New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents
| Autor: | Irene Lagunes, Inés Maya, Luis Emiliano Peña-Altamira, Barbara Monti, Daniel Alejandre-Ramos, Maria Laura Bolognesi, José M. Padrón, Jesús M. Roldán-Peña, Manuela Bartolini, José G. Fernández-Bolaños, Óscar López |
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| Přispěvatelé: | Roldán-Peña, Jesús M., Alejandre-Ramos, Daniel, López, O scar, Maya, Iné, Lagunes, Irene, Padrón, José M., Peña-Altamira, Luis Emiliano, Bartolini, Manuela, Monti, Barbara, Bolognesi, Maria L., Fernández-Bolaños, José G., Universidad de Sevilla. Departamento de Química orgánica, Dirección General de Investigación (DGI). España, Junta de Andalucía, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), EU Research Potential |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Amyloid beta-Peptide Protein aggregation 01 natural sciences Antioxidants Antineoplastic Agent chemistry.chemical_compound Mice Peptide Fragment AChE inhibition Organoselenium Compounds Drug Discovery Cholinesterase Inhibitor Organoselenium Compound Molecular Structure Chemistry General Medicine Cell cycle Acetylcholinesterase Tacrine dimers Anti-Alzheimer Tacrine Tacrine dimer Antioxidant Dimerization medicine.drug Human Stereochemistry Antineoplastic Agents Chalcogen Protein Aggregates 03 medical and health sciences Structure-Activity Relationship Alzheimer Disease Cell Line Tumor medicine Animals Humans Structure–activity relationship Cell Proliferation Cisplatin Pharmacology Amyloid beta-Peptides Dose-Response Relationship Drug 010405 organic chemistry Cell growth Animal Drug Discovery3003 Pharmaceutical Science Organic Chemistry Peptide Fragments 0104 chemical sciences 030104 developmental biology Cell culture Antiproliferative agent Chalcogens Protein Aggregate Cholinesterase Inhibitors Drug Screening Assays Antitumor |
| Popis: | We have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives. The three most promising homodimers also showed a good inhibitory activity towards amyloid-β self aggregation. The symmetric disulfide derivative bis[5-(1′,2′,3′,4’-tetrahydroacridin-9′-ylamino)pentyl]disulfide (19) showed the best multipotent profile and was not neurotoxic on immortalized mouse cortical neurons even at 50 μM concentration. These results represent an improvement in activity and selectivity compared to parent tacrine, the first marketed drug against Alzheimer's disease. Title compounds also exhibited excellent in vitro antiproliferative activities against a panel of 6 human tumor cell lines, with GI50 values within the submicromolar range for the most potent derivatives (0.12–0.95 μM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306−fold) and cisplatin (up to 162−fold). Cell cycle experiments indicated the accumulation of cells in the G1 phase of the cycle, a different mechanism than the reported for cisplatin. The breast cancer cell lines turned out to be the most sensitive one of the panel tested. Dirección General de Investigación CTQ2016-78703-P, CTQ2011-28417-C02-01, CEI10/00018 Junta de Andalucía FQM134 Fondo Europeo de Desarrollo Regional 501100008530 EU Research Potential FP7-REGPOT-2012-CT2012-31637-IMBRAIN |
| Databáze: | OpenAIRE |
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