Publications by authors named "Andreea L Turcu"

5 Publications

  • Page 1 of 1

A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice.

Pharmaceutics 2020 Mar 22;12(3). Epub 2020 Mar 22.

Pharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, University of Barcelona (NeuroUB), Av. Joan XXIII 27-31, 08028 Barcelona, Spain.

Alzheimer's disease (AD) is the leading cause of dementia. Non-competitive N-Methyl-D-aspartate (NMDA) receptor antagonist memantine improved cognition and molecular alterations after preclinical treatment. Nevertheless, clinical results are discouraging. In vivo efficacy of the RL-208, a new NMDA receptor blocker described recently, with favourable pharmacokinetic properties was evaluated in Senescence accelerated mice prone 8 (SAMP8), a mice model of late-onset AD (LOAD). Oral administration of RL-208 improved cognitive performance assessed by using the three chamber test (TCT), novel object recognition test (NORT), and object location test (OLT). Consistent with behavioural results, RL-208 treated-mice groups significantly changed NMDAR2B phosphorylation state levels but not NMDAR2A. Calpain-1 and Caspase-3 activity was reduced, whereas B-cell lymphoma-2 (BCL-2) levels increased, indicating reduced apoptosis in RL-208 treated SAMP8. Superoxide Dismutase 1 (SOD1) and Glutathione Peroxidase 1 (GPX1), as well as a reduction of hydrogen peroxide (HO), was also determined in RL-208 mice. RL-208 treatment induced an increase in mature brain-derived neurotrophic factor (mBDNF), prevented Tropomyosin-related kinase B full-length (TrkB-FL) cleavage, increased protein levels of Synaptophysin (SYN) and Postsynaptic density protein 95 (PSD95). In whole, these results point out to an improvement in synaptic plasticity. Remarkably, RL-208 also decreased the protein levels of Cyclin-Dependent Kinase 5 (CDK5), as well as p25/p35 ratio, indicating a reduction in kinase activity of CDK5/p25 complex. Consequently, lower levels of hyperphosphorylated Tau (p-Tau) were found. In sum, these results demonstrate the neuroprotectant role of RL-208 through NMDAR blockade.
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http://dx.doi.org/10.3390/pharmaceutics12030284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151078PMC
March 2020

DMT1 Inhibitors Kill Cancer Stem Cells by Blocking Lysosomal Iron Translocation.

Chemistry 2020 Jun 26;26(33):7369-7373. Epub 2020 May 26.

Institut Curie, 26 rue d'Ulm, 75248, Paris Cedex 05, France.

Cancer stem cells (CSC) constitute a cell subpopulation in solid tumors that is responsible for resistance to conventional chemotherapy, metastasis and cancer relapse. The natural product Salinomycin can selectively target this cell niche by directly interacting with lysosomal iron, taking advantage of upregulated iron homeostasis in CSC. Here, inhibitors of the divalent metal transporter 1 (DMT1) have been identified that selectively target CSC by blocking lysosomal iron translocation. This leads to lysosomal iron accumulation, production of reactive oxygen species and cell death with features of ferroptosis. DMT1 inhibitors selectively target CSC in primary cancer cells and circulating tumor cells, demonstrating the physiological relevance of this strategy. Taken together, this opens up opportunities to tackle unmet needs in anti-cancer therapy.
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http://dx.doi.org/10.1002/chem.202000159DOI Listing
June 2020

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors.

Eur J Med Chem 2019 Oct 17;180:613-626. Epub 2019 Jul 17.

Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028, Barcelona, Spain. Electronic address:

The development of multitarget compounds against multifactorial diseases, such as Alzheimer's disease, is an area of very intensive research, due to the expected superior therapeutic efficacy that should arise from the simultaneous modulation of several key targets of the complex pathological network. Here we describe the synthesis and multitarget biological profiling of a new class of compounds designed by molecular hybridization of an NMDA receptor antagonist fluorobenzohomoadamantanamine with the potent acetylcholinesterase (AChE) inhibitor 6-chlorotacrine, using two different linker lengths and linkage positions, to preserve or not the memantine-like polycyclic unsubstituted primary amine. The best hybrids exhibit greater potencies than parent compounds against AChE (IC 0.33 nM in the best case, 44-fold increased potency over 6-chlorotacrine), butyrylcholinesterase (IC 21 nM in the best case, 24-fold increased potency over 6-chlorotacrine), and NMDA receptors (IC 0.89 μM in the best case, 2-fold increased potency over the parent benzohomoadamantanamine and memantine), which suggests an additive effect of both pharmacophoric moieties in the interaction with the primary targets. Moreover, most of these compounds have been predicted to be brain permeable. This set of biological properties makes them promising leads for further anti-Alzheimer drug development.
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http://dx.doi.org/10.1016/j.ejmech.2019.07.051DOI Listing
October 2019

Palladium-catalyzed cocyclotrimerization of arynes with a pyramidalized alkene.

Chem Commun (Camb) 2018 Jun;54(47):5996-5999

Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.

The metal-catalyzed [2+2+2] cocycloaddition of arynes with pyramidalized alkenes is presented. The generation of a highly reactive pyramidalized alkene in the presence of a large excess of in situ-produced arynes led to the corresponding cocyclotrimerization (1 : 2)-adducts in good yields, establishing the first example of a palladium-based reaction of a pyramidalized alkene.
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http://dx.doi.org/10.1039/c8cc03188fDOI Listing
June 2018

Pharmacological and Electrophysiological Characterization of Novel NMDA Receptor Antagonists.

ACS Chem Neurosci 2018 11 1;9(11):2722-2730. Epub 2018 Jun 1.

Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia i Ciències de l'Alimentació i Institut de Biomedicina (IBUB) , Universitat de Barcelona , Av. Joan XXIII, 27-31 , 08028 Barcelona , Spain.

This work reports the synthesis and pharmacological and electrophysiological evaluation of new N-methyl-d-aspartic acid receptor (NMDAR) channel blocking antagonists featuring polycyclic scaffolds. Changes in the chemical structure modulate the potency and voltage dependence of inhibition. Two of the new antagonists display properties comparable to those of memantine, a clinically approved NMDAR antagonist.
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http://dx.doi.org/10.1021/acschemneuro.8b00154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249113PMC
November 2018