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

The Journal of Physical Chemistry A

ARTICLE

Scheme 1

In this work, a set of Cu(II)-containing complexes based on

ligands previously reported by some of us

and that include

diﬀerent aromatic features have been studied by means of density

functional theory (DFT) calculations. These ligands that are

based on the main structural and aromatic features of thioﬂavin-T

(ThT) and the metal-chelating properties of clioquinol (HCQ),

ÀOH1), 2-(2-hydroxy-

are 2-(2-hydroxyphenyl)benzoxazole (N

phenyl)benzothiazole (N

-OH1) and 2-(2-hydroxyphenyl)-

1H-benzimidazole (N

-H1) (see Scheme 1). The complexes

formed with these ligands exhibit two metalated rings that may

manifest aromatic properties. The π electrons of each metalla-

cycle, however, contribute at the same time to the π-electron

system of the aromatic rings belonging to the ligands. To analyze

how this fact inﬂuences the metalloaromaticity and the complex

stability, we have performed calculations for [Cu(L)

] complexes

ÀOH1,

with diﬀerent ligands derived from the previous ones (N

X = O, S, NH) by sequentially removing the aromatic moieties

deﬁned as “a”, “b” and “c” in Scheme 1. These ligands will be

ÀOHn (n = 2, 3, and 4). The chelating

hereafter referred to as N

properties of the ligands toward Cu(II) have been assessed by

calculating the stability constants of the complexes and by a detailed

analysis of the metalÀligand bonding through diﬀerent aromaticity

criteria.

’ METHODS

Full geometry optimizations and harmonic frequency calcula-

tions were performed using DFT with the nonlocal hybrid

39,40

B3LYP

functional, a well-tested functional that has been

successfully used for a wide variety of systems, including open-

shell Cu(II) complexes with saturated coordination environ-

41À43

ments and similar spin density distributions.

Additionally,

our previous study

on the chelating properties of diﬀerent

ligands toward Cu(II) and Zn(II) showed good agreement with

residues or from the carbonyl group of the peptide backbone may

the observed experimental trends. All calculations were carried

23À32

be involved in the coordination sphere.

Therefore, it is not

out using the following basis sets: For Cu, we used the Watcher’s

surprising that among the various chelating agents studied to

primitive set (14s9p5d),

supplemented with one s, two p, and

and one f polarization function, the ﬁnal

date, clioquinol (HCQ, 5-chloro-7-iodo-8-hydroxyquinoline),

one d diﬀuse function

containing N and O chelating atoms, has proven to be particu-

basis set being (15s11p6d1f)/[10s7p4d1f]; for iodine, we used

larly eﬀective not only in experiments in vitro on brain tissue but

the quasi-relativistic eﬀective core potential (ECP) of Hay and

also in preliminary clinical studies.

Although the observed

Wadt

to represent the innermost electrons and the standard

toxicity has prevented further clinical trials, the results obtained

double-ζ LANL2DZ set associated to the ECP for the valence

have turned the rational design of new chelators into a very active

and outermost core orbitals; and for H, C, N, O, and S, we used

area of research, in which in silico strategies can play a very

the standard 6-31++G(d,p) basis set. Thermodynamic correc-

important role.

In particular, the combination of virtual screen-

tions have been obtained assuming an ideal gas, unscaled

ing methods with quantum chemical calculations appears to be a

harmonic vibrational frequencies, and the rigid rotor approxima-

promising protocol to design new metal chelating ligands with

tion by standard statistical methods.

Solvation eﬀects were

the desired properties for application in neurodegenerative diseases.

modeled through single-point energy calculations at the same

Virtual screening enables us to identify commercial compounds

level of theory, with water as solvent, using the self-consistent

ﬁeld polarizable continuum model, COSMO.

48,49

that enclose the desired molecular framework and include the

To compute

proper pharmacokinetic properties, whereas quantum chemical

the free energy of the [Cu(H

]

+ 2HL f [Cu(L)

] +

calculations provide information on the electronic and molecular

O + 2H

reaction in water solution (ΔG

), we have

sol

structure of the coordinating complexes as well as on the metal

followed the strategy adopted by some of us in previous

33,50

binding aﬃnity.

works

using the experimental free energy values for the

À1 51

= À6.31 kcal mol

Most of the metal chelators that fulﬁll the proper pharmaco-

solvation of water and H

(ΔG

Solv(H

À1

and ΔG

= À265.9 kcal mol

kinetic properties for their potential use in AD disease, such as

respectively). Because

Solv(H

)

crossing the blood brain barrier (BBB), contain aromatic moi-

this reaction occurs in solution, the entropy obtained in gas phase

eties. Upon coordination, these ligands can lead to the formation

was converted from 1 atm to 1 M by subtracting the R ln(V1/V2)

À1

34À37

of metalated rings with aromatic properties,

which may

cal K

mol

term to account for the volume change between

exert some eﬀect on the stability of the complexes formed, hence

the two states at 298 K.

Also, the term of RT ln(55.6) was

added to the ΔG

inﬂuencing the eﬀectiveness of the chelating ligands to remove

term because liquid water concentra-

Solv(H

metal ions in Aβ deposits.

tion is 55.6 M. Further details are available in the Supporting

12660

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

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