化药合成抗肿瘤新药Synthesis,acuteto_icities,andantitumore?ectsofnovel9-substitutedb-carbolinederivativesRihuiCao,QiChen,_ueruiHou,HongshengChen,HuajiGuan,YanMa,WenliePengandAnlong_u_DepartmentofBiochemistryandCenterforBiopharmaceuticalResearch,CollegeofLifeSciences,SunYat-sen(Zhongshan)University,135_inGang_iRoad,Guangzhou510275,PRChinaReceived3May____;revised27June____;accepted28June____Abstract—Aseriesofnovel9-substitutedb-carbolinederivativeswassynthesizedfromharmineandL-tryptophan,respectively.Cy-toto_icactivitiesofthesecompoundsinvitrowereinvestigated.Theresultsshowedthatmostcompoundsof9-substitutedb-carb-olinederivativeshadmoreremarkablecytoto_icactivitiesinvitrothantheircorrespondingparentcompounds.Acuteto_icitiesandantitumore?ectsoftheselectedb-carbolinederivativesinmicewerealsoe_amined.Theresultsdemonstratedthatashortalkylorbenzylsubstituentatposition-9increasedtheantitumoractivitiessigni?cantlyandaetho_ycarbonylorcarbo_ylsubstituentatposi-tion-3reducedtheacuteto_icityandneuroto_icityoftheseb-carbolinederivativesdramatically.Moreoverthecompoundsbothwithanalko_ycarbonylorcarbo_ylsubstituentatposition-3andashortalkylorbenzylsubstituentatpositon-9e_hibitedmoresigni?cantantitumoractivitiesandloweracuteto_icitiesandneuroto_icitiesthantheothercompounds.Thecompound8c,havingann-butylandacarbo_ylsubstituentatposition-9and3,respectively,wasfoundtohavethehighestantitumore?ectandthelowestacuteto_icityandneuroto_icity.Thesedatasuggestedthat(1)appropriatesubstituentsatbothposition-9and3ofb-carbolinederivativesmightplayacrucialroleindeterminingtheirenhancedantitumoractivitiesanddecreasedacuteto_icitiesandneuroto_ice?ects;(2)theb-carbolinederivativeshavethepotentialtobeusedasantitumordrugleads.__211;____PublishedbyElsevierLtd.1.Introductionb-Carbolinesarealargegroupofnaturallyoccurringandsyntheticindolealkaloidswithdi?erentdegreesofaromaticity,someofwhicharewidelydistributedinnat-ure,includingvariousplants,1–3marinecreatures,4in-sects,5mammaliansaswellashumantissuesandbody?uids.6–9ThesecompoundsareofgreatinterestduetotheirvariousbiologicalactivitiessuchasintercalatingintoDNA,10,11inhibitingCDK,12andTopisom-erase,13,14inhibitingmonoamineo_idase15,16aswellasinteractingwithbenzodiazepinereceptors17–19and5-hydro_yserotoninreceptors,20andtheirbroadspectrumpharmacologicalpropertiesincludingan_iolytic,hyp-notic,anticonvulsant,21–23parasiticidal,24antiviral25aswellasantimicrobialactivities.30Recentwork26–28andourpreliminaryinvestigationresultsdemonstratedthatthecompoundswithb-carbolinenucleushavepotentialantitumoractivities.Yetwealsofoundthatthisclassofcompoundscausedremarkableacuteneuroto_icitycharacterizedbytremble,twitch,andjumpingine_per-imentalmicemodels.Manypreviousreportsfocusedonthee?ectsofthesecompoundsonthecentralnervoussystem(CNS),suchastheira?nitywithbenzodiazepinereceptors,17–195-HT2Aand5-HT2Creceptors20andimidazolinerecep-tor32,andsoon.Howeversofartherehavebeenfewsuchliteraturesabouttheircytoto_icactivitiesofthesecompoundsinvitro,evennoreportsareavailabledeal-ingwithsystematicanddetailedstudiesofstructure–activityrelationshipsonbothantitumoractivitiesandneuroto_icactivitiesinvivo.Aprobablereasonforthisisthatmanyoftheb-carbolinederivativesofinterestarenotreadilyavailable.Onegoalofthepresentinvestiga-tionswastosynthesizeaseriesofnovelb-carbolinederivativesandelucidatetheirpreliminaryrelationshipsbetweenstructuresandantitumoractivitiesaswellas0968-0896/$-seefrontmatter__211;____PublishedbyElsevierLtd.doi:10.1016/j.bmc.____.06.038Keywords:b-Carboline;Synthesis;Acuteto_icity;Antitumor;Neuro-to_icity._Correspondingauthor.Tel.:+86-20-84113655;fa_:+86-20-84038377;e-mail:ls36@Bioorganic_amp;MedicinalChemistry12(____)4613–4623
