Artículo
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New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents
Autor/es | Roldán Peña, Jesús Miguel
Alejandre Ramos, Daniel López López, Óscar ![]() ![]() ![]() ![]() ![]() ![]() ![]() Maya Castilla, Inés ![]() ![]() ![]() ![]() ![]() ![]() ![]() Lagunes, Irene Padrón, José M. Peña Altamira, Luis Emiliano Bartolini, Manuela Monti, Barbara Bolognesi, Maria L. Fernández-Bolaños Guzmán, José María ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
Departamento | Universidad de Sevilla. Departamento de Química orgánica |
Fecha de publicación | 2017 |
Fecha de depósito | 2023-05-26 |
Publicado en |
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Premios | Premio Mensual Publicación Científica Destacada de la US. Escuela Politécnica Superior |
Resumen | 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 ... 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. |
Agencias financiadoras | Dirección General de Investigación (DGI). España Junta de Andalucía European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) EU Research Potential |
Identificador del proyecto | CTQ2016-78703-P
![]() CTQ2011-28417-C02-01 ![]() CEI10/00018 ![]() FQM134 ![]() 501100008530 ![]() FP7-REGPOT-2012-CT2012-31637-IMBRAIN ![]() |
Cita | Roldán Peña, J.M., Alejandre Ramos, D., López López, Ó., Maya Castilla, I., Lagunes, I., Padrón, J.M.,...,Fernández-Bolaños Guzmán, J.M. (2017). New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents. European Journal of Medicinal Chemistry, 138, 761-773. https://doi.org/10.1016/j.ejmech.2017.06.048. |
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New tacrine dimers.pdf | 5.055Mb | ![]() | Ver/ | |