Interaction studies of oxindole-derivatives with ß-amyloid peptides inhibiting its aggregation induced by metal ions.

Some hydrazones and Schiff bases derived from isatin, an endogenous oxindole formed in the metabolism of tryptophan, were obtained to investigate their effects on in vitro aggregation of ß-amyloid peptides (Aß), macromolecules implicated in Alzheimer's disease. Some hydrazone ligands, prepared by condensation reactions of isatin with hydrazine derivatives, showed a large affinity binding to the synthetic peptides Aß, particularly to Aß1-16. Measurements by NMR spectroscopy indicated that those interactions occur mainly at the metal binding site of the peptide, involving His6, His13, and His14 residues, and that hydrazone E-diastereoisomer interacts preferentially with the amyloid peptides. Experimental results were consistent with simulations using a docking approach, where it is demonstrated that the amino acid residues Glu3, His6, His13, and His14 are those that mostly interact with the ligands. Further, these oxindole-derived ligands can efficiently chelate copper(II) and zinc(II) ions, forming moderate stable [ML] 1:1 species. The corresponding formation constants were determined by UV/Vis spectroscopy, by titrations of the ligands with increasing amounts of metal salts, and the obtained log K values were in the range 2.74 to 5.11. Both properties, good affinity for amyloid peptides, and reasonably good capacity of chelating biometal ions, like copper and zinc, can explain the efficient inhibition of Aß fragments aggregation, as shown by experiments carried out with the oxindole derivatives in the presence of metal ions.

Magnetic particles for enzyme immobilization: A versatile support for ligand screening.

Enzyme inhibitors represent a substantial fraction of all small molecules currently in clinical use. Therefore, the early stage of drug-discovery process and development efforts are focused on the identification of new enzyme inhibitors through screening assays. The use of immobilized enzymes on solid supports to probe ligand-enzyme interactions have been employed with success not only to identify and characterize but also to isolate new ligands from complex mixtures. Between the available solid supports, magnetic particles have emerged as a promising support for enzyme immobilization due to the high superficial area, easy separation from the reaction medium and versatility. Particularly, the ligand fishing assay has been employed as a very useful tool to rapidly isolate bioactive compounds from complex mixtures, and hence the use of magnetic particles for enzyme immobilization has been widespread. Thus, this review provides a critical overview of the screening assays using immobilized enzymes on magnetic particles between 2006 and 2021.

Anticancer Compounds Based on Isatin-Derivatives: Strategies to Ameliorate Selectivity and Efficiency.

In this review we compare and discuss results of compounds already reported as anticancer agents based on isatin-derivatives, metalated as well as non-metallated. Isatin compounds can be obtained from plants, marine animals, and is also found in human fluids as a metabolite of amino acids. Its derivatives include imines, hydrazones, thiosemicarbazones, among others, already focused on numerous anticancer studies. Some of them have entered in pre-clinical and clinical tests as antiangiogenic compounds or inhibitors of crucial proteins. As free ligands or coordinated to metal ions, such isatin derivatives showed promising antiproliferative properties against different cancer cells, targeting different biomolecules or organelles. Binding to metal ions usually improves its biological properties, indicating a modulation by the metal and by the ligand in a synergistic process. They also reveal diverse mechanisms of action, being able of binding DNA, generating reactive species that cause oxidative damage, and inhibiting selected proteins. Strategies used to improve the efficiency and selectivity of these compounds comprise structural modification of the ligands, metalation with different ions, syntheses of mononuclear and dinuclear species, and use of inserted or anchored compounds in selected drug delivery systems.