RESUMO
Hydride transfer reactions involving 1,4-dihydropyridines play a central role in bioorganic chemistry as they represent an important share of redox metabolism. For this class of reactions, direct hydride transfer is the commonly accepted mechanism; however, an Alder-Ene-like pathway has been proposed as a plausible alternative. The reaction between 1,4-ditrimethylsilyl-1,4-dihydropyridine and α,ß-unsaturated nitriles is a solid candidate for this latter pathway. In this work, we perform high level ab initio and density functional theory computations to characterize the mechanism of this reaction, taking into account diverse reaction paths, and evaluating the effect of solvent polarity and variations in the chemical structure. Our analysis explains the stereochemical aspects of the reaction, characterizing the up to now unresolved spatial configurations of the predominant products, and may contribute to the understanding of enzymatic reactions involving NADP(H). The reactions are found to proceed in an asynchronous fashion, with transition states that display significant aromatic features. With this observation in mind, Alder-Ene and direct hydride transfer pathways can be understood as two extremes of a continuous mechanistic spectrum for this kind of reaction, with the analyzed systems located approximately equidistant from both ends.
Assuntos
Di-Hidropiridinas , Nitrilas , Nitrilas/química , Di-Hidropiridinas/química , OxirreduçãoRESUMO
Voltage-gated calcium (Cav) channels malfunction may lead to Alzheimer's and cardiovascular disorders, thus a critical protein target for drug development and treatment against several diseases. Indeed, dihydropyridines (DHPs) as nifedipine and amlodipine are top-selling pharmaceuticals and, respectively, the 121st and 5th most prescribed drugs in the United States that have been used as successful selective blockers for L-type Ca2+ channels (LCC) and may be helpful model structures to compare with new DHP analogs. In this context, we have performed a structure-based drug design (SBDD) study of several fluorinated DHPs by using homology modeling, molecular docking, quantitative structure activity relationship (QSAR) and molecular dynamics calculations. Such approaches combined with molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) interaction energy results and screening of ADMET (absorption, distribution, metabolism, excretion and toxicity) properties indicate that all ligands in this study are potential new candidates to be tested experimentally for inhibition of LCC and may have higher affinities than the commonly used drugs, being convenient synthetic routes proposed for 11-16, which are among the ligands that showed the best theoretical results concerning LCC inhibition. Furthermore, the ligand interactions with the binding site were carefully examined using the topological noncovalent interactions (NCI) method, which highlighted specifically responsible amino acid residues that increase the spontaneity of the new proposed DHP ligands.Communicated by Ramaswamy H. Sarma.
Assuntos
Di-Hidropiridinas , Di-Hidropiridinas/química , Canais de Cálcio Tipo L/química , Canais de Cálcio Tipo L/metabolismo , Simulação de Acoplamento Molecular , Nifedipino , Sítios de Ligação , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/metabolismo , Cálcio/metabolismoRESUMO
This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (CI/CII) is particularly large for chloride buffer (CI/CII = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 µm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions.
Assuntos
Di-Hidropiridinas/química , Disponibilidade Biológica , Di-Hidropiridinas/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Tamanho da Partícula , SolubilidadeAssuntos
Doença de Chagas/tratamento farmacológico , Clofazimina/uso terapêutico , Di-Hidropiridinas/uso terapêutico , Nitroimidazóis/uso terapêutico , Tripanossomicidas/uso terapêutico , Animais , Doença de Chagas/patologia , Chlorocebus aethiops , Doença Crônica , Clofazimina/química , Terapia Combinada , Di-Hidropiridinas/química , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C3H , Nitroimidazóis/química , Tripanossomicidas/química , Células VeroRESUMO
Dihydropyridines (DHPs) obtained from Hantzsch multicomponent reactions are an important pharmaceutical class of compounds marketed as antihypertensive (e.g., nifedipine, nitrendipine, and amlodipine) drugs. This study synthesized new symmetrical and unsymmetrical long-chain fatty DHPs using multicomponent reactions under metal-free conditions with sulfamic acid as a catalyst. The DHPs were tested for antioxidant activity using three different methods. The insertion of a long chain into the DHP core contributed to antioxidant potential, and compounds derived from nitro aldehydes have better antioxidant potential than the antihypertensive drug nifedipine. In addition, fatty analogs to nifedipine derived from palmitic and oleic chains showed similar antioxidant activity to the common standards butylated hydroxytoluene and vitamin E. These results showed that our new synthesized products may find novel applications as antioxidant additives or for tools for use in drug discovery.
