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Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors

Background: Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones as inhibitors of HSP90. Methods: In the present work, various compounds with new chromenopyridinone and thiochromeno...

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Autores principales: Bizarro, Ana, Sousa, Diana, Lima, Raquel T., Musso, Loana, Cincinelli, Raffaella, Zuco, Vantina, De Cesare, Michelandrea, Dallavalle, Sabrina, Vasconcelos, M. Helena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017909/
https://www.ncbi.nlm.nih.gov/pubmed/29438315
http://dx.doi.org/10.3390/molecules23020407
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author Bizarro, Ana
Sousa, Diana
Lima, Raquel T.
Musso, Loana
Cincinelli, Raffaella
Zuco, Vantina
De Cesare, Michelandrea
Dallavalle, Sabrina
Vasconcelos, M. Helena
author_facet Bizarro, Ana
Sousa, Diana
Lima, Raquel T.
Musso, Loana
Cincinelli, Raffaella
Zuco, Vantina
De Cesare, Michelandrea
Dallavalle, Sabrina
Vasconcelos, M. Helena
author_sort Bizarro, Ana
collection PubMed
description Background: Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones as inhibitors of HSP90. Methods: In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds (5 and 8) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. Results: Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as “clients” of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. Conclusions: Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition.
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spelling pubmed-60179092018-11-13 Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors Bizarro, Ana Sousa, Diana Lima, Raquel T. Musso, Loana Cincinelli, Raffaella Zuco, Vantina De Cesare, Michelandrea Dallavalle, Sabrina Vasconcelos, M. Helena Molecules Article Background: Heat shock protein 90 (HSP90) is a well-known target for cancer therapy. In a previous work, some of us have reported a series of 3-aryl-naphtho[2,3-d]isoxazole-4,9-diones as inhibitors of HSP90. Methods: In the present work, various compounds with new chromenopyridinone and thiochromenopyridinone scaffolds were synthesized as potential HSP90 inhibitors. Their binding affinity to HSP90 was studied in vitro. Selected compounds (5 and 8) were further studied in various tumor cell lines regarding their potential to cause cell growth inhibition, alter the cell cycle profile, inhibit proliferation, and induce apoptosis. Their effect on HSP90 client protein levels was also confirmed in two cell lines. Finally, the antitumor activity of compound 8 was studied in A431 squamous cell carcinoma xenografts in nude mice. Results: Our results indicated that treatment with compounds 5 and 8 decreased the proliferation of tumor cell lines and compound 8 induced apoptosis. In addition, these two compounds were able to downregulate selected proteins known as “clients” of HSP90. Finally, treatment of xenografted mice with compound 5 resulted in a considerable dose-dependent inhibition of tumor growth. Conclusions: Our results show that two new compounds with a chromenopyridinone and thiochromenopyridinone scaffold are promising putative HSP90 inhibitors causing tumor cell growth inhibition. MDPI 2018-02-13 /pmc/articles/PMC6017909/ /pubmed/29438315 http://dx.doi.org/10.3390/molecules23020407 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bizarro, Ana
Sousa, Diana
Lima, Raquel T.
Musso, Loana
Cincinelli, Raffaella
Zuco, Vantina
De Cesare, Michelandrea
Dallavalle, Sabrina
Vasconcelos, M. Helena
Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors
title Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors
title_full Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors
title_fullStr Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors
title_full_unstemmed Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors
title_short Synthesis and Evaluation of the Tumor Cell Growth Inhibitory Potential of New Putative HSP90 Inhibitors
title_sort synthesis and evaluation of the tumor cell growth inhibitory potential of new putative hsp90 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017909/
https://www.ncbi.nlm.nih.gov/pubmed/29438315
http://dx.doi.org/10.3390/molecules23020407
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