RESUMO
The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.
Assuntos
Di-Hidroergotamina , Escopolamina , Animais , Ratos , Histamina , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Encéfalo , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Antagonistas dos Receptores H2 da HistaminaRESUMO
Poly-ADP-Ribose Polymerase (PARP-1) is an overexpressed enzyme in several carcinomas; consequently, the design of PARP-1 inhibitors has acquired special attention. Hence, in the present study, three compounds (8-10) were produced through a Michael addition protocol, using phenylmethanethiol, 5-fluoro-2-mercaptobenzyl alcohol, and 4-mercaptophenylacetic acid, respectively, as nucleophiles and perezone as the substrate, expecting them to be convenient candidates that inhibit PARP-1. It is convenient to note that in the first stage of the whole study, the molecular dynamics (MD) simulations and the quantum chemistry studies of four secondary metabolites, i.e., perezone (1), perezone angelate (2), hydroxyperezone (3), and hydroxyperezone monoangelate (4), were performed, to investigate their interactions in the active site of PARP-1. Complementarily, a docking study of a set of eleven sulfur derivatives of perezone (5-15) was projected to explore novel compounds, with remarkable affinity to PARP-1. The molecules 8-10 provided the most adequate results; therefore, they were evaluated in vitro to determine their activity towards PARP-1, with 9 having the best IC50 (0.317 µM) value. Additionally, theoretical calculations were carried out using the density functional theory (DFT) with the hybrid method B3LYP with a set of base functions 6-311++G(d,p), and the reactivity properties were compared between the natural derivatives of perezone and the three synthesized compounds, and the obtained results exhibited that 9 has the best properties to bind with PARP-1. Finally, it is important to mention that 9 displays significant inhibitory activity against MDA-MB-231 and MCF-7 cells, i.e., 145.01 and 83.17 µM, respectively.
Assuntos
Cicloexenos , Neoplasias , Inibidores de Poli(ADP-Ribose) Polimerases , Sesquiterpenos , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Células MCF-7 , Simulação de Dinâmica Molecular , Neoplasias/tratamento farmacológicoRESUMO
Three novel biomaterials obtained via inclusion complexes of ß-cyclodextrin, 6-deoxi-6-amino-ß-cyclodextrin and epithelial growth factor grafted to 6-deoxi-6-amino-ß-cyclodextrin with polycaprolactone. Furthermore, some physicochemical, toxicological and absorption properties were predicted using bioinformatics tools. The electronic, geometrical and spectroscopical calculated properties agree with the properties obtained via experimental methods, explaining the behaviors observed in each case. The interaction energy was obtained, and its values were -60.6, -20.9 and -17.1 kcal/mol for ß-cyclodextrin/polycaprolactone followed by the 6-amino-ß-cyclodextrin-polycaprolactone complex and finally the complex of epithelial growth factor anchored to 6-deoxy-6-amino-ß-cyclodextrin/polycaprolactone. Additionally, the dipolar moments were calculated, achieving values of 3.2688, 5.9249 and 5.0998 Debye, respectively, and in addition the experimental wettability behavior of the studied materials has also been explained. It is important to note that the toxicological predictions suggested no mutagenic, tumorigenic or reproductive effects; moreover, an anti-inflammatory effect has been shown. Finally, the improvement in the cicatricial effect of the novel materials has been conveniently explained by comparing the poly-caprolactone data obtained in the experimental assessments.
Assuntos
Ciclodextrinas , Poliésteres , Peptídeos e Proteínas de Sinalização Intercelular , Solubilidade , 2-Hidroxipropil-beta-Ciclodextrina/químicaRESUMO
To aid the possible prevention of multidrug resistance in tumors and cause lower toxicity, a set of sixteen novel dihydropyridine carboxylic acids derivatives 3a-p were produced; thus, the activation of various ynones with triflic anhydride was performed, involving a nucleophilic addition of several bis(trimethylsilyl) ketene acetals, achieving good yields requiring easy workup. The target molecules were unequivocally characterized by common spectroscopic methods. In addition, two of the tested compounds (3a, and 3b) were selected to perform in silico studies due to the highest cytotoxic activity towards the HCT-15 cell line (7.94 ± 1.6 µM and 9.24 ± 0.9 µM, respectively). Employing theoretical calculations with density functional theory (DFT) using the B3LYP/6-311++G(d,p) showed that the molecular parameters correlate adequately with the experimental results. In contrast, predictions employing Osiris Property Explorer showed that compounds 3a and 3b present physicochemical characteristics that would likely make it an orally active drug. Moreover, the performance of Docking studies with proteins related to the apoptosis pathway allowed a proposal of which compounds could interact with PARP-1 protein. Pondering the obtained results (synthesis, in silico, and cytotoxic activity) of the target compounds, they can be judged as suitable antineoplastic agent candidates.
