1. Academic Validation
  2. New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents

New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents

  • Eur J Med Chem. 2017 Sep 29:138:761-773. doi: 10.1016/j.ejmech.2017.06.048.
Jesús M Roldán-Peña 1 Daniel Alejandre-Ramos 2 Óscar López 3 Inés Maya 1 Irene Lagunes 4 José M Padrón 4 Luis Emiliano Peña-Altamira 5 Manuela Bartolini 5 Barbara Monti 5 Maria L Bolognesi 5 José G Fernández-Bolaños 6
Affiliations

Affiliations

  • 1 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain.
  • 2 Escuela Politécnica Superior, Universidad de Sevilla, Virgen de África 7, E-41011 Seville, Spain.
  • 3 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain. Electronic address: osc-lopez@us.es.
  • 4 BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, C/ Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain.
  • 5 Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, via Belmeloro 6, 40126 Bologna, Italy.
  • 6 Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain. Electronic address: bolanos@us.es.
Abstract

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.

Keywords

AChE inhibition; Anti-Alzheimer; Antioxidant; Antiproliferative agent; Tacrine dimers.

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