Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17474 |
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| author | Sergio Ramos Alba Vicente-Blázquez Marta López-Rubio Laura Gallego-Yerga Raquel Álvarez Rafael Peláez |
| author_facet | Sergio Ramos Alba Vicente-Blázquez Marta López-Rubio Laura Gallego-Yerga Raquel Álvarez Rafael Peláez |
| author_sort | Sergio Ramos |
| collection | DOAJ |
| description | 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 G<sub>2</sub>/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. |
| first_indexed | 2024-03-08T20:40:30Z |
| format | Article |
| id | doaj.art-11cd78c01a504b259a39ab2261a417f3 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:40:30Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-11cd78c01a504b259a39ab2261a417f32023-12-22T14:14:40ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241747410.3390/ijms242417474Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin InhibitionSergio Ramos0Alba Vicente-Blázquez1Marta López-Rubio2Laura Gallego-Yerga3Raquel Álvarez4Rafael Peláez5Laboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Campus Miguel de Unamuno, Universidad de Salamanca, 37008 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Campus Miguel de Unamuno, Universidad de Salamanca, 37008 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Campus Miguel de Unamuno, Universidad de Salamanca, 37008 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Campus Miguel de Unamuno, Universidad de Salamanca, 37008 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Campus Miguel de Unamuno, Universidad de Salamanca, 37008 Salamanca, SpainLaboratorio de Química Orgánica y Farmacéutica, Departamento de Ciencias Farmacéuticas, Campus Miguel de Unamuno, Universidad de Salamanca, 37008 Salamanca, SpainAntimitotic 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 G<sub>2</sub>/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.https://www.mdpi.com/1422-0067/24/24/17474drug repurposingfrentizoletubulinantimitoticcolchicine siteantitumor |
| spellingShingle | Sergio Ramos Alba Vicente-Blázquez Marta López-Rubio Laura Gallego-Yerga Raquel Álvarez Rafael Peláez Frentizole, a Nontoxic Immunosuppressive Drug, and Its Analogs Display Antitumor Activity via Tubulin Inhibition International Journal of Molecular Sciences drug repurposing frentizole tubulin antimitotic colchicine site antitumor |
| title | 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_short | 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 |
| topic | drug repurposing frentizole tubulin antimitotic colchicine site antitumor |
| url | https://www.mdpi.com/1422-0067/24/24/17474 |
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