Assuntos
Antineoplásicos , Di-Hidropiridinas , Neoplasias , Humanos , Linhagem Celular , Antineoplásicos/química , Compostos Orgânicos , Ácidos Carboxílicos/farmacologia , Di-Hidropiridinas/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Estrutura MolecularRESUMO
Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer's disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme-drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC50 = 72.89 µM and 45.01 µM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.
Assuntos
Histamina , Transferases , Histamina/metabolismo , Histamina N-Metiltransferase/metabolismo , Cloridrato de Vilazodona , Simulação de Acoplamento Molecular , Reposicionamento de Medicamentos , Di-HidroergotaminaRESUMO
Glioblastoma multiforme (GBM) represents the most malignant type of astrocytoma, with a life expectancy of two years. It has been shown that Poly (ADP-ribose) polymerase 1 (PARP-1) protein is over-expressed in GBM cells, while its expression in healthy tissue is low. In addition, perezone, a phyto-compound, is a PARP-1 inhibitor with anti-neoplastic activity. As a consequence, in the present study, both in vitro and computational evaluations of perezone and its chemically related compound, perezone angelate, as anti-GBM agents were performed. Hence, the anti-proliferative assay showed that perezone angelate induces higher cytotoxicity in the GBM cell line (U373 IC50 = 6.44 µM) than perezone (U373 IC50 = 51.20 µM) by induction of apoptosis. In addition, perezone angelate showed low cytotoxic activity in rat glial cells (IC50 = 173.66 µM). PARP-1 inhibitory activity (IC50 = 5.25 µM) and oxidative stress induction by perezone angelate were corroborated employing in vitro studies. In the other hand, the performed docking studies allowed explaining the PARP-1 inhibitory activity of perezone angelate, and ADMET studies showed its probability to permeate cell membranes and the blood-brain barrier, which is an essential characteristic of drugs to treat neurological diseases. Finally, it is essential to highlight that the results confirm perezone angelate as a potential anti-GBM agent.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Sesquiterpenos , Animais , Apoptose , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ratos , Sesquiterpenos/farmacologiaRESUMO
Cancer is one of the leading causes of morbidity and mortality worldwide. This disease is characterized by uncontrolled growth and proliferation of abnormal cells with a high probability to develop metastasis. Recently, it was demonstrated that perezone, a sesquiterpene quinone, is capable to induce cell death in leukemia (K562), prostate (PC-3), colorectal (HCT-15) and lung (SKLU-1) cancer cell lines; however, its mechanism of action is unknown. Therefore, in this study, in vitro and computational studies were performed to determine the mechanism of action of perezone. Firstly, changes in K562â¯cell viability, as well as changes in the redox status of the cell in response to treatment with several concentrations of perezone were analyzed. The type of cell death induced, and the modification of the cell cycle were determined. In addition, MD simulations and docking studies were performed to investigate the interaction of perezone with seven regulators of the apoptotic process. Finally, the ability of perezone to inhibit PARP-1 was evaluated by in vitro studies. K562 cells treated with perezone exhibited decreased viability and more oxidized status, being this effect concentration-dependent. In addition, the increase of G0/G1 phase of cell cycle and apoptosis were observed. According to the performed computational studies conducted, perezone showed the highest affinity to PARP-1 enzyme being this complex the most stable due to the presence of a small and deep cavity in the active site, which allows perezone to fit deeply by forming hydrogen bonds and hydrophobic interactions, which drive this interaction. The activity of perezone as PARP-1 inhibitor was corroborated with an IC50â¯=â¯181.5⯵M. The pro-apoptotic action of perezone may be related to PARP-1 inhibition and changes in the redox state of the cell. The obtained results allowed to understand the biological effect of perezone and, consequently, these could be employed to develop novel PARP-1 inhibitors.
