Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3)
The superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and nocod...
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MDPI AG
2022-07-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/7/835 |
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| author | Marta Gargantilla Leentje Persoons Tereza Kauerová Natalia del Río Dirk Daelemans Eva-María Priego Peter Kollar María-Jesús Pérez-Pérez |
| author_facet | Marta Gargantilla Leentje Persoons Tereza Kauerová Natalia del Río Dirk Daelemans Eva-María Priego Peter Kollar María-Jesús Pérez-Pérez |
| author_sort | Marta Gargantilla |
| collection | DOAJ |
| description | The superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and nocodazole using a salicylanilide core structure. Interestingly, salicylanilides, such as niclosamide, are well-established signal transducers and activators of transcription (STAT3) inhibitors with anticancer properties. Thus, different compounds with this new scaffold have been synthesized with the aim to identify compounds inhibiting tubulin polymerization and/or STAT3 signaling. As a result, we have identified new salicylanilides (<b>6</b> and <b>16</b>) that showed significant antiproliferative activity against a panel of cancer cells. Both compounds were able to reduce the levels of p-STAT3<sup>Tyr705</sup> without affecting the total expression of STAT3. While compound <b>6</b> inhibited tubulin polymerization and arrested the cell cycle of DU145 cells at G2/M, similar to TUB015, compound <b>16</b> showed a more potent effect on inhibiting STAT3 phosphorylation and arrested the cell cycle at G1/G0, similar to niclosamide. In both cases, no toxicity towards PBMC cells was detected. Thus, the salicylanilides described here represent a new class of antiproliferative agents affecting tubulin polymerization and/or STAT3 phosphorylation. |
| first_indexed | 2024-03-09T10:13:03Z |
| format | Article |
| id | doaj.art-04e92709cd6e42d5898a508c9cf4eb8f |
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| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T10:13:03Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-04e92709cd6e42d5898a508c9cf4eb8f2023-12-01T22:33:27ZengMDPI AGPharmaceuticals1424-82472022-07-0115783510.3390/ph15070835Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3)Marta Gargantilla0Leentje Persoons1Tereza Kauerová2Natalia del Río3Dirk Daelemans4Eva-María Priego5Peter Kollar6María-Jesús Pérez-Pérez7Instituto de Quimica Medica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainKU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 42 Brno, Czech RepublicInstituto de Quimica Medica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainKU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, BelgiumInstituto de Quimica Medica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 42 Brno, Czech RepublicInstituto de Quimica Medica (IQM, CSIC) c/Juan de la Cierva 3, 28006 Madrid, SpainThe superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and nocodazole using a salicylanilide core structure. Interestingly, salicylanilides, such as niclosamide, are well-established signal transducers and activators of transcription (STAT3) inhibitors with anticancer properties. Thus, different compounds with this new scaffold have been synthesized with the aim to identify compounds inhibiting tubulin polymerization and/or STAT3 signaling. As a result, we have identified new salicylanilides (<b>6</b> and <b>16</b>) that showed significant antiproliferative activity against a panel of cancer cells. Both compounds were able to reduce the levels of p-STAT3<sup>Tyr705</sup> without affecting the total expression of STAT3. While compound <b>6</b> inhibited tubulin polymerization and arrested the cell cycle of DU145 cells at G2/M, similar to TUB015, compound <b>16</b> showed a more potent effect on inhibiting STAT3 phosphorylation and arrested the cell cycle at G1/G0, similar to niclosamide. In both cases, no toxicity towards PBMC cells was detected. Thus, the salicylanilides described here represent a new class of antiproliferative agents affecting tubulin polymerization and/or STAT3 phosphorylation.https://www.mdpi.com/1424-8247/15/7/835tubulin polymerization inhibitorscolchicine sitesalicylanilidesniclosamidesignal transducer and activator of transcription (STAT3) inhibitors |
| spellingShingle | Marta Gargantilla Leentje Persoons Tereza Kauerová Natalia del Río Dirk Daelemans Eva-María Priego Peter Kollar María-Jesús Pérez-Pérez Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3) Pharmaceuticals tubulin polymerization inhibitors colchicine site salicylanilides niclosamide signal transducer and activator of transcription (STAT3) inhibitors |
| title | Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3) |
| title_full | Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3) |
| title_fullStr | Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3) |
| title_full_unstemmed | Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3) |
| title_short | Hybridization Approach to Identify Salicylanilides as Inhibitors of Tubulin Polymerization and Signal Transducers and Activators of Transcription 3 (STAT3) |
| title_sort | hybridization approach to identify salicylanilides as inhibitors of tubulin polymerization and signal transducers and activators of transcription 3 stat3 |
| topic | tubulin polymerization inhibitors colchicine site salicylanilides niclosamide signal transducer and activator of transcription (STAT3) inhibitors |
| url | https://www.mdpi.com/1424-8247/15/7/835 |
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