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dc.contributor.authorI. Montero, Evaen_US
dc.contributor.authorZhang, Junyongen_US
dc.contributor.authorJ. Moniodis, Josephen_US
dc.contributor.authorBerners-Price, Sueen_US
dc.contributor.authorFarrell, Nicholasen_US
dc.date.accessioned2017-05-03T11:51:55Z
dc.date.available2017-05-03T11:51:55Z
dc.date.issued2010en_US
dc.date.modified2011-03-04T03:17:02Z
dc.identifier.issn14341948en_US
dc.identifier.doi10.1002/chem.200903578en_AU
dc.identifier.urihttp://hdl.handle.net/10072/36774
dc.description.abstractTo examine the effect of leaving group and trans influence on the geenral reactivity of polynuclear platinum antitumor agents we investigated substitution of the chloride leaving groups with nitrite ion, which forms strong bonds to Pt. It was of interest to explore whether nitrite could be used to modulate biological properties of these agents, in particular the deactivating reactions that occur on reaction with S-nucleophiles, involving loss of linking diamine under the trans influence of sulfur. Reported herein is a study of the synthesis, aquation, DNA binding and reactions with glutathione (GSH), methionine (met) and acetylmethione (AcMet) of nitro derivatives of di- and trinuclear platinum antitumor compounds: To examine the effect of leaving group and trans influence on the general reactivity of polynuclear platinum antitumor agents we investigated substitution of the chloride leaving groups with nitrite ion, which forms strong bonds to Pt. It was of interest to explore whether nitrite could be used to modulate biological properties of these agents, in particular the deactivating reactions that occur on reaction with S-nucleophiles, nvolving loss of the linking diamine under the trans influence of sulfur. Reported herein is a study of the synthesis, aquation, DNA binding and reactions with glutathione (GSH), methionine (Met) and acetylmethione (AcMet) of nitrito derivatives of di- and trinuclear platinum antitumor compounds: [{trans-PtNO2-ACHTUNGTRENUNG(NH3)2}2ACHTUNGTRENUNG(m-NH2ACHTUNGTRENUNG(CH2)6NH2)]ACHTUNGTRENUNG(NO3)2 (1- NO2) and [{trans-PtNO2ACHTUNGTRENUNG(NH3)2}2(mtrans- PtACHTUNGTRENUNG(NH3)2ACHTUNGTRENUNG{NH2ACHTUNGTRENUNG(CH2)6NH2}2)]- ACHTUNGTRENUNG(NO3)4 (1'-NO2). {1H,15N}-HSQC NMR studies revealed that 1-NO2 is inert to aquation reactions, even after prolonged incubation at physiological pH. Monitoring of the interaction of 1-NO2 with the duplex 5'-d(ATATGTACATAT) 2 (I) showed only unreacted complex, consistent with activation by aquation being a requirement for covalent DNA binding. The reaction of 1-NO2 with GSH was studied by 1H, 195Pt, 15N and {1H,15N}-HSQC NMR spectroscopy. For the parent dichlorido compounds (1 and 1') substitution of chloride by GS leads to drug degradation involving liberation of the diamine linker. While the same final products trans-[Pt(SG)2ACHTUNGTRENUNG(NH3)2] (5) and trans-[{Pt(SG)ACHTUNGTRENUNG(NH3)2}2-m-SG] (6) are formed, different mechanisms are involved, consistent with the trans influence NO2 > Cl ; the half-life is slightly longer for 1-NO2 (1.8 h) compared with 1 (1.3 h). Identification of the intermediate trans-[PtACHTUNGTRENUNG(NH3)2ACHTUNGTRENUNG(NO2)(SG)] (4) shows that the nitrito group remains coordinated while the linker amine is substituted by coordination of GS , and then trans labilization of the nitrito group occurs leading to 5 and 6. Reaction of the trinuclear 1'-NO2 with GSH follows essentially the same reaction pathway. Reaction of 1-NO2 with Met and AcMet is much slower and only 20% liberated amine was observed after reaction with Met for 24 h at 37 8C. The final product from reaction with AcMet is trans-[PtACHTUNGTRENUNG(NH3)2ACHTUNGTRENUNG(NO2)- ACHTUNGTRENUNG(AcMet)], as in this case coordination of the S-nucleophile does not lead to trans labilization of the nitrito group.en_US
dc.description.peerreviewedYesen_US
dc.description.publicationstatusYesen_AU
dc.languageEnglishen_US
dc.language.isoen_AU
dc.publisherWileyen_US
dc.publisher.placeGermanyen_US
dc.relation.ispartofstudentpublicationNen_AU
dc.relation.ispartofpagefrom9175en_US
dc.relation.ispartofpageto9185en_US
dc.relation.ispartofissue30en_US
dc.relation.ispartofjournalChemistry - A European Journalen_US
dc.relation.ispartofvolume16en_US
dc.rights.retentionYen_AU
dc.subject.fieldofresearchBioinorganic Chemistryen_US
dc.subject.fieldofresearchcode030201en_US
dc.titleThe trans Influence in the Modulation of Platinum Anticancer Agent Biology: The Effect of Nitrite Leaving Group on Aquation, Reactions with S-Nucleophiles and DNA Binding of Dinuclear and Trinuclear Compoundsen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.date.issued2010
gro.hasfulltextNo Full Text


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