Assuntos
Oxirredução/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Sesquiterpenos/farmacologia , Apoptose/efeitos dos fármacos , Asteraceae/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células K562 , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/isolamento & purificação , Sesquiterpenos/isolamento & purificaçãoRESUMO
Perezone, a sesquiterpene quinone, is a very important molecule due to its pharmacological activities in addition to the fact that it is considered to be the first secondary metabolite isolated in the new world (America-Mexico, 1852). This study aims to offer a green comparative study about the extraction of the target molecule from the roots of the vegetable specimen Acourtia platyphilla (A. Grey). The study was performed comparing five different modes of extraction: supercritical CO2, electromagnetic infrared and microwave irradiations, mechanical-wave ultrasound versus typical mantle heating procedure. An exhaustive comparative-discussion of the obtained results is provided. It is worth noting that the corresponding quantifications were established using 1H NMR, correlating appropriately the integrals of the vinylic proton H-6 of perezone with the aromatic singlet of p-dinitrobenzene employed as an internal reference. It is also important to highlight that the four presented procedures are novel modes to extract perezone. Finally, a complementary study about the solubility of the target sesquiterpene quinone related to the use of supercritical CO2 is also reported.
Assuntos
Asteraceae/química , Dióxido de Carbono/química , Extratos Vegetais/química , Raízes de Plantas/química , Sesquiterpenos/química , Cromatografia com Fluido SupercríticoRESUMO
Several indolylquinone analogues of perezone, a natural sesquiterpene quinone, were characterized in this work by theoretical methods. In addition, some physicochemical, toxicological and metabolic properties were predicted using bioinformatics software. The predicted physicochemical properties are in agreement with the solubility and cLogP values, the penetration across the cell membrane, and absorption values, as well as with a possible apoptosis-activated mechanism of cytotoxic action. The toxicological predictions suggest no mutagenic, tumorigenic or reproductive effects of the four target molecules. Complementarily, the results of a performed docking study show high scoring values and hydrogen bonding values in agreement with the cytotoxicity IC50 value ranking, i.e: indolylmenadione > indolylperezone > indolylplumbagine > indolylisoperezone. Consequently, it is possible to suggest an appropriate apoptotic pathway for each compound. Finally, potential metabolic pathways of the molecules were proposed.
Assuntos
Biologia Computacional/métodos , Neoplasias/metabolismo , Quinonas/química , Quinonas/farmacologia , Sesquiterpenos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Humanos , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias/tratamento farmacológico , Teoria Quântica , Transdução de Sinais/efeitos dos fármacosRESUMO
The structure of the ortho-, meta- and para- hybrid diindolylmethane-phenylboronic acids and their interactions were optimized with by a quantum chemical method, using density functional theory at the (DFT) level. Thus, infrared bands were assigned based on the scaled theoretical wavenumbers by correlating the respective experimental data of the molecules. In addition, the corresponding ¹H-/13C-/11B-NMR experimental and theoretical chemical shifts were correlated. The target molecules showed a poor treatment of the OH shifts in the GIAO method due to the absence of explicit solvent effects in these calculations; therefore, they were explicitly considered with acetone molecules. Moreover, the electron density at the hydrogen bond critical point increased, generating stabilization energy, from weak to moderate or weak to strong, serving as an indicator of the strength of the hydrogen bond between the different intermolecular interactions. Finally, some properties related to the reactive behavior of the target molecules associated with their cytotoxic effects and metabolic pathways were also calculated.
