生物无机化学翻译

1.IntroductionTheinteractionoftransitionmetalcomplexeswithnucleicacidshasbeenoneofthemostmostvibrantareasofbioinorganicchemistrybe-causenucleicacidsrepresentveryimportantimportantpotentialtargetsofcan-cerdiagnosticandchemotherapydrugs.Amongthemetalcomplexesstudiedinthiscontext,ruthenium(II)complexeshaveattractedpar-ticularinterestinterestasDNAstructuralprobes,DNAfootprintingreagents,DNAsequence-specificcleavingagents,antitumordrugsandsoon[1–7],owingtotheirrichphotochemical,photophysicalandredoxproperties.MuchworkpertainingtotheRNAbindingproperties[8–11],RNAstructuralprobes[12,13],andRNAbindingpertinentanti-HIV(HumanImmunodeficiencyVirus)activityofruthenium(II)complexes[14–16]hasalsobeenreported,buttheRNAbindingprop-ertiesofruthenium(II)complexesremainratherfragmentaryascom-paredtotheirDNAbindingstudies.InordertodeeplyunderstandtheRNAbindingproperties,andprovideimportantfundamentaldataforRNA-targetingdrugs,moreworkisrequired.CalfthymusDNA(ct-DNA)differsfromRNAnotonlyinthecompo-sitionofbasesbutalsoinstructure.Thect-DNAisB-formdouble-helicalconfigurationwithawidemajorgrooveandrelativelynarrowminorgroove,whileyeasttRNAhasanA-formconfigurationwithL-shapedtertiarystructure(mainlyunispiral),andadeepandwideshallowminorgroove.Thesedifferenceswouldprobablyleadtodifferentbind-ingmodesandaffinities[17].Theseinspiredustoconductcomparativestudiesontheinteractionofruthenium(II)complexeswiththeDNAandtheRNA.Ourgroupfoundthat[Ru(bpy)(iip)2]2+{iip=2-(1H-indole-3-yl)-1H-imidazo[4,5-f]1,10-phenanthroline}[11]morestronglyboundtotheRNAthantotheDNA,incontrasttothebehaviorof[(bpy)2Ru(ebipc)Ru(bpy)2]4+{ebipc=N-ethyl-4,7-bis(imidazolo[4,5-f]-(1,10-phenanthrolin)-2-yl-)carbazole}[9].SinceCisplatinwasapprovedforuseintesticularandovariancan-cersbytheU.S.FoodandDrugAdministrationin1978,thedevelopmentofmetal-basedcancerchemotherapeuticagentshasattractedsignifi-cantattention.AsalternativecandidatestoCisplatin,ruthenium-basedmoleculeshaveemergedaspromisingchemotherapeuticdrugsofplatinum-resistanttumors[18,19].Forexample,imidazoliumtrans-imidazoledimethylsulfoxidetetrachlororuthenatedisplaysaveryhighactivityagainstmetastasesalthoughitdoesnotshowdramaticcytotox-icityintumorcelllinesinvitro[18,19].Owingtotheirreversibleredoxproperty,goodcellpermeability,andstabilityinbiologicalaqueous,aerobicmedia,ferroceneanditsderivativeshavealsoattractedmuchattentionforbioorganometallicanticancerdrugs[20–23].Forinstance,theferrocenyl1.简介过渡金属配合物与核酸的相互作用已经成为生物无机化学的最具活力的地区进行，导致核酸代表了CAN-CER诊断和化疗药物非常重要的潜在目标之一。