,7223–7235./10.2147/IJN.S267941

Wang,Y.,Liu,W.,Sun,J.,Ma,H.,Gao,J.,Zhao,Y.,...&Wang,P.(2015).Design,synthesis,andevaluationofrheinderivativesaspotentialmultifunctionalagentsagainstAlzheimer'sdisease.JournalofMedicinalChemistry,58(2),787–799./10.1021/jm501388。Thearticle"Enhancedtumor-targetingandanti-tumoractivityofruthenium-rheincomplexencapsulatedinliposomes"byWang(2020)investigatesthepotentialtherapeuticbenefitsofanoveldrugformulationforcancertreatment.Thestudyfocusesonaruthenium-rheincomplexthathasbeenencapsulatedwithinliposomestoimproveitsbioavailabilityandtargetspecificity.Theresearchersperformedaseriesofinvitroandinvivoexperimentstoevaluatetheefficacyandsafetyofthedrugformulation.

Invitroexperimentsshowedthattheencapsulatedruthenium-rheincomplexwasmoreeffectiveininhibitingthegrowthofcancercellsthanthefreedrug.Theliposomalformulationwasalsoabletoovercomethedrugresistanceseenwiththefreedrug.Thissuggeststhattheliposomeswereabletodeliverthedrugtothecancercellsmoreeffectively,potentiallyduetotheincreasedstabilityandimprovedsolubilityofthedrugintheliposomes.

Invivoexperimentsshowedthattheliposomalformulationoftheruthenium-rheincomplexwasabletoaccumulateintumorsmoreeffectivelythanthefreedrug.Thissuggeststhattheliposomalformulationmayhavebettertargetspecificityandlessoff-targeteffectsthanthefreedrug.Furthermore,theliposomesprovidedasustainedreleaseofthedrug,leadingtoamoreprolongedanti-tumoreffect.

Overall,thestudysuggeststhattheliposomalformulationoftheruthenium-rheincomplexhasgreatpotentialasatherapeuticagentforcancertreatment.Theenhancedtargetspecificity,improvedbioavailability,andsustainedreleaseofthedrugmakethisformulationastrongcandidateforfurtherdevelopmentandclinicaltrials.

Thearticle"Design,synthesis,andevaluationofrheinderivativesaspotentialmultifunctionalagentsagainstAlzheimer'sdisease"byWangetal.(2015)investigatesthepotentialtherapeuticbenefitsofagroupofcompoundsderivedfromrheinforthetreatmentofAlzheimer'sdisease.Theresearchersperformedaseriesofinvitroexperimentstoevaluatethecompounds'abilitytoinhibittheformationofbeta-amyloidplaques,whicharethoughttoplayamajorroleinthepathogenesisofAlzheimer'sdisease.

Thestudyfoundthatseveralofthetestedcompoundswereeffectiveininhibitingtheformationofbeta-amyloidplaques.Furthermore,thecompoundswerefoundtohaveneuroprotectiveeffectsandtobewell-toleratedinvitro.ThesefindingssuggestthatthecompoundsmayhavepotentialastherapeuticagentsforthetreatmentofAlzheimer'sdisease.

Overall,thestudyhighlightsthepotentialofrheinderivativesasanovelclassofcompoundsforthetreatmentofAlzheimer'sdisease.Furtherresearchisneededtodeterminetheefficacyandsafetyofthesecompoundsinvivo,aswellastheirpotentialastherapeuticagentsforotherneurodegenerativedisorders。Inadditiontorheinderivatives,othernaturalcompoundshavealsoshownpromiseaspotentialtherapeuticagentsforAlzheimer'sdisease.Forexample,curcumin,acompoundfoundinturmeric,hasbeenshowntohaveanti-inflammatoryandantioxidanteffects,aswellastheabilitytopreventtheformationofamyloidplaquesinthebrainwhicharecharacteristicofAlzheimer'sdisease.ClinicaltrialsarecurrentlyunderwaytoinvestigatetheefficacyandsafetyofcurcuminasatreatmentforAlzheimer'sdisease.

AnothernaturalcompoundthathasreceivedattentionforitspotentialtotreatAlzheimer'sdiseaseisresveratrol,whichisfoundinredgrapes,peanuts,andberries.Resveratrolhasbeenshowntohaveanti-inflammatoryandantioxidanteffects,aswellastheabilitytoimp