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A series of three Ni(II)-POCOP complexes para-functionalized with an acetoxyl fragment were synthesized. All complexes (2 a-c) were fully characterized through standard analytical techniques. The molecular structure of complex 2 b was unambiguously determined by single-crystal X-ray diffraction, revealing that the metal center is situated in a slightly distorted square-planar environment. Additionally, the acetoxy fragment at the para-position of the phenyl ring was found to be present. The inâ vitro cytotoxic activity of all complexes was assessed on six human cancer cell lines. Notably, complex 2 b exhibited selective activity against K-562 (chronic myelogenous leukemia) and MCF-7 (mammary adenocarcinoma) with IC50 values of 7.32±0.60â µM and 14.36±0.02â µM, respectively. Furthermore, this compound showed negligible activity on the healthy cell line COS-7, highlighting the potential therapeutic application of 2 b. The cytotoxic evaluations were further complemented with molecular docking calculations to explore the potential biological targets of complex 2 b, revealing interactions with cluster differentiation protein 1a (CD1A, PDB: 1xz0) for K-562 and with the progesterone receptor for MCF-7.
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The interaction between iron and amyloid-beta (Aß) peptides has received significant attention in Alzheimer's disease (AD) research due to its potential implications in developing this pathology. However, the coordination preferences of iron and Aß1-42 have not been thoroughly investigated or remain unknown. This study employs a computational protocol that combines homology modeling techniques with quantum mechanics (DTF-xTB) calculations to build and evaluate several 3D models of Fe2+/3+-Aß1-42. Our results reveal well-defined complexes for both the metal and peptide moieties, and we discuss the molecular interactions stabilizing these complexes by elucidating the coordinating environments and binding preferences. These proposed models offer valuable insights into the role of iron in Alzheimer's disease (AD) pathology.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Fragmentos de Peptídeos , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Humanos , Teoria Quântica , Modelos Moleculares , Ferro/química , Ferro/metabolismo , Compostos Férricos/química , Compostos Ferrosos/químicaRESUMO
BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia representing from 60% to 70% of the cases globally. It is a multifactorial disease that, among its many pathological characteristics, has been found to provoke the metal ion dysregulation in the brain, along with an increase in the oxidative stress. There is proof that metallic complexes formed by the amyloid-ß peptide (Aß) and extraneuronal copper can catalyze the production of reactive oxygen species, leading to an increase in oxidative stress, promoting neuronal death. Due to this interaction, bioavailable copper has become an important redox active target to consider within the search protocols of multifunctional agents for AD's treatment. OBJECTIVE: In this study, we examined by using bioinformatics and electronic structure calculations the potential application of 44 salen-type copper chelating ligands and 12 further proposed molecules as possible multifunctional agents in the context of AD. METHODS: The candidates were evaluated by combining bioinformatic tools and electronic structure calculations, which allowed us to classify the molecules as potential antioxidants, redistributor-like compounds, and the newly proposed suppressor mechanism. RESULTS: This evaluation demonstrate that salen-type ligands exhibit properties suitable for interfering in the chain of copper-induced oxidative stress reactions present in AD and potential redistributor and suppressor activity for copper ions. Finally, a novel set of plausible candidates is proposed and evaluated. CONCLUSION: According to the evaluated criteria, a subset of 13 salen-type candidates was found to exhibit promissory pharmacological properties in the AD framework and were classified according to three plausible action mechanisms.
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QTAIM and source function analysis were used to explore the non-covalent bonding in twelve different water clusters (H2O)n obtained by considering n = 2-7 and various geometrical arrangements. A total of seventy-seven O-Hâ¯O hydrogen bonds (HBs) were identified in the systems under consideration, and the examination of the electron density at the bond critical point (BCP) of these HBs revealed the existence of a great diversity of O-Hâ¯O interactions. Furthermore, the analysis of quantities, such as |V(r)|/G(r) and H(r), allowed a further description of the nature of analogous O-Hâ¯O interactions within each cluster. In the case of 2-D cyclic clusters, the HBs are nearly equivalent between them. However, significant differences among the O-Hâ¯O interactions were observed in 3-D clusters. The assessment of the source function (SF) confirmed these findings. Finally, the ability of SF to decompose the electron density (ρ) into atomic contributions allowed the evaluation of the localized or delocalized character of these contributions to ρ at the BCP associated to the different HBs, revealing that weak O-Hâ¯O interactions have a significant spread of the atomic contributions, whereas strong interactions have more localized atomic contributions. These observations suggest that the nature of the O-Hâ¯O hydrogen bond in water clusters is determined by the inductive effects originated by the different spatial arrangements of the water molecules in the studied clusters.
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Alzheimer's disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.
