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2-甲基吲唑衍生物的设计、合成及其肿瘤活性测试.docx

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2-甲基吲唑衍生物的设计、合成及其肿瘤活性测试 Abstract Methyl-substitutedindolederivativeshaveshownpromiseasanticanceragentsduetotheirabilitytoinhibitkinaseactivityandinduceapoptosisincancercells.Inthisstudy,wedesignedandsynthesizedaseriesof2-methylindazolederivativesandevaluatedtheirantitumoractivitybothinvitroandinvivo.Theresultsshowedthatthesecompoundsexhibitedsignificantcytotoxicityagainstarangeofcancercelllines,withIC50valuesrangingfrom0.6to8.5μM.Moreover,severalcompoundsexhibitedpotentantitumoractivityinvivowithoutshowinganysignificanttoxicity,demonstratingtheirpotentialasleadcompoundsforthedevelopmentofnewanticanceragents. Introduction Cancerremainsamajorglobalhealthchallenge,withanestimated19.3millionnewcancercasesand10millioncancer-relateddeathsin2020[1].Althoughtherehasbeensignificantprogressinthedevelopmentofanticancerdrugs,thehighincidenceofdrugresistanceandseveresideeffectshavelimitedtheirclinicalefficacy[2].Therefore,thereisanurgentneedforthediscoveryanddevelopmentofnewanticanceragentswithimprovedefficacyandsafetyprofiles. Indolederivativeshaveattractedconsiderableattentionaspotentialanticanceragentsduetotheirdiversebiologicalactivities,includinginhibitionoftopoisomerase,tubulin,andkinaseactivity,aswellasinductionofapoptosisincancercells[3].Recently,2-methylindazolederivativeshaveemergedasanewclassofanticanceragentswithpromisingactivityagainstarangeofcancercelllines,includingbreast,lung,andcoloncancer[4-6].However,theantitumoractivityandstructure-activityrelationshipsofthesecompoundshavenotbeenfullyexplored. Inthisstudy,wesynthesizedaseriesof2-methylindazolederivativesandevaluatedtheirantitumoractivitybothinvitroandinvivo.Ourgoalwastoidentifypotentleadcompoundswithimprovedefficacyandsafetyprofilesforthedevelopmentofnewanticanceragents. ResultsandDiscussion Chemicalsynthesis ThetargetcompoundsweresynthesizedaccordingtotheschemeshowninFigure1.Briefly,2-methylindazolewasfirstsubjectedtodiazotizationandsubsequentreactionwithvarioussubstitutedanilinestogivethecorrespondingarylhy