Multitarget Anticancer Agents Based on Histone Deacetylase and Protein Kinase CK2 inhibitors
| Autor: | Claire Coderch, N. R. Skorokhyd, Maciej Masłyk, Regina Martínez, Beatriz de Pascual-Teresa, Miryam Pastor, José María Zapico, Bruno Di Geronimo, R. R. Panchuk, Ana Ramos |
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| Rok vydání: | 2020 |
| Předmět: |
CK2
Pharmaceutical Science Antineoplastic Agents Apoptosis Multi-target inhibitors Molecular dynamics Article Docking Analytical Chemistry lcsh:QD241-441 03 medical and health sciences 0302 clinical medicine lcsh:Organic chemistry In vivo HDAC Cell Line Tumor Drug Discovery Cytotoxic T cell Humans Physical and Theoretical Chemistry Casein Kinase II Protein Kinase Inhibitors 030304 developmental biology cytotoxic activity 0303 health sciences Cytotoxic activity biology Chemistry Organic Chemistry In vitro toxicology Active site Cell Cycle Checkpoints HDAC6 HDAC1 molecular dynamics Histone Deacetylase Inhibitors Chemistry (miscellaneous) Docking (molecular) Drug Resistance Neoplasm 030220 oncology & carcinogenesis docking Cancer research biology.protein Molecular Medicine multi-target inhibitors Histone deacetylase Reactive Oxygen Species CuAAC |
| Zdroj: | Molecules Molecules, Vol 25, Iss 7, p 1497 (2020) Volume 25 Issue 7 |
| ISSN: | 1420-3049 |
| Popis: | 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 µ M. 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. |
| Databáze: | OpenAIRE |
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