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Balancing Affinity, Selectivity, and Cytotoxicity of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon β Genes in Cancer Cells
[Image: see text] G-quadruplex (G4) ligands are investigated to discover new anticancer drugs with increased cell-killing potency. These ligands can induce genome instability and activate innate immune genes at non-cytotoxic doses, opening the discovery of cytostatic immune-stimulating ligands. Howe...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9511478/ https://www.ncbi.nlm.nih.gov/pubmed/36074772 http://dx.doi.org/10.1021/acs.jmedchem.2c00772 |
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author | Marzano, Simona Miglietta, Giulia Morigi, Rita Marinello, Jessica Arleo, Andrea Procacci, Monica Locatelli, Alessandra Leoni, Alberto Pagano, Bruno Randazzo, Antonio Amato, Jussara Capranico, Giovanni |
author_facet | Marzano, Simona Miglietta, Giulia Morigi, Rita Marinello, Jessica Arleo, Andrea Procacci, Monica Locatelli, Alessandra Leoni, Alberto Pagano, Bruno Randazzo, Antonio Amato, Jussara Capranico, Giovanni |
author_sort | Marzano, Simona |
collection | PubMed |
description | [Image: see text] G-quadruplex (G4) ligands are investigated to discover new anticancer drugs with increased cell-killing potency. These ligands can induce genome instability and activate innate immune genes at non-cytotoxic doses, opening the discovery of cytostatic immune-stimulating ligands. However, the interplay of G4 affinity/selectivity with cytotoxicity and immune gene activation is not well-understood. We investigated a series of closely related hydrazone derivatives to define the molecular bases of immune-stimulation activity. Although they are closely related to each other, such derivatives differ in G4 affinity, cytotoxicity, genome instability, and immune gene activation. Our findings show that G4 affinity of ligands is a critical feature for immune gene activation, whereas a high cytotoxic potency interferes with it. The balance of G4 stabilization versus cytotoxicity can determine the level of immune gene activation in cancer cells. Thus, we propose a new rationale based on low cell-killing potency and high immune stimulation to discover effective anticancer G4 ligands. |
format | Online Article Text |
id | pubmed-9511478 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-95114782022-09-27 Balancing Affinity, Selectivity, and Cytotoxicity of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon β Genes in Cancer Cells Marzano, Simona Miglietta, Giulia Morigi, Rita Marinello, Jessica Arleo, Andrea Procacci, Monica Locatelli, Alessandra Leoni, Alberto Pagano, Bruno Randazzo, Antonio Amato, Jussara Capranico, Giovanni J Med Chem [Image: see text] G-quadruplex (G4) ligands are investigated to discover new anticancer drugs with increased cell-killing potency. These ligands can induce genome instability and activate innate immune genes at non-cytotoxic doses, opening the discovery of cytostatic immune-stimulating ligands. However, the interplay of G4 affinity/selectivity with cytotoxicity and immune gene activation is not well-understood. We investigated a series of closely related hydrazone derivatives to define the molecular bases of immune-stimulation activity. Although they are closely related to each other, such derivatives differ in G4 affinity, cytotoxicity, genome instability, and immune gene activation. Our findings show that G4 affinity of ligands is a critical feature for immune gene activation, whereas a high cytotoxic potency interferes with it. The balance of G4 stabilization versus cytotoxicity can determine the level of immune gene activation in cancer cells. Thus, we propose a new rationale based on low cell-killing potency and high immune stimulation to discover effective anticancer G4 ligands. American Chemical Society 2022-09-08 2022-09-22 /pmc/articles/PMC9511478/ /pubmed/36074772 http://dx.doi.org/10.1021/acs.jmedchem.2c00772 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Marzano, Simona Miglietta, Giulia Morigi, Rita Marinello, Jessica Arleo, Andrea Procacci, Monica Locatelli, Alessandra Leoni, Alberto Pagano, Bruno Randazzo, Antonio Amato, Jussara Capranico, Giovanni Balancing Affinity, Selectivity, and Cytotoxicity of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon β Genes in Cancer Cells |
title | Balancing Affinity,
Selectivity, and Cytotoxicity
of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon
β Genes in Cancer Cells |
title_full | Balancing Affinity,
Selectivity, and Cytotoxicity
of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon
β Genes in Cancer Cells |
title_fullStr | Balancing Affinity,
Selectivity, and Cytotoxicity
of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon
β Genes in Cancer Cells |
title_full_unstemmed | Balancing Affinity,
Selectivity, and Cytotoxicity
of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon
β Genes in Cancer Cells |
title_short | Balancing Affinity,
Selectivity, and Cytotoxicity
of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon
β Genes in Cancer Cells |
title_sort | balancing affinity,
selectivity, and cytotoxicity
of hydrazone-based g-quadruplex ligands for activation of interferon
β genes in cancer cells |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9511478/ https://www.ncbi.nlm.nih.gov/pubmed/36074772 http://dx.doi.org/10.1021/acs.jmedchem.2c00772 |
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