Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition

[EN]Antimitotic agents are one of the more successful types of anticancer drugs, but they suffer from toxicity and resistance. The application of approved drugs to new indications (i.e., drug repurposing) is a promising strategy for the development of new drugs. It relies on finding pattern similari...

Full description

Bibliographic Details
Authors: Ramos, Sergio, Vicente-Blázquez, Alba, López-Rubio, Marta, Gallego-Yerga, Laura, Álvarez, Raquel, Peláez, Rafael
Format: article
Status:Published version
Publication Date:2023
Country:España
Institution:Universidad de Salamanca (USAL)
Repository:GREDOS. Repositorio Institucional de la Universidad de Salamanca
OAI Identifier:oai:gredos.usal.es:10366/163952
Online Access:http://hdl.handle.net/10366/163952
Access Level:Open access
Keyword:drug repurposing
frentizole
tubulin
antimitotic
colchicine site
antitumor
drug design
synthesis
benzothiazole
id ES_52d496b618a50a4e66c0cb41f9cfc986
oai_identifier_str oai:gredos.usal.es:10366/163952
network_acronym_str ES
network_name_str España
repository_id_str
spelling Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin InhibitionRamos, SergioVicente-Blázquez, AlbaLópez-Rubio, MartaGallego-Yerga, LauraÁlvarez, RaquelPeláez, Rafaeldrug repurposingfrentizoletubulinantimitoticcolchicine siteantitumordrug designsynthesisbenzothiazole[EN]Antimitotic agents are one of the more successful types of anticancer drugs, but they suffer from toxicity and resistance. The application of approved drugs to new indications (i.e., drug repurposing) is a promising strategy for the development of new drugs. It relies on finding pattern similarities: drug effects to other drugs or conditions, similar toxicities, or structural similarity. Here, we recursively searched a database of approved drugs for structural similarity to several antimitotic agents binding to a specific site of tubulin, with the expectation of finding structures that could fit in it. These searches repeatedly retrieved frentizole, an approved nontoxic anti-inflammatory drug, thus indicating that it might behave as an antimitotic drug devoid of the undesired toxic effects. We also show that the usual repurposing approach to searching for targets of frentizole failed in most cases to find such a relationship. We synthesized frentizole and a series of analogs to assay them as antimitotic agents and found antiproliferative activity against HeLa tumor cells, inhibition of microtubule formation within cells, and arrest at the G2/M phases of the cell cycle, phenotypes that agree with binding to tubulin as the mechanism of action. The docking studies suggest binding at the colchicine site in different modes. These results support the repurposing of frentizole for cancer treatment, especially for glioblastoma.202520252023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10366/163952reponame:GREDOS. Repositorio Institucional de la Universidad de Salamancainstname:Universidad de Salamanca (USAL)InglésPID2021-127471OB-I00SA116P20info:eu-repo/semantics/openAccessoai:gredos.usal.es:10366/1639522026-06-07T06:28:51Z
dc.title.none.fl_str_mv Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
title Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
spellingShingle Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
Ramos, Sergio
drug repurposing
frentizole
tubulin
antimitotic
colchicine site
antitumor
drug design
synthesis
benzothiazole
title_short Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
title_full Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
title_fullStr Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
title_full_unstemmed Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
title_sort Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
dc.creator.none.fl_str_mv Ramos, Sergio
Vicente-Blázquez, Alba
López-Rubio, Marta
Gallego-Yerga, Laura
Álvarez, Raquel
Peláez, Rafael
author Ramos, Sergio
author_facet Ramos, Sergio
Vicente-Blázquez, Alba
López-Rubio, Marta
Gallego-Yerga, Laura
Álvarez, Raquel
Peláez, Rafael
author_role author
author2 Vicente-Blázquez, Alba
López-Rubio, Marta
Gallego-Yerga, Laura
Álvarez, Raquel
Peláez, Rafael
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv drug repurposing
frentizole
tubulin
antimitotic
colchicine site
antitumor
drug design
synthesis
benzothiazole
topic drug repurposing
frentizole
tubulin
antimitotic
colchicine site
antitumor
drug design
synthesis
benzothiazole
description [EN]Antimitotic agents are one of the more successful types of anticancer drugs, but they suffer from toxicity and resistance. The application of approved drugs to new indications (i.e., drug repurposing) is a promising strategy for the development of new drugs. It relies on finding pattern similarities: drug effects to other drugs or conditions, similar toxicities, or structural similarity. Here, we recursively searched a database of approved drugs for structural similarity to several antimitotic agents binding to a specific site of tubulin, with the expectation of finding structures that could fit in it. These searches repeatedly retrieved frentizole, an approved nontoxic anti-inflammatory drug, thus indicating that it might behave as an antimitotic drug devoid of the undesired toxic effects. We also show that the usual repurposing approach to searching for targets of frentizole failed in most cases to find such a relationship. We synthesized frentizole and a series of analogs to assay them as antimitotic agents and found antiproliferative activity against HeLa tumor cells, inhibition of microtubule formation within cells, and arrest at the G2/M phases of the cell cycle, phenotypes that agree with binding to tubulin as the mechanism of action. The docking studies suggest binding at the colchicine site in different modes. These results support the repurposing of frentizole for cancer treatment, especially for glioblastoma.
publishDate 2023
dc.date.none.fl_str_mv 2023
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10366/163952
url http://hdl.handle.net/10366/163952
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv PID2021-127471OB-I00
SA116P20
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:GREDOS. Repositorio Institucional de la Universidad de Salamanca
instname:Universidad de Salamanca (USAL)
instname_str Universidad de Salamanca (USAL)
reponame_str GREDOS. Repositorio Institucional de la Universidad de Salamanca
collection GREDOS. Repositorio Institucional de la Universidad de Salamanca
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869408075715182592
score 15,811543

Similar Items