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SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances Antiproliferative Activity through Binding to Microtubules
[Image: see text] A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para analogues. These compounds were initially proposed as inhibit...
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/PMC9098178/ https://www.ncbi.nlm.nih.gov/pubmed/35290041 http://dx.doi.org/10.1021/acs.jmedchem.1c01936 |
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author | Elhemely, Mai A. Belgath, Asma A. El-Sayed, Sherihan Burusco, Kepa K. Kadirvel, Manikandan Tirella, Annalisa Finegan, Katherine Bryce, Richard A. Stratford, Ian J. Freeman, Sally |
author_facet | Elhemely, Mai A. Belgath, Asma A. El-Sayed, Sherihan Burusco, Kepa K. Kadirvel, Manikandan Tirella, Annalisa Finegan, Katherine Bryce, Richard A. Stratford, Ian J. Freeman, Sally |
author_sort | Elhemely, Mai A. |
collection | PubMed |
description | [Image: see text] A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para analogues. These compounds were initially proposed as inhibitors of N-ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(meta-fluorophenyl)isoquinolin-1(2H)-one (4) could mimic colchicine and interact with microtubules, a recognized target for cancer therapy. Subsequent docking, molecular dynamics simulations, and free energy analysis further suggested that compound 4 bound well into the colchicine-binding pocket of tubulin. Indeed, 4 suppressed tubulin polymerization, caused G(2)/M cell cycle arrest, and induced apoptosis. Also, 4 inhibited the formation of endothelial cell capillary-like tubes and further disrupted the structure of preestablished tubes; the effects were not observed with para analogue 5. In accordance with this, the computed free energy of binding of 5 to tubulin was lower in magnitude than that for 4 and appeared to arise in part from the inability of the para substituent to occupy a tubulin subpocket, which is possible in the meta orientation. In conclusion, the antiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure (meta versus para). The meta-substituted isoquinolinone 4 is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features. |
format | Online Article Text |
id | pubmed-9098178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-90981782022-05-13 SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances Antiproliferative Activity through Binding to Microtubules Elhemely, Mai A. Belgath, Asma A. El-Sayed, Sherihan Burusco, Kepa K. Kadirvel, Manikandan Tirella, Annalisa Finegan, Katherine Bryce, Richard A. Stratford, Ian J. Freeman, Sally J Med Chem [Image: see text] A set of meta-substituted 3-arylisoquinolinones have been identified that show substantial cytotoxicity in breast, liver, lung and colon cancer cell lines; these are up to 700-fold more active than the corresponding para analogues. These compounds were initially proposed as inhibitors of N-ribosyl dihydronicotinamide (NRH): quinone oxidoreductase 2 (NQO2) but were found to be inactive against the enzyme. Instead, COMPARE analysis suggested that 6-fluoro-3-(meta-fluorophenyl)isoquinolin-1(2H)-one (4) could mimic colchicine and interact with microtubules, a recognized target for cancer therapy. Subsequent docking, molecular dynamics simulations, and free energy analysis further suggested that compound 4 bound well into the colchicine-binding pocket of tubulin. Indeed, 4 suppressed tubulin polymerization, caused G(2)/M cell cycle arrest, and induced apoptosis. Also, 4 inhibited the formation of endothelial cell capillary-like tubes and further disrupted the structure of preestablished tubes; the effects were not observed with para analogue 5. In accordance with this, the computed free energy of binding of 5 to tubulin was lower in magnitude than that for 4 and appeared to arise in part from the inability of the para substituent to occupy a tubulin subpocket, which is possible in the meta orientation. In conclusion, the antiproliferative potential of the novel 3-arylisoquinolinones is markedly influenced by a subtle change in the structure (meta versus para). The meta-substituted isoquinolinone 4 is a microtubule-destabilizing agent with potential tumor-selectivity and antiangiogenic and vascular disrupting features. American Chemical Society 2022-03-15 2022-03-24 /pmc/articles/PMC9098178/ /pubmed/35290041 http://dx.doi.org/10.1021/acs.jmedchem.1c01936 Text en © 2022 American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Elhemely, Mai A. Belgath, Asma A. El-Sayed, Sherihan Burusco, Kepa K. Kadirvel, Manikandan Tirella, Annalisa Finegan, Katherine Bryce, Richard A. Stratford, Ian J. Freeman, Sally SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances Antiproliferative Activity through Binding to Microtubules |
title | SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances
Antiproliferative Activity through Binding to Microtubules |
title_full | SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances
Antiproliferative Activity through Binding to Microtubules |
title_fullStr | SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances
Antiproliferative Activity through Binding to Microtubules |
title_full_unstemmed | SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances
Antiproliferative Activity through Binding to Microtubules |
title_short | SAR of Novel 3-Arylisoquinolinones: meta-Substitution on the Aryl Ring Dramatically Enhances
Antiproliferative Activity through Binding to Microtubules |
title_sort | sar of novel 3-arylisoquinolinones: meta-substitution on the aryl ring dramatically enhances
antiproliferative activity through binding to microtubules |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9098178/ https://www.ncbi.nlm.nih.gov/pubmed/35290041 http://dx.doi.org/10.1021/acs.jmedchem.1c01936 |
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