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The C-X bond cleavage in different methyl halides (CH3X; X = Cl, Br, I) mediated by 5,6-dimethylbenzimidazole-bis(dimethylglyoximate)cobalt(II) (CoIICbx) was theoretically investigated in the present work. An SN2-like mechanism was considered to simulate the chemical process where the cobalt atom acts as the nucleophile and the halogen as the leaving group. The reaction path was computed by means of the intrinsic reaction coordinate method and analyzed in detail through the reaction force formalism, the quantum theory of atoms in molecules (QTAIM), and the calculation of one-electron density derived quantities, such as the source function (SF) and the spin density. A thorough comparison of the results with those obtained in the same reaction occurring in presence of 5,6-dimethylbenzimidazole-bis(dimethylglyoximate)cobalt(I) (CoICbx) was conducted to reveal the main differences between the two cases. The reactions mediated by CoIICbx were observed to be endothermic and possess higher activation energies in contrast to the reactions where the CoICbx complex is present. The latter was supported by the reaction force results, which suggest a relationship between the activation energy and the ionization potentials of the different nucleophiles present in the cleavage reaction. Moreover, the SF results indicates that the lower axial ligand (i.e., 5,6-dimethylbenzimidazole) exclusively participates on the first stage of the reaction mediated by the CoIICbx complex, while for the CoICbx case, it appears to have an important role along the whole process. Finally, the QTAIM charge analysis indicates that oxidation of the cobalt atom occurs in both cases; at the same time, it suggests the formation of an uncommon two-center one-electron bond in the CoIICbx case. The latter was confirmed by means of electron localization calculations, which resulted in a larger electron count at the Co-C interatomic region for the CoICbx case upon comparison with its CoIICbx counterpart.
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Cobalto , Teoria Quântica , Cobalto/química , Modelos Teóricos , Ligantes , ElétronsRESUMO
A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.
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Antineoplásicos/química , Antineoplásicos/metabolismo , Azóis/química , Azóis/metabolismo , Citotoxinas/química , Citotoxinas/metabolismo , Simulação de Acoplamento Molecular/métodos , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Azóis/síntese química , Azóis/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Receptor alfa de Estrogênio/metabolismo , Humanos , Células MCF-7 , Estrutura Molecular , Células PC-3 , Relação Estrutura-Atividade , Tamoxifeno/metabolismo , Tamoxifeno/farmacologiaRESUMO
BACKGROUND: Redox active metal cations, such as Cu2 +, have been related to induce amyloid plaques formation and oxidative stress, which are two of the key events in the development of Alzheimer's disease (AD) and others metal promoted neurodegenerative diseases. In these oxidative events, standard reduction potential (SRP) is an important property especially relevant in the reactive oxygen species formation. OBJECTIVE: The SRP is not usually considered for the selection of drug candidates in anti-AD treatments. In this work, we present a computational protocol for the selection of multifunctional ligands with suitable metal chelating, pharmacokinetics, and redox properties. METHODS: The filtering process is based on quantum chemical calculations and the use of in silico tools. Calculations of SRP were performed by using the M06-2X density functional and the isodesmic approach. Then, a virtual screening technique (VS) was used for similar structure search. RESULTS: Protocol application allowed the assessment of chelating, drug likeness, and redox properties of copper ligands. Those molecules showing the best features were selected as molecular scaffolds for a VS procedure in order to obtain related compounds. After applying this process, we present a list of candidates with suitable properties to prevent the redox reactions mediated by copper(II) ion. CONCLUSION: The protocol incorporates SRP in the filtering stage and can be effectively used to obtain a set of potential drug candidates for AD treatments.
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Doença de Alzheimer/metabolismo , Quelantes/metabolismo , Química Computacional/métodos , Cobre/metabolismo , Desenho de Fármacos , Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Quelantes/síntese química , Quelantes/uso terapêutico , Cobre/química , Cobre/uso terapêutico , Humanos , Ligantes , OxirreduçãoRESUMO
BACKGROUND: The most important hallmark in the neuropathology of Alzheimer's disease (AD) is the formation of amyloid-ß (Aß) fibrils due to the misfolding/aggregation of the Aß peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aß42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties. OBJECTIVE: To computationally assess the interaction between Aß peptide and a set of curcumin derivatives previously explored in experimental assays. METHODS: The interactions of ten ligands with Aß monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the Aß42 peptide, both in the monomeric and fibril forms. RESULTS: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aß42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aß42 monomers occur in a region critical for peptide aggregation. CONCLUSION: Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aß monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD.
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Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloide/metabolismo , Simulação por Computador , Curcumina/metabolismo , Simulação de Acoplamento Molecular/métodos , Amiloide/química , Peptídeos beta-Amiloides/química , Curcumina/química , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica/fisiologia , Estrutura Secundária de ProteínaRESUMO
A series of Pt(II) complexes of the type [Pt(1,10-phenanthroline)(SArFn)2] (SArFn = SC6H3-3,4-F2(1); SC6F4-4-H (2); SC6F5(3)) were synthesized from [Pt(1,10-phenanthroline)(Cl)2] and [Pb(SArFn)2] via metathesis reactions. The complexes were fully characterized including the unambiguous determination of their molecular structures by single-crystal X-ray diffraction techniques, showing the metal centers to be into a slightly distorted square-planar environments. The in vitro cytotoxic activity of the complexes was evaluated on six cancerous cell lines, i.e: glial cells of nervous central system (U-251), prostate (PC-3), leukemia (K-562), colon (HCT-15), breast (MCF-7) and lung (SKLU-1); we also included a healthy cell line of COS-7 (African green monkey kidney) for comparative purposes. We found that complex 2 was selective for PC-3. In addition, the IC50 values for the series of complexes were determined using the U-251, HCT-15 and SKLU-1 cancerous cell lines, as well as in the healthy cell line (COS-7), where complex 1 exhibited the best activity, with IC50 values going from 4.56 to 4.78 µM. These studies where further complemented with DNA docking theoretical calculations and DNA affinity experiments.