Abstract

Abstract A series of O2-(2,4-dinitrophenyl)diazeniumdiolates derivatives were designed, synthesized and antiproliferative activities evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferases π (GSTπ). Most of these derivatives exhibited significant antiproliferative activities compared to the reported NO-donor prodrug JS-K, among which compounds 27 and 36 had superior potency with IC50 below 1 μM. NO released amounts detection of all derivatives indicated that the antiproliferative activities were positively correlated with the levels of intracellular NO release in HCT116 cells. The most potent compound 36 exhibited improved uncatalyzed stability of GSTπ. Additionally, 36 showed remarkably multidrug resistance reversal activity which reversed multidrug resistance of adriamycin (ADR) in MCF-7/ADR cells with IC50 from 84.94 μM to 1.13 μM. Highlights A series of diazeniumdiolates derivatives were designed and synthesized. Most of the derivatives exhibited significant cytotoxicities compared to JS-K. The cytotoxicities positively correlated with the amounts of NO release in HCT116. The most potent compound 36 exhibited improved uncatalyzed stability of GSTπ. Compound 36 also showed remarkably multidrug resistance reversal activity. Graphical abstract A series of O2-(2,4-dinitrophenyl) diazeniumdiolates derivatives were designed, synthesized and antiproliferative activities evaluated as novel nitric oxide (NO)-releasing prodrugs that could be activated by glutathione S-transferases π (GSTπ). Compound 36 showed remarkably multidrug resistance reversal activity which reversed multidrug resistance of adriamycin (ADR) in MCF-7/ADR cells. [DISPLAY OMISSION]

주제어

#Diazeniumdiolates   #No-Releasing   #JS-K   #Adriamycin   #Multidrug resistance  

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