Assuntos
Ácidos Borônicos/química , Indóis/química , Análise Espectral , Ácidos Borônicos/metabolismo , Ligação de Hidrogênio , Indóis/metabolismo , Espectroscopia de Ressonância Magnética , Desintoxicação Metabólica Fase I , Redes e Vias Metabólicas , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral/métodosRESUMO
Polymeric hybrid films, for their application in organic electronics, were produced from new ruthenium indanones in poly(methyl methacrylate) (PMMA) by the drop-casting procedure. Initially, the synthesis and structural characterization of the ruthenium complexes were performed, and subsequently, their properties as a potential semiconductor material were explored. Hence hybrid films in ruthenium complexes were deposited using PMMA as a polymeric matrix. The hybrid films were characterized by infrared spectrophotometry and atomic force microscopy. The obtained results confirmed that the presence of the ruthenium complexes enhanced the mechanical properties in addition to increasing the transmittance, favoring the determination of their optical parameters. Both hybrid films exhibited a maximum stress around 10.5 MPa and a Knoop hardness between 2.1 and 18.4. Regarding the optical parameters, the maximum transparency was obtained at wavelengths greater than 590 nm, the optical band gap was in the range of 1.73-2.24 eV, while the Tauc band gap was in the range of 1.68-2.17 eV, and the Urbach energy was between 0.29 and 0.50 eV. Consequently, the above comments are indicative of an adequate semiconductor behavior; hence, the target polymeric hybrid films must be welcomed as convenient candidates as active layers or transparent electrodes in organic electronics.
RESUMO
Aflatoxin B1 (AFB1) exhibits the most potent mutagenic and carcinogenic activity among aflatoxins. For this reason, AFB1 is recognized as a human group 1 carcinogen by the International Agency of Research on Cancer. Consequently, it is essential to determine its properties and behavior in different chemical systems. The chemical properties of AFB1 can be explored using computational chemistry, which has been employed complementarily to experimental investigations. The present review includes in silico studies (semiempirical, Hartree-Fock, DFT, molecular docking, and molecular dynamics) conducted from the first computational study in 1974 to the present (2022). This work was performed, considering the following groups: (a) molecular properties of AFB1 (structural, energy, solvent effects, ground and the excited state, atomic charges, among others); (b) theoretical investigations of AFB1 (degradation, quantification, reactivity, among others); (c) molecular interactions with inorganic compounds (Ag+, Zn2+, and Mg2+); (d) molecular interactions with environmentally compounds (clays); and (e) molecular interactions with biological compounds (DNA, enzymes, cyclodextrins, glucans, among others). Accordingly, in this work, we provide to the stakeholder the knowledge of toxicity of types of AFB1-derivatives, the structure-activity relationships manifested by the bonds between AFB1 and DNA or proteins, and the types of strategies that have been employed to quantify, detect, and eliminate the AFB1 molecule.
Assuntos
Aflatoxina B1 , Aflatoxinas , Humanos , Aflatoxina B1/toxicidade , Simulação de Acoplamento Molecular , Aflatoxinas/metabolismo , Relação Estrutura-Atividade , Carcinógenos , DNA/metabolismoRESUMO
This chapter covers a sesquiterpene quinone, commonly named perezone. This molecule is documented as the first secondary metabolite isolated in crystalline form in the New World in 1852. An introduction, with its structure, the IUPAC nomenclature, and the most recent physical and spectroscopic characterizations are firstly described initially. Alongside this, a timeline and scheme with summarized information of the history of this molecule is given including the "Códice Badiano de la Cruz, 1552, highlighting the year of its isolation culminating with information up to 2005. Subsequently, in a chronological order the most recent advances of the target molecule are included and organized in subsections covering the last 15-year period 2006-2020. Finally, recently submitted contributions from the laboratory of the authors are described. It is important to note that the details provided highlight the importance and relevance of perezone.
Assuntos
Sesquiterpenos , QuinonasRESUMO
Employing theoretical calculations with density functional theory (DFT) using the B3LYP/6-311++G(d,p) functional and basis set, the interaction of the aflatoxin B1 (AFB1) molecule and the functional groups present in the Pyracantha koidzumii biosorbent was investigated. Dissociation free energy and acidity equilibrium constant values were obtained theoretically both in solution (water) and gas phases. Additionally, the molecular electrostatic potential for the protonated molecules was calculated to verify the reactivity. Thus, methanol (hydroxyl group), methylammonium ion (amino group), acetate ion (carboxyl group), and acetone (carbonyl group), were used as representatives of the substrates present in the biomass; these references were considered using the corresponding protonated or unprotonated forms at a pH value of 5. The experimental infrared spectrophotometric data suggested the participation of these functional groups in the AFB1 biosorption process, indicating that the mechanism was dominated by electrostatic interactions between the charged functional groups and the positively charged AFB1 molecule. The theoretical determination indicated that the carboxylate ion provided the highest interaction energy with the AFB1 molecule. Consequently, an enriched biosorbent with compounds containing carboxyl groups could improve the yield of the AFB1 adsorption when using in vitro and in vivo trials.
