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http://hdl.handle.net/10637/13383
Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 Inhibitors.
Title: | Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 Inhibitors. |
Authors : | Martínez, Regina Di Geronimo Quintero, Bruno Pastor, Myriam Zapico Rodríguez, José María Coderch Boué, Claire Panchuk, Rostyslav Skorokhyd, Nadia Maslyk, Maciej Ramos González, Ana Pascual-Teresa Fernández, Beatriz de |
Keywords: | HDAC; CK2; Multi-target inhibitors; Docking; Molecular dynamics; CuAAC; Cytotoxic activity |
Abstract: | 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, N-Hydroxy-6-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)hexanamide (11b) is the most interesting compound, with IC50 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 N-Hydroxy-8-(4,5,6,7-tetrabromo-2-(dimethylamino)-1H-benzo[d]imidazol-1-yl)octanamide (11d). 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. |
Description: | Molecules, e-ISSN 1420-3049 , 2020, 25, 1497 |
URI: | http://hdl.handle.net/10637/13383 |
Rights : | http://creativecommons.org/licenses/by-nc-nd/4.0/deed.es |
Issue Date: | 15-Feb-2020 |
Center : | Universidad San Pablo-CEU |
Appears in Collections: | Facultad de Farmacia |
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