Assuntos
Antioxidantes/farmacologia , Benzotiazóis/antagonistas & inibidores , Compostos de Bifenilo/antagonistas & inibidores , Di-Hidropiridinas/farmacologia , Picratos/antagonistas & inibidores , Ácidos Sulfônicos/antagonistas & inibidores , Antioxidantes/síntese química , Antioxidantes/química , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Interações Hidrofóbicas e Hidrofílicas , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This study aims to examine the effects of a new 1,4-dihydropyridine derivative, VdiE-2N, on cell signaling pathways and mitochondrial events in head and neck squamous cell carcinoma (HNSCC) cells, and on a mice model of xenograft tumor growth/cell proliferation. Four HNSCC cell lines (HN13, HN12, HN6, and CAL27), HEK293 cells (human embryonic kidney 293 cells), and human oral healthy mucosa fibroblasts (OHMF) were used for in vitro assessment of cell viability (resazurin assay) and invasion capacity (modified Boyden chamber assay), and mitochondrial membrane potential (JC-1 fluorescence assay), morphology (transmission electron microscopy), and number of mitochondria (MitoTracker® imaging). SET and pDRP1 proteins were analyzed by immunofluorescence, and proteins involved in cell death/survival pathways were analyzed by Western blotting. HN12 xenograft tumors were established in the flank of Balb/c nude mice, and their characteristics and sensitivity to VdiE-2N were determined by immunohistochemistry and histology. VdiE-2N decreased cell viability in HNSCC cells (IC50 = 9.56 and 22.45µM for HN13 and HN12 cells, respectively) more strongly than it decreased cell viability in OHMF and HEK293 cells (IC50 = 32.90 and > 50µM, respectively). In HN13 cells, VdiE-2N dissipated mitochondrial membrane potential and altered the mitochondria size, shape, and number in a concentration-dependent manner, as well as it induced apoptosis and reduced their invasion capacity. Treatment of mice bearing xenograft tumors with VdiE-2N significantly diminished proliferation of cancer cells. Therefore, VdiE-2N induces HNSCC cell death in vitro through mitochondria-mediated apoptotic pathways and dampens tumor growth in vivo, thus supporting a potential anti-cancer effect.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/patologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Neoplasias de Cabeça e Pescoço/patologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/irrigação sanguínea , Carcinoma de Células Escamosas/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc/genética , Neoplasias de Cabeça e Pescoço/irrigação sanguínea , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Tamanho Mitocondrial/efeitos dos fármacos , Invasividade Neoplásica , Neovascularização Patológica/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Over the years, with the instrumental analysis evolution, the relationships between the carried-out results with the data of theoretical analysis in silico and the Hammett's parameters have been reported. They have been very useful for chemical characterization of small organic molecules. Thus, this work aims at showing the feasibility and limitations for Hammett's and density functional theory applications in electrospray ionization-collision-induced dissociation (ESI-CID) fragmentation provision. For this, 13 dihydropyrimidinones para, meta, and orto monosubstituted were studied using ESI and CID in positive mode. As a result, it was observed that the main fragmentation includes the isocyanate and ethanol loses at low energy. Nevertheless, at higher energies, radical ions formed by McLafferty rearrangement were observed. The Hammett plots were correlated fragmentation profiles, showing good linearity for the [M + H]+ , which does not occur to radical ions and carbocation's. These tendencies had demonstrated that the stability of protonate and activation energy of secondary ions changes with the pKa. The density functional theory studies indicated that, both nitrogen atoms in the dihydropyrimidinone's prototypes are capable of being protonated. However, the activation energy of fragmentation products is not changed. Therefore, this work has shown information, which can be useful to understand tandem mass spectrometry in ESI-CID conditions for small organic molecules series. This is the first step for normalization of fragmentation pathway.
