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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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