We analyzed the conformational plasticity of calmodulin (CaM) when it is bound to the oedema factor (EF) of Bacillus anthracis and its response to calcium complexation with molecular dynamics (MD) simulations. The EF-CaM complex was simulated during 15 ns for three different levels of calcium bound to CaM. They were respectively no calcium ion (EF-(Apo-CaM)), two calcium ions bound to the C-terminal domain of CaM (EF-(2Ca-CaM)), and four calcium ions bound to CaM (EF-(4Ca-CaM)). Calculations were performed using AMBER package. The analysis of the MD simulations illustrates how CaM forces EF in an open conformation to form the adenylyl cyclase enzymatic site, especially with the two calcium form of CaM, best suited to fit the open conformation of EF. By contrast, CaM encounters bending and unwinding of its flexible interlinker in EF-(Apo-CaM) and EF-(4Ca-CaM). Calcium binding to one domain of CaM affects the other one, showing a transmission of information along the protein structure. The analysis of the CaM domains conformation along the simulations brings an atomistic and dynamic explanation for the instability of these complexes. Indeed the EFhand helices of the N-terminal domain tend to open upon calcium binding (EF-(4Ca-CaM)), although the domain is locked by EF. By contrast, the C-terminal domain is strongly locked in the open conformation by EF, and the removal of calcium induces a collapse of EF catalytic site (EF-(Apo-CaM)).
Substituent effects are widely used to investigate the factors affecting carbon‐13 chemical shifts. Adamantane and its derivatives are convenient probes for relative contributions to these factors owing to their symmetry and relative absence of ring strain. We have extended our studies on NMR chemical shifts of 1‐ and 2‐methyladamantanes to hydroxy, bromo, methoxy and acetamide substituents and also certain disubstituted (one of the groups being methyl) analogs. DFT/GIAO calculations at the B3LYP/6–31G(d,p) level show that, except for α‐effects, steric interactions are mainly responsible for substituent effects on chemical shifts. The CHARGE program is particularly well suited for localizing these effects and estimating their approximate shape and range.
Recebido em 30/11/06; aceito em 16/3/07; publicado na web em 9/11/07 CAMPHOR: A GOOD MODEL FOR ILLUSTRATING NMR TECHNIQUES. The use of Nuclear Magnetic Resonance spectroscopy to establish the three-dimensional structures of molecules is an important component of modern Chemistry courses. The combination of techniques that can be used for this purpose is conveniently illustrated by their application to the camphor molecule. This paper presents applications of several techniques used in NMR spectral interpretation in an increasing order of complexity. The result of individual experiments is illustrated in order to familiarize the user with the way connectivity through bonds and through space is established from 1D/2D-NMR spectra and molecular stereochemistry is determined from different NMR experiments.Keywords: organic chemistry; NMR spectroscopy; camphor.
INTRODUÇÃOA cânfora (Figura 1) é uma cetona terpenóide obtida da árvore cânfora, encontrada no Oriente e na América do Sul, e representa uma classe de compostos bioativos que são sintetizados por plantas. É um bom exemplo de molécula utilizada no cotidiano que pode servir para induzir estudantes de química a exercitar seu raciocínio 1 na identificação de monoterpenos desconhecidos por Ressonância Magnética Nuclear (RMN) 2 . A cânfora tem um cheiro forte e penetrante, gosto amargo e é ligeiramente fria ao tato. Ela tem se revelado como excelente excitante em casos de parada cardíaca causada por doenças ou resultantes de febres infecciosas, tais como tifóide e pneumonia. A cânfora é utilizada internamente por sua influência calmante em histeria, nervosismo e neuralgia, e para diarréia, e externamente em reumatismos, bronquites e condições inflamatórias. É largamente empregada contra gripes, resfriados e complicações inflamatórias 3 . Além disso, tem largo uso como incenso, anti-sépti-co e sedativo em problemas genital-urinários. É também usada na fabricação de nitrocelulose, materiais plásticos, produtos químicos e repelentes para insetos 4 . Seu preço modesto, fácil acesso e baixa toxicidade (LD 50 em ratos: 3000 mg/kg) 5 permite sua manipulação em sala de aula sem maiores cuidados.A estrutura molecular da cânfora foi determinada em uma épo-ca em que estudos de determinação estrutural eram inteiramente baseados em reações químicas, geralmente aquelas em que certas ligações no composto eram quebradas, dando origem a compostos sucessivamente mais simples, e cada qual era isolado, purificado e analisado. Estas seqüências de reações eventualmente levavam a substâncias de estruturas conhecidas e o caminho de volta aos compostos originais era estabelecido pelo conhecimento de mudanças estruturais que se tinha sobre uma reação particular 6 . A estrutura da cânfora foi particularmente difícil de ser determinada porque sistemas de anéis bicíclicos eram previamente desconhecidos e passavam por rearranjo de carbocátions, o que era uma dificuldade para os primeiros trabalhos na área daqueles que tentavam determinar suas respectivas estruturas 7 . A cânfora é um bom modelo p...
With the aim of discovering new anticancer agents, we have designed and synthesized novel 6-hydroxy-benzo[d][1,3]oxathiol-2-one Schiff bases. The synthesis started with the selective nitration at 5-position of 6-hydroxybenzo[d][1,3]oxathiol-2-one (1) leading to the nitro derivative 2. The nitro group of 2 was reduced to give the amino intermediate 3. Schiff bases 4a–r were obtained from coupling reactions between 3 and various benzaldehydes and heteroaromatic aldehydes. All the new compounds were fully identified and characterized by NMR (1H and 13C) and specifically for 4q by X-ray crystallography. The in vitro cytotoxicity of the compounds was evaluated against cancer cell lines (ACP-03, SKMEL-19 and HCT-116) by using MTT assay. Schiff bases 4b and 4o exhibited promising cytotoxicity against ACP-03 and SKMEL-19, respectively, with IC50 values lower than 5 μM. This class of compounds can be considered as a good starting point for the development of new lead molecules in the fight against cancer.
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