Assuntos
Aflatoxina B1/química , Descontaminação , Teoria da Densidade Funcional , Modelos Químicos , Pyracantha/química , Adsorção , Aflatoxina B1/metabolismo , Ligação de Hidrogênio , Estrutura Molecular , Prótons , Pyracantha/metabolismo , Espectrofotometria Infravermelho , Eletricidade Estática , Relação Estrutura-AtividadeRESUMO
The reduction of NaNO2 and safety in meat products have been a concern to the meat industry for the last years. This research evaluated the changes in total fatty acids (TFAs) and myoglobin forms by adding starter culture (Lactobacillus sakei/Staphylococcus carnosus) and 50 ppm of NaNO2 during salami processing. In the postripening stage, the starter culture influenced the concentration of the palmitic, oleic, vaccenic, and γ-linolenic TFAs, whereas the metmyoglobin concentration was lower (which could be related to the antioxidant effect of the starter culture). In this stage, an increase in enthalpy, specific heat, and onset temperature was found when adding starter culture and NaNO2, which is directly related to polyunsaturated TFA. However, when adding just the starter culture without 50 ppm NaNO2, the E. coli population was reduced in 4 log CFU/g. This study proposes the analysis of changes in meat product processing like salami in a holistic form, where the application of starter culture with low nitrite concentrations could be in the meat industry an upward trend for reducing this additive.
RESUMO
Theoretical studies of 8-chloro-9-hydroxy-aflatoxin B1 (2) were carried out by Density Functional Theory (DFT). This molecule is the reaction product of the treatment of aflatoxin B1 (1) with hypochlorous acid, from neutral electrolyzed water. Determination of the structural, electronic and spectroscopic properties of the reaction product allowed its theoretical characterization. In order to elucidate the formation process of 2, two reaction pathways were evaluated-the first one considering only ionic species (Cl⺠and OH(-)) and the second one taking into account the entire hypochlorous acid molecule (HOCl). Both pathways were studied theoretically in gas and solution phases. In the first suggested pathway, the reaction involves the addition of chlorenium ion to 1 forming a non-classic carbocation assisted by anchimeric effect of the nearest aromatic system, and then a nucleophilic attack to the intermediate by the hydroxide ion. In the second studied pathway, as a first step, the attack of the double bond from the furanic moiety of 1 to the hypochlorous acid is considered, accomplishing the same non-classical carbocation, and again in the second step, a nucleophilic attack by the hydroxide ion. In order to validate both reaction pathways, the atomic charges, the highest occupied molecular orbital and the lowest unoccupied molecular orbital were obtained for both substrate and product. The corresponding data imply that the C9 atom is the more suitable site of the substrate to interact with the hydroxide ion. It was demonstrated by theoretical calculations that a vicinal and anti chlorohydrin is produced in the terminal furan ring. Data of the studied compound indicate an important reduction in the cytotoxic and genotoxic potential of the target molecule, as demonstrated previously by our research group using different in vitro assays.
Assuntos
Aflatoxinas/química , Modelos Químicos , Água/química , Aflatoxinas/toxicidade , Eletrólise , Gases , Ácido Hipocloroso/química , Modelos Moleculares , Estrutura Molecular , Espectroscopia de Prótons por Ressonância Magnética , Soluções , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid ß peptide (Aß) is considered the most important due to the ability of the 42-amino acid Aß peptides (Aß1-42) to form oligomers and fibrils, which constitute Aß pathological aggregates. For this reason, the development of inhibitors of Aß1-42 pathological aggregation represents a field of research interest. Several Aß1-42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aß1-42 in α-helix (Aß-α), random coil (Aß-RC) and ß-sheet (Aß-ß) conformations. Docking studies revealed that compound 5 had a higher affinity for Aß-α and Aß-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aß1-42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aß1-42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aß-α and Aß-RC prevented the formation of oligomeric species.