Alzheimer's disease remains largely unknown, and currently there is no complete cure for the disease. New synthetic approaches have been developed to create multi-target agents, such as RHE-HUP, a rhein-huprine hybrid which can modulate several biological targets that are relevant to the development of the disease. While RHE-HUP has shown in vitro and in vivo beneficial effects, the molecular mechanisms by which it exerts its protective effect on cell membranes have not been fully clarified. To better understand RHE-HUP interactions with cell membranes, we used synthetic membrane models and natural models of human membranes. For this purpose, human erythrocytes and molecular model of its membrane built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. The latter correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. X-ray diffraction and differential scanning calorimetry (DSC) results indicated that RHE-HUP was able to interact mainly with DMPC. In addition, scanning electron microscopy (SEM) analysis showed that RHE-HUP modified the normal biconcave shape of erythrocytes inducing the formation of echinocytes. Moreover, the protective effect of RHE-HUP against the disruptive effect of Aβ(1-42) on the studied membrane models was tested. X-ray diffraction experiments showed that RHE-HUP induced a recovery in the ordering of DMPC multilayers after the disruptive effect of Aβ(1-42), confirming the protective role of the hybrid.
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http://dx.doi.org/10.1016/j.bpc.2023.107061 | DOI Listing |
Pharmaceutics
July 2024
Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
Multitarget compounds have emerged as promising drug candidates to cope with complex multifactorial diseases, like Alzheimer's disease (AD). Most multitarget compounds are designed by linking two pharmacophores through a tether chain (linked hybrids), which results in rather large molecules that are particularly useful to hit targets with large binding cavities, but at the expense of suffering from suboptimal physicochemical/pharmacokinetic properties. Molecular size reduction by removal of superfluous structural elements while retaining the key pharmacophoric motifs may represent a compromise solution to achieve both multitargeting and favorable physicochemical/PK properties.
View Article and Find Full Text PDFBiophys Chem
September 2023
Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland; Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
Alzheimer's disease remains largely unknown, and currently there is no complete cure for the disease. New synthetic approaches have been developed to create multi-target agents, such as RHE-HUP, a rhein-huprine hybrid which can modulate several biological targets that are relevant to the development of the disease. While RHE-HUP has shown in vitro and in vivo beneficial effects, the molecular mechanisms by which it exerts its protective effect on cell membranes have not been fully clarified.
View Article and Find Full Text PDFCell Biosci
March 2023
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain.
Background: Alzheimer's disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features.
View Article and Find Full Text PDFFuture Med Chem
June 2017
Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy & Food Sciences, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
Aim: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition.
Materials & Methods: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Aβ42 and tau aggregation, of antioxidant activity, and of brain permeation.
Results: Using, as a template, a lead rhein-huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring.
Curr Alzheimer Res
October 2017
CARE Biomedical Center, P. Catholic University of Chile, Postal code 8331150, PO Box 114-D, Santiago, Chile.
Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-β (Aβ) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both Aβ and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the AβPPswe/PS-1 Alzheimer´s model, including a reduction in the Aβ levels, tau phosphorylation and memory impairment with both treatments.
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