Studies on the mechanism of action of anti-tumor bis(aminophenolate) ruthenium(III) complexes

摘要

Two udrecently published udRu(III) compudlexes bearing ud(udNud2udOud2ud) udtetradentate bis(aminophenolate) ligands, ud20udformulated asud[Ru(III)(udsudalanud)(PPhud3ud)Cl] ud(udwhere udsudalanudis the udtetradentate ligand ud6,6'ud-ud(1S,2S)ud-ud21udcyclohexaneud-ud1,2ud-uddiylbis(azanediyl)bis(metudhylene)bis(3ud-udmethoxyphenol) in cudomplex ud1ud, udorud2,2'ud-ud(1S,2S)ud-ud22udcyclohexaneud-ud1,2ud-uddiylbis(azanediyl)bis(methudylene)bis(4ud-udmethoxyphenol)udin cudomplex ud2ud,udandudPPhud3udis ud23udtriphenylphosphaneud)udwere studied udherein to outline theirudantitumor udmode of action.udPreviously, it was ud24udfound that they were very active against human udovarudianudand breudaudst adenocarcinomaudcells ud(on a ud72 h ud25udchallengeud)ud. udIn this work, udthe human udcisplatinud-udsensitive oudvarian udadenoudcarcinomaudline udA2780udwas used ud26udas the cell model for further studiesudaudtuda 24 h challengeud. Budoth complexes are activeud,udtheir cytotoxicityud27udbeingudcudomparable to that udof cudisplatinudin the same conditions.ud28udAuds a possible target in the cell for their action, the intuderaction udof ud1udand ud2udwith DNA was assessed ud29udthrough displacement ofudwellud-udestablished DNAudfluorescent probes ud(udethidium bromideud,udEB, udandud4',6ud-ud30uddudiamidinoud-ud2ud-udpudhenylindole, udDAPIud) udthrough udsudteadyud-udstate and timeud-udresolved fluorescenceudspectroscopyud.ud31udThe complete udemission spectra were analysed globally for the binary DNAud‒udpudrobe and ternary DNAud‒ud32udpudrobeud‒udRu(III)udcomplexudsystemsud. udBudoth Ru(III) complexes can uddisplace udEBudand udbind to DNA with ud33udsimilar and udmoderate strong affinityudwith conditional stability constants udof udlogudK’ud=ud(ud5.05 ± 0.01ud)udfor ud1ud34udandudlog K’= ud(ud4.79ud± 0.01ud)udfor ud2ud.udThe analysis of timeud-uddomain fluorescence intensity decays confirmed ud35udboth qualitatively and quantitatively the model used to describe the binding and competition processes. ud36udCell studies indicated that apoptosis is udtudhe major mechanism of cell death udfor both complexesud, udwith ud2ud37ud(the moudreudactive udcomplexud) udpromotingudthat process more efficiently than ud1ud.udTransmission udelectron ud38udmicroudgraphsudrevealedudclear audlterationuds on udintracellular udorganizationudconsistent with the induction of ud39udprogrammed cell death processes.