New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action
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| Format: | Recurso digital |
| Language: | English |
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Zenodo
2023
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| author | Luque Navarro, Pilar María Carrasco Jimenez, Maria Paz Goracci, Laura Paredes, Jose Manuel Espinar-Barranco, Laura Valverde-Pozo, Javier Torretta, Archimede PARISINI, Emilio Mariotto, Elena Marchioro, Chiara Laso, Alejandro Marco De La Calle, Carmen Viola, Giampietro Lanari, Daniela LOPEZ-CARA, LUISA CARLOTA |
| author_facet | Luque Navarro, Pilar María Carrasco Jimenez, Maria Paz Goracci, Laura Paredes, Jose Manuel Espinar-Barranco, Laura Valverde-Pozo, Javier Torretta, Archimede PARISINI, Emilio Mariotto, Elena Marchioro, Chiara Laso, Alejandro Marco De La Calle, Carmen Viola, Giampietro Lanari, Daniela LOPEZ-CARA, LUISA CARLOTA |
| contents | <p>Since the identification of human choline kinase as a protein target against cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series. Docking analysis using FLAP suggests that for hits to leads, binding mostly involves an interaction with the Mg<sup>2+</sup> cofactor, or its destabilization. The most active compounds of the two series are capable of inducing apoptosis following the mitochondrial pathway and to significantly reduce the expression of anti-apoptotic proteins such as the Mcl-1. The fluorescence properties of the compounds of the PL library allowed the tracking of their mode of action, while PAINS (Pan Assays Interference Structures) filtration databases suggest the lack of any unspecific biological response.</p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_14629845 |
| institution | Zenodo |
| language | eng |
| publishDate | 2023 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action Luque Navarro, Pilar María Carrasco Jimenez, Maria Paz Goracci, Laura Paredes, Jose Manuel Espinar-Barranco, Laura Valverde-Pozo, Javier Torretta, Archimede PARISINI, Emilio Mariotto, Elena Marchioro, Chiara Laso, Alejandro Marco De La Calle, Carmen Viola, Giampietro Lanari, Daniela LOPEZ-CARA, LUISA CARLOTA Antitumoral drug; Bioisosterism; Choline kinase inhibition; Environmental synthesis <p>Since the identification of human choline kinase as a protein target against cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series. Docking analysis using FLAP suggests that for hits to leads, binding mostly involves an interaction with the Mg<sup>2+</sup> cofactor, or its destabilization. The most active compounds of the two series are capable of inducing apoptosis following the mitochondrial pathway and to significantly reduce the expression of anti-apoptotic proteins such as the Mcl-1. The fluorescence properties of the compounds of the PL library allowed the tracking of their mode of action, while PAINS (Pan Assays Interference Structures) filtration databases suggest the lack of any unspecific biological response.</p> |
| title | New bioisosteric sulphur-containing choline kinase inhibitors with a tracked mode of action |
| topic | Antitumoral drug; Bioisosterism; Choline kinase inhibition; Environmental synthesis |
| url | https://doi.org/10.5281/zenodo.14629845 |