ABSTRACT
Amyloid fibroproliferation leads to organ damage and is associated with a number of neurodegenerative diseases affecting populations worldwide. There are several ways to protect against fibril formation, including inhibition. A variety of organic compounds based on molecular recognition of amino acids within the protein have been proposed for the design of such inhibitors. However, the role of macrocyclic compounds, i.e., thiacalix[4]arenes, in inhibiting fibrillation is still almost unknown. In the present work, the use of water-soluble thiacalix[4]arene derivatives for the inhibition of hen egg-white lysozyme (HEWL) amyloid fibrillation is proposed for the first time. The binding of HEWL by the synthesized thiacalix[4]arenes (logKa = 5.05-5.13, 1:1 stoichiometry) leads to the formation of stable supramolecular systems capable of stabilizing the protein structure and protecting against fibrillation by 29-45%. The macrocycle conformation has little effect on protein binding strength, and the native HEWL secondary structure does not change via interaction. The synthesized compounds are non-toxic to the A549 cell line in the range of 0.5-250 µg/mL. The results obtained may be useful for further investigation of the anti-amyloidogenic role of thiacalix[4]arenes, and also open up future prospects for the creation of new ways to prevent neurodegenerative diseases.
Subject(s)
Carboxylic Acids , Muramidase , Muramidase/chemistry , Humans , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Animals , A549 Cells , Amyloid/chemistry , Amyloid/metabolism , Amyloid/antagonists & inhibitors , Protein Binding , Phenols/chemistry , Phenols/pharmacology , Calixarenes/chemistry , Calixarenes/pharmacology , SulfidesABSTRACT
The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the synthesis of 3-N'-arylaminophenothiazines and asymmetrical 3,7-di(N'-arylamino)phenothiazines. This approach included the optimization of synthetic strategy by quantification analysis of the positive charge distribution in the cation of 3-N'-arylaminophenothiazine derivative. The obtained experimental data are confirmed by DFT studies. Two synthetic routes for asymmetrical phenothiazine diarylamino derivatives were suggested and verified. The developed convenient and versatile synthetic approach makes it easy to obtain aromatic Methylene Blue isostructural analogues with various substituents. As a result, a series of novel 3-N'-arylaminophenothiazines and asymmetrical 3,7-di(N'-arylamino)phenothiazines containing ester, tert-butoxycarbonyl, sulfonic acid, hydroxyl and amine groups were obtained in high yields.
Subject(s)
Antipsychotic Agents , Methylene Blue , Methylene Blue/chemistry , Phenothiazines/chemistryABSTRACT
For the first time, a series of catechol-containing Schiff bases, tetrasubstituted at the lower rim thiacalix[4]arene derivatives in three stereoisomeric forms, cone, partial cone, and 1,3-alternate, were synthesized. The structure of the obtained compounds was proved by modern physical methods, such as NMR, IR spectroscopy, and HRMS. Selective recognition (Kb difference by three orders of magnitude) of copper (II) cation in the series of d-metal cations (Cu2+, Ni2+, Co2+, Zn2+) was shown by UV-vis spectroscopy. Copper (II) ions are coordinated at the nitrogen atom of the imine group and the nearest oxygen atom of the catechol fragment in the thiacalixarene derivatives. High thermal stable organic-inorganic copper-based materials were obtained on the base of 1,3-alternate + Cu (II) complexes.
