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Ab Initio Design of Chelating Ligands Relevant to Alzheimer’s Disease:

Influence of Metalloaromaticity

†

‡

Albert Rimola,

Jorge Alí-Torres,

Cristina Rodríguez-Rodríguez,

Jordi Poater,

Eduard Matito,

‡

,†

Miquel Sola,

and Mariona Sodupe*

†

Departament de Química, Universitat Autonoma de Barcelona, 08193 Bellaterra, Catalonia, Spain

‡

Institut de Química Computacional and Departament de Química, Universitat de Girona, Campus de Montilivi, 17071 Girona,

Catalonia, Spain

Institute of Physics, University of Szczecin, 70-451 Szczecin, Poland

Supporting Information

ABSTRACT:

Evidence supporting the role of metal ions in

Alzheimer’s disease (AD) has rendered metal ion chelation as a

promising therapeutic treatment. The rational design of eﬃ-

cient chelating ligands requires, however, a good knowledge of

the electronic and molecular structure of the complexes formed.

In the present work, the coordinative properties of a set of

chelating ligands toward Cu(II) have been analyzed by means of

DFT(B3LYP) calculations. Special attention has been paid to

the aromatic behavior of the metalated rings of the complex and its inﬂuence on the chelating ability of the ligand. Ligands

considered have identical metal binding sites (through N/O coordination) and only diﬀer on the kind and size of the aromatic

moieties. Results indicate that there is a good correlation between the stability constants (log β

) and the degree of

metalloaromaticity determined through the I

and HOMA indices; that is, the higher the metalloaromaticity, the larger the log

value. MOs and aromaticity descriptors conﬁrm that present complexes exhibit Mobius metalloaromaticity. Detailed analysis of

the nature of the Cu(II)-ligand bonding, performed through an energy decomposition analysis, indicates that ligands with less

aromatic moieties have the negative charge more localized in the metalated ring, thus increasing their σ-donor character and the

metalloaromaticity of the complexes they form.

’ INTRODUCTION

leading to an extensive oxidative damage in the brain that causes

11À16

the neuronal cell loss in AD.

Excellent reviews on the

The Alzheimer’s disease (AD) is nowadays the most common

chemistry of AD and on the role of metal ions have recently been

form of neurodegenerative dementia and a major health concern

11,17

published.

to our society.

It is characterized by a progressive loss of neuronal

On the basis of the stated above, one of the potential

abilities, and its hallmarks are intracellular neuroﬁbrillary tangles

antiamyloid aggregation therapeutic approach consists of the

2,3

and extracellular amyloid deposits or senile plaques.

These

treatment with metal-complexing agents to solubilize the toxic

plaques are formed by the aggregation of amyloid-beta peptide

18À20

deposits of Aβ peptides.

In the metal-ion chelation therapy,

(Aβ), a 39- to 42-residue fragment cleaved from the much larger

however, the chosen chelators should exhibit an adequate metal

amyloid precursor protein (APP). The main alloforms of Aβ

aﬃnity to sequester the metal ion from the metalÀprotein complex

found in brain plaques are 40 and 42 amino acids long, the Aβ42

but not high enough to cause its removal from an essential metal

being the least soluble and the one that displays enhanced

site; that is, they should act as metal-protein attenuating com-

neurotoxicity.

21,22

pounds (MPAC).

Although the coordination environment

The origin and mechanism of the Aβ aggregation is still not

of Cu(II) in Cu(II)-Aβ is controversial and pH-dependent, EPR

clearly understood, and multiple factors have been reported as

and NMR experiments revealed that the N atoms from His6,

triggering their formation. In particular, analysis of post-mortem

His13, and His14 residues, NH

terminus, or the amide peptide

brain tissues shows high concentrations (about millimolars) of

backbone as well as O atoms from carboxylate groups of diﬀerent

Fe(III), Cu(II), and Zn(II) transition-metal ions in AD plaques,

thereby suggesting that Aβ aggregation could be mediated by

4À8

some of these essential ions.

Indeed, in vitro studies revealed

Special Issue:

A: Richard F. W. Bader Festschrift

that Cu(II) forms a high-aﬃnity complex with the Aβ peptide,

which, in turn, may induce its aggregation and the formation

Received:

April 13, 2011

of ﬁbrils. Additionally, the Cu(II)ÀAβ complex can also parti-

Revised:

May 24, 2011

9,10

June 23, 2011

cipate in the generation of reactive oxygen species (ROS),

Published:

12659

r 2011 American Chemical Society

J. Phys. Chem. A 2011, 115, 12659–12666

Ab Initio Design Of Chelating Ligands Relevant To Alzheimer'S Disease: Influence Of Metalloaromaticity - Physical Chemisrty

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