dc.contributor.author |
Maciag, Anna E. |
en_US |
dc.contributor.author |
CHAKRAPANI, HARINATH et al. |
en_US |
dc.date.accessioned |
2020-10-19T04:06:23Z |
|
dc.date.available |
2020-10-19T04:06:23Z |
|
dc.date.issued |
2011-10 |
en_US |
dc.identifier.citation |
Journal of Medicinal Chemistry, 54(22), 7751-7758. |
en_US |
dc.identifier.issn |
0022-2623 |
en_US |
dc.identifier.uri |
http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/5137 |
|
dc.identifier.uri |
https://doi.org/10.1021/jm2004128 |
en_US |
dc.description.abstract |
Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs. |
en_US |
dc.language.iso |
en |
en_US |
dc.publisher |
American Chemical Society |
en_US |
dc.subject |
Cell Lung-Cancer |
en_US |
dc.subject |
JS-K; In-Vitro |
en_US |
dc.subject |
Endothelial-Cells |
en_US |
dc.subject |
Induced Apoptosis |
en_US |
dc.subject |
Death Pathway |
en_US |
dc.subject |
DNA-Damage |
en_US |
dc.subject |
Kinase |
en_US |
dc.subject |
Gene |
en_US |
dc.subject |
Vivo |
en_US |
dc.subject |
2011 |
en_US |
dc.title |
Activation of the c-Jun N-terminal Kinase/Activating Transcription Factor 3 (ATF3) Pathway Characterizes Effective Arylated Diazeniumdiolate-Based Nitric Oxide-Releasing Anticancer Prodrugs |
en_US |
dc.type |
Article |
en_US |
dc.contributor.department |
Dept. of Chemistry |
en_US |
dc.identifier.sourcetitle |
Journal of Medicinal Chemistry |
en_US |
dc.publication.originofpublisher |
Foreign |
en_US |