在所研究在这方面的金属络合物，钌（II）配合物已经引起同水准满足特殊兴趣的DNA结构的探针，DNA足迹试剂，DNA序列特异性断裂剂，抗肿瘤药物等[1-7]，由于它们的丰富的光化学，光物理和氧化还原特性。有关的RNA结合性质[8-11]许多工作，RNA结构的探针[12,13]，以及RNA结合相关的抗HIV（人免疫缺陷病毒）钌的活性（II）的配合物[14-16]也已经的报道，但该RNA结合丙ERTIES钌（II）配合保持，而局部作为COM-相比于它们的DNA结合研究。为了深入了解RNA绑定属性，并为RNA靶向药物的重要基础数据，更多的工作是必需的。小牛胸腺DNA（小牛胸腺DNA）不同于RNA不仅在COMPO-习得的碱基，而且在结构。的小牛胸腺DNA是具有宽大沟和相对窄的小沟B型双螺旋结构，而酵母tRNA具有L形的三级结构（主要unispiral）的A-形式配置，并且一个又深又宽浅次要槽。这些差异可能会导致不同的绑定，荷兰国际集团模式和亲和力[17]。这些启发我们进行比较研究上的钌（II）配合物的DNA和RNA的相互作用。我们的研究小组发现，使用[Ru（联吡啶）（IIP）2]2+{IIP=2-（1H-吲哚-3-基）-1H-咪唑并[4,5-f]的1,10-菲咯啉}[11]更牢固地结合到RNA的比对的DNA，与此相反的行为[(bpy)2Ru(ebipc)Ru(bpy)2]4+{ebipc=N-ethyl-4,7-bis(imidazolo[4,5-f]-(1,10-phenanthrolin)-2-yl-)carbazole}[9]。由于顺铂被批准用于睾丸和卵巢的使用可以-核证减排量在1978年由美国食品和药物管理局，金属为基础的癌症化疗药物的发展吸引了显-着关注。作为替代候选顺铂，钌系分子已经成为有希望的化学治疗药物的铂-耐药性肿瘤[18,19]。例如，咪唑鎓反式imidazoledimethylsulfoxidetetrachlororuthenate显示针对转移非常高的活性，尽管它不显示戏剧性cytotox-孵化城在肿瘤细胞系的体外[18,19]。由于它们的可逆的氧化还原性质，良好的细胞渗透性和稳定性在生物水溶液，有氧媒体，二茂铁及其衍生物也备受关注为bioorganometallic抗癌药物[20-23]。例如，二茂铁部分中ferrocifen，这是一个二茂铁共轭TA-moxifen，显着增强了他莫昔芬[20]的抗癌活性。因此，可以推断，二茂铁基的钌络合物附件可能得到新的moietyinferrocifen,whichisaferrocene-conjugatedta-moxifen,remarkablyaugmentstheanticanceractivityoftamoxifen[20].Therefore,itcanbeinferredthattheattachmentofferrocenylgrouptorutheniumcomplexesmayobtainnovelmetallodrugswithbetterchemotherapeuticeffects.Also,animportantcriterionforthede-velopmentofmetallodrugsasphotodynamicagentsistheirabilitytophotocleaveDNA.Agreatmanyofruthenium(II)complexeshavebeenfoundtoshowinterestingphotoactivatedDNAcleavage[24–30],orthemetal-activatedhydrolyticcleavage[31–33].SomeferroceniumcationicsaltshavebeenfoundbyOsellaandco-workerstoshowoxida-tiveDNAdamage[34].Above-mentionedexcitingresultspromptedustoconductthestudiesontheDNA-[35]andRNA-bindingandpUC18DNAphotocleavagepropertiesofaferrocenyl-containingruthenium(II)complex.Asanticipated,themetalcomplexconsistingofthephoto-activerutheniumpolypyridylandredox-activeferrocenylmoieties,[Ru(bpy)2(fip)](PF6)2{fip=2-ferrocenyl-1H-imidazo[4,5-f][1,10]phe-nanthroline}(seeScheme1formolecularstructure),wasfoundtoex-hibitenhancedDNAcleavageefficiencycomparedtoaferrocene-freeanalogue[Ru(bpy)2(pip)]2+{pip=2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline}.2.ExperimentalsectionMaterials,instrumentations,andmethodsforspectroscopicmea-surements,nucleicacidbindingstudiesandtheoreticalcalculationsareshownintheSupplementarymaterials.PhotoinducedDNAcleav-ageby[Ru(bpy)2(fip)]2+and[Ru(bpy)2(ip)]2+wasexaminedbyAgarosegelelectrophoresis.SupercoiledpUC18DNA(0.2μg)wastreatedwith