Structure-based design, synthesis and antitumoral evaluation of enulosides.

Enulosides, carbohydrate derivatives containing an α,ß-unsaturated carbonyl unit, were designed and obtained in high yields and isomeric purity. All synthesized compounds exhibited antitumoral activity in micromolar range against four tested tumor cells lines, being the best results observed for HL-60 cells. These compounds open new possibilities to prepare an array of more active, site-specific or selective antitumor agents. 2016 Elsevier Ltd. All rights reserved.

QM/MM simulations of amyloid-ß 42 degradation by IDE in the presence and absence of ATP.

The ability of the insulin-degrading enzyme (IDE) to degrade amyloid-ß 42 (Aß42), a process regulated by ATP, has been studied as an alternative path in the development of drugs against Alzheimer's disease. In this study, we calculated the potential of mean force for the degradation of Aß42 by IDE in the presence and absence of ATP by umbrella sampling with hybrid quantum mechanics and molecular mechanics (QM/MM) calculations, using the SCC-DFTB QM Hamiltonian and Amber ff99SB force field. Results indicate that the reaction occurs in two steps: The first step is characterized by the formation of the intermediate. The second step is characterized by breaking the peptide bond of the substrate, the latter being the rate-determining step. In our simulations, the activation energy barrier in the absence of ATP is 15 ± 2 kcal mol(-1), which is 7 kcal mol(-1) lower than in the presence of ATP, indicating that the presence of the nucleotide decreases the reaction rate by about 10(5) times.

Molecular dynamics simulations reveal a novel mechanism for ATP inhibition of insulin degrading enzyme.

Regulation of brain levels of the Amyloid-ß 42 (Aß42) polypeptide by IDE has recently been linked with possible routes for new therapies against Alzheimer's disease (AD). One important aspect is the regulatory mechanism of IDE by ATP, which is an IDE activator in degrading small peptides and an inhibitor in degrading larger peptides, such as Aß42. This relationship was investigated in this study. We present molecular dynamics simulations of Aß42 complexed with IDE, in the absence or presence of either ATP or excess Na(+) and Cl(-) ions. Results suggest a previously unreported inhibition mechanism that depends on charge-induced structural modifications in the active site and interactions simultaneously involving ATP, Aß42, and IDE. Such interactions exist only when both ATP and Aß42 are simultaneously present in the catalytic chamber. This mechanism results in allosteric, noncompetitive inhibition with apparent decrease of substrate affinity, in accordance with experiment.

Synthesis and evaluation of (-)-Massoialactone and analogues as potential anticancer and anti-inflammatory agents.

(-)-Massoialactone, an α,ß-unsaturated δ-lactone isolated from Cryptocarya massoia, and five analogues were synthesized and their antiproliferative and anti-inflammatory activities were evaluated. The lactones were able to mimic the "core" functional group required for the biological activity of their parent natural compounds suggesting that substantially altered analogues may retain their properties.