Multinuclear Supramolecular Complexes:Self-assembly And Its Inhibition To Aβ Protein Aggregation

Protein is the material basis of life phenomena and the main carrier of life activities.Among them,amyloid-β(Aβ)has attracted extensive attention due to the aggregation in and out of cells,which leads to Alzheimer’s disease.At present,supramolecular self-assembly complexes have attracted much attention in the field of bioinorganic chemistry due to their structural diversity and functionality,and more pertinence in design and development.In this paper,we aimed to design and synthesize novel multinuclear supramolecular complexes that can effectively inhibit Aβ aggregation,and to further explore the influence of various structural factors of the complexes on its inhibitory ability.Mainly from the following three aspects:1.The inhibitory effect and structure-activity relationship of binuclear supramolecular complexes on amyloid-β aggregation were firstly studied.A series of binuclear supramolecular complexes(1-4)with Fe(II)or Ni(II)as the metal centers were designed and synthesized.The X-ray single crystal diffraction confirmed the successful synthesis of complexes 1-4 and the relevant molecular data were obtained.The interactions and mode of action between binuclear supramolecular complexes and amyloid-β were studied by circular dichroism(CD),atomic force microscope(AFM)and fluorescence spectrophotometry.The results showed that the binuclear supramolecular complexes have certain effects on the secondary structure of Aβ protein,which could effectively inhibit the aggregation,and the metal center ion species have certain effects on its performance.At the same time,the pyridine ring-containing complexes 1-2 had better inhibition ability than the imidazole ring-containing complexes 3-4,indicating that the inhibition capacity of the binuclear supramolecular complexes was affected by the ligand structures and the metal center ion species,and none of them could play a decisive role.2.The inhibitory effect and structure-activity relationship of trinuclear supramolecular complexes on Aβ aggregation were investigated.By controlling the "distance" between two nitrogen atoms in the raw material amine,the number of crystal nucleus is controlled,and a series of trinuclear supramolecular complexes 5-7 were synthesized with Fe(II)or Ni(II)as the metal center.These exact structures and associated crystal data of the complexes were obtained by various characterization methods and X-ray single crystal diffraction tests.Studies with the interactions of Aβ protein showed that complexes 5-7 had good inhibitory effects on Aβ aggregation,but did not show more advantages than binuclear supramolecular complexes 1-4.Considering their structural characteristics(abandoning the aromatic groups and increasing the charges),it is indicated that the electrostatic interaction and π-π stacking have great effects on the binding mechanism.In addition,compared with the dependence of chiral supramolecular complexes on ligand structure and metal central ion species,the chiral characteristic has more influence on the regulation of complexes inhibitory ability.3.The inhibitory effect and structure-activity relationship of tetranuclear supramolecular enantiomeric complexes on amyloid-β aggregation were explored.With Ni(II)as the metal center,the length of the alkyl chain was adjusted to regulate the molecular size of the complexes,and the chiral characteristic was introduced to synthesize a series of tetranuclear supramolecular enantiomeric complexes 8-11 with tetrahedral configurations,which were characterized by X-ray single crystal diffraction and other spectral features.Studies of interactions with Aβ protein showed that complexes 8-11 had excellent inhibitory properties,and the binding ratio was 1:1.This is mainly due to their larger space size,more charged numbers,and larger π-π stacking interactions.At the same time,the molecular size of the complexes is closely related to their inhibitory ability.As the size of the complexes increased,the inhibition capacity increased gradually in this paper.Moreover,the S configuration complexes have better inhibitory performance in each pair of enantiomers,and indicate that the tetranuclear supramolecular enantiomers have chiral selective effects on the inhibition of Aβ aggregation.