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A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts
We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414177/ https://www.ncbi.nlm.nih.gov/pubmed/25595904 |
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author | De Luca, Anastasia Rotili, Dante Carpanese, Debora Lenoci, Alessia Calderan, Laura Scimeca, Manuel Mai, Antonello Bonanno, Elena Rosato, Antonio Geroni, Cristina Quintieri, Luigi Caccuri, Anna Maria |
author_facet | De Luca, Anastasia Rotili, Dante Carpanese, Debora Lenoci, Alessia Calderan, Laura Scimeca, Manuel Mai, Antonello Bonanno, Elena Rosato, Antonio Geroni, Cristina Quintieri, Luigi Caccuri, Anna Maria |
author_sort | De Luca, Anastasia |
collection | PubMed |
description | We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC(50) in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells. MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations. Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo. |
format | Online Article Text |
id | pubmed-4414177 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-44141772015-05-08 A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts De Luca, Anastasia Rotili, Dante Carpanese, Debora Lenoci, Alessia Calderan, Laura Scimeca, Manuel Mai, Antonello Bonanno, Elena Rosato, Antonio Geroni, Cristina Quintieri, Luigi Caccuri, Anna Maria Oncotarget Research Paper We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC(50) in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells. MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations. Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo. Impact Journals LLC 2015-02-14 /pmc/articles/PMC4414177/ /pubmed/25595904 Text en Copyright: © 2015 De Luca et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper De Luca, Anastasia Rotili, Dante Carpanese, Debora Lenoci, Alessia Calderan, Laura Scimeca, Manuel Mai, Antonello Bonanno, Elena Rosato, Antonio Geroni, Cristina Quintieri, Luigi Caccuri, Anna Maria A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts |
title | A novel orally active water-soluble inhibitor of human glutathione
transferase exerts a potent and selective antitumor activity against human
melanoma xenografts |
title_full | A novel orally active water-soluble inhibitor of human glutathione
transferase exerts a potent and selective antitumor activity against human
melanoma xenografts |
title_fullStr | A novel orally active water-soluble inhibitor of human glutathione
transferase exerts a potent and selective antitumor activity against human
melanoma xenografts |
title_full_unstemmed | A novel orally active water-soluble inhibitor of human glutathione
transferase exerts a potent and selective antitumor activity against human
melanoma xenografts |
title_short | A novel orally active water-soluble inhibitor of human glutathione
transferase exerts a potent and selective antitumor activity against human
melanoma xenografts |
title_sort | novel orally active water-soluble inhibitor of human glutathione
transferase exerts a potent and selective antitumor activity against human
melanoma xenografts |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414177/ https://www.ncbi.nlm.nih.gov/pubmed/25595904 |
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