简介：Cytarabine(1-β-D-arabinofuranosylcytosine,Ara-C),isolatedfromaCaribbeanspongespeciesTethyacrypta,isthefirstantitumordrugfromamarineresource.In1980,theUSFoodandDrugAdministrationapprovedthisdrugforthetreatmentofdifferenttypesofleukemia.Thisdrughasashortplasmahalf-life,lowstability,limitedbioavailability,andseveresideeffects.Toimprovestabilityandbioavailability,wesynthesizedninenovelderivativesbyblockingthecytarabinemetabolicsitesandimprovinglipophilicity.ThecLogPvaluesofthenewlysynthesizedcompoundswerecalculated.Allthesynthesizedcompoundsweremorelipophilicthancytarabine,resultinginmembranepermeabilityandbioavailabilityimprovement.TheantitumoractivitiesagainstleukemiacelllineHL-60wereevaluatedbyusingtheMTTassay.ThebioassayresultsrevealedthattheIC50valuesofcompounds5,8and9were0.080,0.090and0.057μmolL-1,respectively,whichwassimilarwiththatofcytarabine(0.056μmolL-1).Incomparison,compound4withaphosphategroupatO5’wasinactive.Becausephosphoesterbondsareeasilyhydrolyzedbyalkalinephosphataseandarecommonlyusedinproducingprodrugstrategies,compound4mightalsobemetabolizedinvivoandgeneratecompound3orevencytarabinethroughamulti-stepreaction.Thus,compound4mightbeapromisingcompoundtobedevelopedasaprodrug.