213768-16-2Relevant academic research and scientific papers
Esterase-sensitive nitric oxide donors of the diazeniumdiolate family: In vitro antileukemic activity
Saavedra, Joseph E.,Shami, Paul J.,Wang, Lai Yi,Davies, Keith M.,Booth, Melissa N.,Citro, Michael L.,Keefer, Larry K.
, p. 261 - 269 (2000)
We have designed a novel prodrug class that is stable in neutral aqueous media but releases bioactive nitric oxide (NO) on metabolism by esterase. Diazeniumdiolates of structure R2NN(O)=N-OR', in which R' = Na, were reacted with BrCH2OAc to convert the spontaneously NO-releasing salts 1a (R2N = diethylamino) and 1b (R2N = pyrrolidino) to prodrugs 2a (AcOM-DEA/NO) and 2b (AcOM-PYRRO/NO), respectively, where R' = CH2OAc. In contrast to anions 1a and 1b (half-lives in pH 7.4 phosphate at 37 °C of 2 min and 3 s, respectively), 2a and 2b showed only minimal decomposition after 16 h under these conditions. Very rapid hydrolysis occurred in the presence of porcine liver esterase, however, with free anion 1a being observed as an intermediate in the esterase-induced generation of NO from 2a. The potential utility of this prodrug class is illustrated with a comparison of 1 and 2 as antiproliferative agents in NO-sensitive human leukemia cell lines HL-60 and U937. While the 72-h IC50'S for 1a and 1b (which generate NO throughout the medium) in HL-60 cell cultures were >600 μM, those of 2a and 2b were 8.3 and 6.4 μM, respectively. This result is consistent with our hypothesis that 2 is selectively hydrolyzed to 1 and thence to NO intracellularly. For U937 cells, the 72-h IC50 for both 2a and 2b was 53 μM. By contrast, relatively high antiproliferative IC50's (≥ 100 μM in U937 cells) were observed for analogues in which R' = CH2CH2SC(O)Me, from which acetyl and 2- mercaptoethyl groups must be successively cleaved to free the NO-releasing diazeniumdiolate function. Within 24 h at initial concentrations of 50 μM, 2a and 2b induced apoptosis in 50% and 57% of the HL-60 cells, respectively (35% and 40% of the U937 cells, respectively). The data reveal significant in vitro antileukemic activity on the part of these novel compounds. Moreover, their substantial ease-of-handling advantages over the anionic diazeniumdiolates from which they are derived suggest their use as convenient agents for probing the biological roles of NO.
NITRIC OXIDE DONORS
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Page/Page column 30, (2018/04/11)
The present invention provides, in part a novel class of nonoate compounds which exhibit nitric oxide releasing activity and their pharmaceutically acceptable salts, esters and prodrugs. The compounds release nitric oxide upon activation by contact with plasma. The present invention also relates to the use of the disclosed compounds to deliver nitric oxide to treat disorders arising from nitric oxide dysregulation.