Assuntos
Di-Hidropiridinas/química , Simulação por Computador , Di-Hidropiridinas/síntese química , Estrutura Molecular , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em TandemRESUMO
The relationship between the chemical structure and biological activity (log IC50) of 40 derivatives of 1,4-dihydropyridines (DHPs) was studied using density functional theory (DFT) and multiple linear regression analysis methods. With the aim of improving the quantitative structure-activity relationship (QSAR) model, the reduced density gradient s( r) of the optimized equilibrium geometries was used as a descriptor to include weak non-covalent interactions. The QSAR model highlights the correlation between the log IC50 with highest molecular orbital energy (E HOMO), molecular volume (V), partition coefficient (log P), non-covalent interactions NCI(H4-G) and the dual descriptor [Δf(r)]. The model yielded values of R 2=79.57 and Q 2=69.67 that were validated with the next four internal analytical validations DK=0.076, DQ=-0.006, R P =0.056, and R N=0.000, and the external validation Q 2boot=64.26. The QSAR model found can be used to estimate biological activity with high reliability in new compounds based on a DHP series. Graphical abstract The good correlation between the log IC50 with the NCI (H4-G) estimated by the reduced density gradient approach of the DHP derivatives.
Assuntos
Anti-Hipertensivos/química , Di-Hidropiridinas/química , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Anti-Hipertensivos/farmacologia , Di-Hidropiridinas/farmacologia , Ligação de Hidrogênio , Conformação Molecular , Estrutura Molecular , Teoria QuânticaRESUMO
Anisotropic and branched gold nanoparticles have great potential in optical, chemical and biomedical applications. However their syntheses involve multi-step protocols and the use of cytotoxic agents. Here, we report a novel one-step method for the preparation of gold nanostructures using only Hantzsch 1,4-dihydropyridines as mild reducing agents. The substituent pattern of the dihydropyridine nucleus was closely related to the ease of formation, morphology and stability of the nanoparticles. We observed nanostructures such as spheres, rods, triangles, pentagons, hexagons, flowers, stars and amorphous. We focused mainly on the synthesis and characterization of well-defined gold nanostars, which were produced quickly at room temperature (25°C) in high yield and homogeneity. These nanostars presented an average size of 68 nm with mostly four or six tips. Based on our findings, we propose that the growth of the nanostars occurs in the (111) lattice plane due to a preferential deposition of the gold atoms in the early stages of particle formation. Furthermore, the nanostars were easily modified with peptides remaining stable for more than six months in their colloidal state and showing a better stability than unmodified nanostars in different conditions. We report a new approach using dihydropyridines for the straightforward synthesis of gold nanostructures with controlled shape, feasible for use in future applications.
Assuntos
Di-Hidropiridinas/química , Ouro/química , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Substâncias Redutoras/química , Nanotecnologia/métodosRESUMO
Dipolar aggregation is in many cases detrimental for the functioning of optical materials. In this study we investigate self-aggregation and optical absorption of stilbazolium merocyanine (SM) in chloroform solution by performing classical Molecular Dynamics (MD) simulations under ambient conditions. The reversal solvatochromic shift, the large bathochromic shift, and the structured absorption band presented by SM in chloroform solution are all aspects of its optical absorption behavior for which the existence of self-aggregation is yet not completely understood. Moreover, the spectroscopic properties of SM oligomers and their occurrence in solvent of low polarity remain a relevant topic that deserves to be investigated. Our analysis of the aggregation behavior of SM in chloroform verified that the majority of the chromophores are involved in the formation of oligomers in solution, where the whole dimer and part of the trimer populations present a stable π-stacking structure. The optical properties of the monomers and oligomers in solution were evaluated by means of a discrete polarizable embedding quantum mechanical/molecular mechanical (PE-QM/MM) response scheme where the quantum part is described at the level of density functional theory. The visible absorption spectrum of SM in chloroform is simulated using time average values obtained for the monomeric and oligomeric forms of SM from the PE-QM/MM calculations performed on uncorrelated configurations extracted from the classical MD simulations. This study shows that the self-aggregation of SM in chloroform may exist, but it is not essential for reproducing the reversal solvatochromic shift in chloroform and that the process does not contribute to enhance the bathochromic shift nor explain the structure observed in its absorption band. Moreover, it is verified that since the electronic transitions of the monomer and oligomers are close together, changes in the interplane separation between the monomeric units of the stacked oligomers substantially affect the spectral resolution of their contribution to the optical absorption spectrum.