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Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships
Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resista...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199632/ https://www.ncbi.nlm.nih.gov/pubmed/25329549 http://dx.doi.org/10.1371/journal.pone.0110291 |
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author | Serda, Maciej Kalinowski, Danuta S. Rasko, Nathalie Potůčková, Eliška Mrozek-Wilczkiewicz, Anna Musiol, Robert Małecki, Jan G. Sajewicz, Mieczysław Ratuszna, Alicja Muchowicz, Angelika Gołąb, Jakub Šimůnek, Tomáš Richardson, Des R. Polanski, Jaroslaw |
author_facet | Serda, Maciej Kalinowski, Danuta S. Rasko, Nathalie Potůčková, Eliška Mrozek-Wilczkiewicz, Anna Musiol, Robert Małecki, Jan G. Sajewicz, Mieczysław Ratuszna, Alicja Muchowicz, Angelika Gołąb, Jakub Šimůnek, Tomáš Richardson, Des R. Polanski, Jaroslaw |
author_sort | Serda, Maciej |
collection | PubMed |
description | Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. |
format | Online Article Text |
id | pubmed-4199632 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41996322014-10-21 Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships Serda, Maciej Kalinowski, Danuta S. Rasko, Nathalie Potůčková, Eliška Mrozek-Wilczkiewicz, Anna Musiol, Robert Małecki, Jan G. Sajewicz, Mieczysław Ratuszna, Alicja Muchowicz, Angelika Gołąb, Jakub Šimůnek, Tomáš Richardson, Des R. Polanski, Jaroslaw PLoS One Research Article Thiosemicarbazones (TSCs) are an interesting class of ligands that show a diverse range of biological activity, including anti-fungal, anti-viral and anti-cancer effects. Our previous studies have demonstrated the potent in vivo anti-tumor activity of novel TSCs and their ability to overcome resistance to clinically used chemotherapeutics. In the current study, 35 novel TSCs of 6 different classes were designed using a combination of retro-fragments that appear in other TSCs. Additionally, di-substitution at the terminal N4 atom, which was previously identified to be critical for potent anti-cancer activity, was preserved through the incorporation of an N4-based piperazine or morpholine ring. The anti-proliferative activity of the novel TSCs were examined in a variety of cancer and normal cell-types. In particular, compounds 1d and 3c demonstrated the greatest promise as anti-cancer agents with potent and selective anti-proliferative activity. Structure-activity relationship studies revealed that the chelators that utilized “soft” donor atoms, such as nitrogen and sulfur, resulted in potent anti-cancer activity. Indeed, the N,N,S donor atom set was crucial for the formation of redox active iron complexes that were able to mediate the oxidation of ascorbate. This further highlights the important role of reactive oxygen species generation in mediating potent anti-cancer activity. Significantly, this study identified the potent and selective anti-cancer activity of 1d and 3c that warrants further examination. Public Library of Science 2014-10-16 /pmc/articles/PMC4199632/ /pubmed/25329549 http://dx.doi.org/10.1371/journal.pone.0110291 Text en © 2014 Serda et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Serda, Maciej Kalinowski, Danuta S. Rasko, Nathalie Potůčková, Eliška Mrozek-Wilczkiewicz, Anna Musiol, Robert Małecki, Jan G. Sajewicz, Mieczysław Ratuszna, Alicja Muchowicz, Angelika Gołąb, Jakub Šimůnek, Tomáš Richardson, Des R. Polanski, Jaroslaw Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships |
title | Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships |
title_full | Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships |
title_fullStr | Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships |
title_full_unstemmed | Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships |
title_short | Exploring the Anti-Cancer Activity of Novel Thiosemicarbazones Generated through the Combination of Retro-Fragments: Dissection of Critical Structure-Activity Relationships |
title_sort | exploring the anti-cancer activity of novel thiosemicarbazones generated through the combination of retro-fragments: dissection of critical structure-activity relationships |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199632/ https://www.ncbi.nlm.nih.gov/pubmed/25329549 http://dx.doi.org/10.1371/journal.pone.0110291 |
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