RESUMO
In this work, the reactions of quadricyclane with dimethyl azodicarboxylate (DMAD) and of quadricyclane with diethyl azodicarboxylate (DEAD) in gas phase and in water environments were studied by a first-principles investigation within the framework of auxiliary density functional theory (ADFT). For these type of organic reactions is known that water is required to accelerate them. Since the reason of why this occur is still unknown, this work aims to gain insight into this reaction mechanism. For this investigation, the generalized gradient approximation as well as a hybrid functional were employed. The obtained optimized structures for the reactants, of the products and of the transition states are reported, together with the corresponding frequency analysis results and the reaction profiles. Along the proposed concerted reaction mechanism, a critical points search of the electron density and a charge analysis were performed. The calculated potential energy barriers of these reactions in gas phase and in water environments are compared. In agreement with experiment, the obtained results indicate that both reactions occur faster in water than in gas phase. This study shows that there is a change in the polarity of the two most important carbon atoms of the formed compounds along the reactions and that the decrease of the activation energy barrier which occurs in liquid phase in these reactions is because the structures of the main transition states are stabilized by the water environment. Therefore, the here obtained results demonstrate the important role played by the water-molecule framework into the activation energy barrier and structures of the molecules that participate in the DMAD and DEAD cycloaddition reactions.
RESUMO
Among the many methods available for accessing conformationally diverse cyclic peptides, the derivatization of macrocyclic iminopeptides has remained notably underexplored. Now, a relevant complexity-generating method expands the repertoire of synthetic strategies exploiting the reactivity of an imino bond embedded in the cyclic peptide skeleton. Here we highlight a recent report describing the on-resin construction of a new family of macrocyclic peptide/natural product-inspired hybrids, namely "PepNats", by derivatization of cyclic iminopeptides through 1,3-cycloaddition reactions. A proof-of-concept with PepNats bearing peptide sequences that mimic protein hot loops demonstrated the potential of this strategy to create novel macrocyclic peptide ligands capable of modulating protein-protein interactions.
Assuntos
Produtos Biológicos/química , Iminas/química , Compostos Macrocíclicos/química , Peptídeos/química , Proteínas/química , Produtos Biológicos/metabolismo , Iminas/metabolismo , Ligantes , Compostos Macrocíclicos/metabolismo , Conformação Molecular , Peptídeos/metabolismo , Ligação ProteicaRESUMO
A small and focused library of steroidal non-fused and fused pyrimidines was prepared from pregnenolone acetate and diosgenin, respectively. The key step was the cycloaddition reaction of nitrogen-containing 1,3-binucleophiles with the steroidal α,ß-unsaturated ketone. Urea, thiourea and guanidine reacted in a similar manner and afforded the steroidal pyrimidines in good yields. The antiproliferative tests against human tumor cell lines gave GI50 values in the micromolar range and had no effect on healthy fibroblasts. Additional experiments indicated that the compounds did not act as P-glycoprotein substrates, thus avoiding the rise of drug resistance. The fused steroidal pyrimidinethione was selected as drug lead for further testing due to its strong antiproliferative activities within the low micromolar range.
Assuntos
Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Pirimidinas/farmacologia , Esteroides/farmacologia , Acetatos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Nitrogênio/química , Pregnenolona/química , Pirimidinas/síntese química , Pirimidinas/química , Esteroides/síntese química , Esteroides/química , Relação Estrutura-AtividadeRESUMO
Epoxide of oestradiol is one of the main risk factors for the genesis and evolution of breast cancer; hence, in recent years there has been considerable interest in the investigation of new inhibitors capable of reducing its carcinogenic activity. The aim of this article is to study the [2 + 2] cycloaddition reaction of epoxide of oestradiol in different pristine (C76 and D5h-C80) and endohedral metallofullerene (C72@Sc2C2, C76@Sc2 and C80@Sc2) by means of molecular electrostatic potential (MEP) topological analysis. Different from other molecular scalar fields, MEP topology enables to find minima related to lone pairs and π electrons, therefore, this molecular scalar field is appropriate to identify the most reactive sites. In consonance with our results, it was found that C80 was the best candidate to carry out the epoxide of oestradiol cycloaddition since more stable adducts were obtained. Furthermore, it is expected that more than one oestradiol epoxide molecule will be added to C80, forasmuch as C80 reactivity is enhanced once the adduct is formed. The study was carried through DFT framework included in the Gaussian 09 package (MPWB95/6-31G(d,p)).
Assuntos
Antineoplásicos/química , Antineoplásicos/síntese química , Fulerenos/química , Animais , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Chemical and pharmacological information on cantharidin-based small molecules was analyzed. The review summarizes new facts about blister beetles' metabolites for the period 2006-2012. General synthetic approaches to cantharidin-based small molecules as well as their chemical transformations and biological activities related to cantharidin, norcantharidin, cantharidimide, and norcantharimide analogs, especially their inhibitory activity of phosphoprotein phosphatases in cancer treatment, were discussed in this mini review, which could help to design new small molecule modulators for other biological models.