Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors
The design of multitarget drugs (MTDs) has become an innovative approach for the search of effective treatments in complex diseases such as cancer. In this work, we communicate our efforts in the design of multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors as a novel therap...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/7/1497 |
| _version_ | 1818172983234002944 |
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| author | Regina Martínez Bruno Di Geronimo Miryam Pastor José María Zapico Claire Coderch Rostyslav Panchuk Nadia Skorokhyd Maciej Maslyk Ana Ramos Beatriz de Pascual-Teresa |
| author_facet | Regina Martínez Bruno Di Geronimo Miryam Pastor José María Zapico Claire Coderch Rostyslav Panchuk Nadia Skorokhyd Maciej Maslyk Ana Ramos Beatriz de Pascual-Teresa |
| author_sort | Regina Martínez |
| collection | DOAJ |
| description | The design of multitarget drugs (MTDs) has become an innovative approach for the search of effective treatments in complex diseases such as cancer. In this work, we communicate our efforts in the design of multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors as a novel therapeutic strategy against cancer. Using tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT) as scaffolds for CK2 inhibition, and a hydroxamate to coordinate the zinc atom present in the active site of HDAC (zinc binding group, ZBG), new multitarget inhibitors have been designed and synthesized. According to the in vitro assays, <i>N</i>-Hydroxy-6-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)hexanamide (<b>11b</b>) is the most interesting compound, with IC<sub>50</sub> values of 0.66; 1.46 and 3.67 µM. for HDAC6; HDAC1 and CK2; respectively. Cellular assays on different cancer cell lines rendered promising results for <i>N</i>-Hydroxy-8-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)octanamide (<b>11d</b>). This inhibitor presented the highest cytotoxic activity, proapoptotic capability, and the best mitochondria-targeting and multidrug-circumventing properties, thus being the most promising drug candidate for further in vivo studies. |
| first_indexed | 2024-12-11T19:21:16Z |
| format | Article |
| id | doaj.art-97dcdbbdeeea4f3e813fe51907d076c3 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T19:21:16Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-97dcdbbdeeea4f3e813fe51907d076c32022-12-22T00:53:31ZengMDPI AGMolecules1420-30492020-03-01257149710.3390/molecules25071497molecules25071497Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitorsRegina Martínez0Bruno Di Geronimo1Miryam Pastor2José María Zapico3Claire Coderch4Rostyslav Panchuk5Nadia Skorokhyd6Maciej Maslyk7Ana Ramos8Beatriz de Pascual-Teresa9Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, SpainDepartamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, SpainDepartamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, SpainDepartamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, SpainDepartamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, SpainInstitute of Cell Biology, NAS of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, UkraineInstitute of Cell Biology, NAS of Ukraine, Drahomanov Str. 14/16, 79005 Lviv, UkraineDepartment of Molecular Biology, Faculty of Biotechnology and Environment Sciences, The John Paul II Catholic University of Lublin, 20-718 Lublin, PolandDepartamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, SpainDepartamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28925 Alcorcón, Madrid, SpainThe design of multitarget drugs (MTDs) has become an innovative approach for the search of effective treatments in complex diseases such as cancer. In this work, we communicate our efforts in the design of multi-targeting histone deacetylase (HDAC) and protein kinase CK2 inhibitors as a novel therapeutic strategy against cancer. Using tetrabromobenzotriazole (TBB) and 2-dimethylamino-4,5,6,7-tetrabromo-benzimidazole (DMAT) as scaffolds for CK2 inhibition, and a hydroxamate to coordinate the zinc atom present in the active site of HDAC (zinc binding group, ZBG), new multitarget inhibitors have been designed and synthesized. According to the in vitro assays, <i>N</i>-Hydroxy-6-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)hexanamide (<b>11b</b>) is the most interesting compound, with IC<sub>50</sub> values of 0.66; 1.46 and 3.67 µM. for HDAC6; HDAC1 and CK2; respectively. Cellular assays on different cancer cell lines rendered promising results for <i>N</i>-Hydroxy-8-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)octanamide (<b>11d</b>). This inhibitor presented the highest cytotoxic activity, proapoptotic capability, and the best mitochondria-targeting and multidrug-circumventing properties, thus being the most promising drug candidate for further in vivo studies.https://www.mdpi.com/1420-3049/25/7/1497hdacck2multi-target inhibitorsdockingmolecular dynamicscuaaccytotoxic activity |
| spellingShingle | Regina Martínez Bruno Di Geronimo Miryam Pastor José María Zapico Claire Coderch Rostyslav Panchuk Nadia Skorokhyd Maciej Maslyk Ana Ramos Beatriz de Pascual-Teresa Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors Molecules hdac ck2 multi-target inhibitors docking molecular dynamics cuaac cytotoxic activity |
| title | Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors |
| title_full | Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors |
| title_fullStr | Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors |
| title_full_unstemmed | Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors |
| title_short | Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors |
| title_sort | multitarget anticancer agents based on histone deacetylase and protein kinase ck2 inhibitors |
| topic | hdac ck2 multi-target inhibitors docking molecular dynamics cuaac cytotoxic activity |
| url | https://www.mdpi.com/1420-3049/25/7/1497 |
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