RESUMO
An amyloidogenic peptide, amyloid-ß (Aß), has been implicated as a contributor to the neurotoxicity of Alzheimer's disease (AD) that continues to present a major socioeconomic burden for our society. Recently, the use of metal complexes capable of cleaving peptides has arisen as an efficient tactic for amyloid management; unfortunately, little has been reported to pursue this strategy. Herein, we report a novel approach to validate the hydrolytic cleavage of divalent metal complexes toward two major isoforms of Aß (Aß40 and Aß42) and tune their proteolytic activity based on the choice of metal centers (M = Co, Ni, Cu, and Zn) which could be correlated to their anti-amyloidogenic properties. Such metal-dependent tunability was facilitated employing a tetra-N-methylated cyclam (TMC) ligand that imparts unique geometric and stereochemical control, which has not been available in previous systems. Co(II)(TMC) was identified to noticeably cleave Aß peptides and control their aggregation, reporting the first Co(II) complex for such reactivities to the best of our knowledge. Through detailed mechanistic investigations by biochemical, spectroscopic, mass spectrometric, and computational studies, the critical importance of the coordination environment and acidity of the aqua-bound complexes in promoting amide hydrolysis was verified. The biological applicability of Co(II)(TMC) was also illustrated via its potential blood-brain barrier permeability, relatively low cytotoxicity, regulatory capability against toxicity induced by both Aß40 and Aß42 in living cells, proteolytic activity with Aß peptides under biologically relevant conditions, and inertness toward cleavage of structured proteins. Overall, our approaches and findings on reactivities of divalent metal complexes toward Aß, along with the mechanistic insights, demonstrate the feasibility of utilizing such metal complexes for amyloid control.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Compostos Heterocíclicos/farmacologia , Metais Pesados/farmacologia , Compostos Organometálicos/farmacologia , Peptídeos beta-Amiloides/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Hidrólise , Metais Pesados/química , Estrutura Molecular , Compostos Organometálicos/químicaRESUMO
Metal(TMC) complexes (TMC = tetramethylcyclam) exclusively form trans-I diastereoisomers; thus, little is known about the trans-III isomers. Herein, we report a new method to prepare the trans-III-[Cu(TMC)]2+ complex via an anion effect. Our crystallographic, spectroscopic, and computational analyses validated that [Cu(TMC)](NO3)2 produced the trans-III complex, different from the trans-I structure of [Cu(TMC)](ClO4)2.