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In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study

A series of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones were prepared from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles and were evaluated for their in vitro antiproliferative activity. After screening using the MTT reduction assay, their IC(50) values were calculated on a panel of...

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Autores principales: Valderrama, Jaime A., Ríos, David, Muccioli, Giulio G., Buc Calderon, Pedro, Benites, Julio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071032/
https://www.ncbi.nlm.nih.gov/pubmed/32093392
http://dx.doi.org/10.3390/molecules25040953
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author Valderrama, Jaime A.
Ríos, David
Muccioli, Giulio G.
Buc Calderon, Pedro
Benites, Julio
author_facet Valderrama, Jaime A.
Ríos, David
Muccioli, Giulio G.
Buc Calderon, Pedro
Benites, Julio
author_sort Valderrama, Jaime A.
collection PubMed
description A series of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones were prepared from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles and were evaluated for their in vitro antiproliferative activity. After screening using the MTT reduction assay, their IC(50) values were calculated on a panel of cancer cells (T24, DU-145, MCF-7). Current standard anticancer drugs were included as control, and their calculated IC(50) values were 7.8 and 23.5 µM for 5-fluorouracil and tamoxifen, respectively. Non-cancer cells (AG1523) were included to assess cancer cell sensitivity and drug selectivity. Four members of the series, with IC(50) values from 0.11 to 2.98 µM, were chosen for further assays. The selected quinones were evaluated regarding their effects on cancer cell proliferation (clonogenic assay) and on Hsp90 and poly(ADPribose)polymerase (PARP) protein integrity. The most active compound (i.e., 15) substantially inhibited colony forming unit (CFU) formation at 0.25 µM. In the presence of ascorbate, it induced an oxidative cleavage of Hsp90 but had no effect on PARP protein integrity. In an in vivo animal model, it discreetly increased the mean survival time (m.s.t.) of tumor-bearing mice. In light of these results, compound 15 represents a potential lead-molecule to be further developed.
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spelling pubmed-70710322020-03-19 In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study Valderrama, Jaime A. Ríos, David Muccioli, Giulio G. Buc Calderon, Pedro Benites, Julio Molecules Article A series of benzo[g]benzothiazolo[2,3-b]quinazoline-7,12-quinones were prepared from 2-acylnaphthohydroquinones and 2-aminobenzothiazoles and were evaluated for their in vitro antiproliferative activity. After screening using the MTT reduction assay, their IC(50) values were calculated on a panel of cancer cells (T24, DU-145, MCF-7). Current standard anticancer drugs were included as control, and their calculated IC(50) values were 7.8 and 23.5 µM for 5-fluorouracil and tamoxifen, respectively. Non-cancer cells (AG1523) were included to assess cancer cell sensitivity and drug selectivity. Four members of the series, with IC(50) values from 0.11 to 2.98 µM, were chosen for further assays. The selected quinones were evaluated regarding their effects on cancer cell proliferation (clonogenic assay) and on Hsp90 and poly(ADPribose)polymerase (PARP) protein integrity. The most active compound (i.e., 15) substantially inhibited colony forming unit (CFU) formation at 0.25 µM. In the presence of ascorbate, it induced an oxidative cleavage of Hsp90 but had no effect on PARP protein integrity. In an in vivo animal model, it discreetly increased the mean survival time (m.s.t.) of tumor-bearing mice. In light of these results, compound 15 represents a potential lead-molecule to be further developed. MDPI 2020-02-20 /pmc/articles/PMC7071032/ /pubmed/32093392 http://dx.doi.org/10.3390/molecules25040953 Text en © 2020 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
Valderrama, Jaime A.
Ríos, David
Muccioli, Giulio G.
Buc Calderon, Pedro
Benites, Julio
In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study
title In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study
title_full In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study
title_fullStr In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study
title_full_unstemmed In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study
title_short In Vitro Inhibition of Hsp90 Protein by Benzothiazoloquinazolinequinones Is Enhanced in The Presence of Ascorbate. A Preliminary In Vivo Antiproliferative Study
title_sort in vitro inhibition of hsp90 protein by benzothiazoloquinazolinequinones is enhanced in the presence of ascorbate. a preliminary in vivo antiproliferative study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071032/
https://www.ncbi.nlm.nih.gov/pubmed/32093392
http://dx.doi.org/10.3390/molecules25040953
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