化药合成,抗肿瘤新药Synthesis,acutetoxicities,andantitumore?ectsofnovel9-substitutedb-carbolinederivativesRihuiCao,QiChen,XueruiHou,HongshengChen,HuajiGuan,YanMa,WenliePengandAnlongXu*DepartmentofBiochemistryandCenterforBiopharmaceuticalResearch,CollegeofLifeSciences,SunYat-sen(Zhongshan)University,135XinGangXiRoad,Guangzhou510275,PRChinaReceived3May2021;revised27June2021;accepted28June2021Abstract—Aseriesofnovel9-substitutedb-carbolinederivativeswassynthesizedfromharmineandL-tryptophan,respectively.Cy-totoxicactivitiesofthesecompoundsinvitrowereinvestigated.Theresultsshowedthatmostcompoundsof9-substitutedb-carb-olinederivativeshadmoreremarkablecytotoxicactivitiesinvitrothantheircorrespondingparentcompounds.Acutetoxicitiesandantitumore?ectsoftheselectedb-carbolinederivativesinmicewerealsoexamined.Theresultsdemonstratedthatashortalkylorbenzylsubstituentatposition-9increasedtheantitumoractivitiessigni?cantlyandaethoxycarbonylorcarboxylsubstituentatposi-tion-3reducedtheacutetoxicityandneurotoxicityoftheseb-carbolinederivativesdramatically.Moreoverthecompoundsbothwithanalkoxycarbonylorcarboxylsubstituentatposition-3andashortalkylorbenzylsubstituentatpositon-9exhibitedmoresigni?cantantitumoractivitiesandloweracutetoxicitiesandneurotoxicitiesthantheothercompounds.Thecompound8c,havingann-butylandacarboxylsubstituentatposition-9and3,respectively,wasfoundtohavethehighestantitumore?ectandthelowestacutetoxicityandneurotoxicity.Thesedatasuggestedthat(1)appropriatesubstituentsatbothposition-9and3ofb-carbolinederivativesmightplayacrucialroleindeterminingtheirenhancedantitumoractivitiesanddecreasedacutetoxicitiesandneurotoxice?ects;(2)theb-carbolinederivativeshavethepotentialtobeusedasantitumordrugleads.2021PublishedbyElsevierLtd.1.Introductionb-Carbolinesarealargegroupofnaturallyoccurringandsyntheticindolealkaloidswithdi?erentdegreesofaromaticity,someofwhicharewidelydistributedinnat-ure,includingvariousplants,1–3marinecreatures,4in-sects,5mammaliansaswellashumantissuesandbody?uids.6–9ThesecompoundsareofgreatinterestduetotheirvariousbiologicalactivitiessuchasintercalatingintoDNA,10,11inhibitingCDK,12andTopisom-erase,13,14inhibitingmonoamineoxidase15,16aswellasinteractingwithbenzodiazepinereceptors17–19and5-hydroxyserotoninreceptors,20andtheirbroadspectrumpharmacologicalpropertiesincludinganxiolytic,hyp-notic,anticonvulsant,21–23parasiticidal,24antiviral25aswellasantimicrobialactivities.30Recentwork26–28andourpreliminaryinvestigationresultsdemonstratedthatthecompoundswithb-carbolinenucleushavepotentialantitumoractivities.Yetwealsofoundthatthisclassofcompoundscausedremarkableacuteneurotoxicitycharacterizedbytremble,twitch,andjumpinginexper-imentalmicemodels.Manypreviousreportsfocusedonthee?ectsofthesecompoundsonthecentralnervoussystem(CNS),suchastheira?nitywithbenzodiazepinereceptors,17–195-HT2Aand5-HT2Creceptors20andimidazolinerecep-tor32,andsoon.Howeversofartherehavebeenfewsuchliteraturesabouttheircytotoxicactivitiesofthesecompoundsinvitro,evennoreportsareavailabledeal-ingwithsystematicanddetailedstudiesofstructure–activityrelationshipsonbothantitumoractivitiesandneurotoxicactivitiesinvivo.Aprobablereasonforthisisthatmanyoftheb-carbolinederivativesofinterestarenotreadilyavailable.Onegoalofthepresentinvestiga-tionswastosynthesizeaseriesofnovelb-carbolinederivativesandelucidateth...