Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783334853964464128 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6017909 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bizarroana synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT sousadiana synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT limaraquelt synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT mussoloana synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT cincinelliraffaella synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT zucovantina synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT decesaremichelandrea synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT dallavallesabrina synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors AT vasconcelosmhelena synthesisandevaluationofthetumorcellgrowthinhibitorypotentialofnewputativehsp90inhibitors |