A gold(III) complex and a tetrachloroaurate salt of the neuroepileptic drug gabapentin

Article abstract of DOI:10.1016/j.inoche.2011.01.017

Gabapentin (2-[1-(aminomethyl)cyclohexyl] acetic acid, Gp), a neuroepileptic drug, has been the subject of renewed interest in the past decade. In order to exploit the therapeutic potential of Gp several metal complexes of Gp have been investigated. In this paper we report on the preparation of a novel, unusually stable Au(III)-gabapentin complex, [Au(Gp ⁰)Cl₃], with a Au(III) - N bond, and a second product, a gabapentin-[AuCl₄]^- salt, both characterized by single-crystal X-ray diffraction and 2-dimensional ¹⁵N-¹H NMR techniques. The crystal structure of [Au(Gp⁰)Cl₃] clearly shows the Au - N coordination (Au - N bond 2.043(2) ?) in the hydrogen bonded dimer. In the crystal, the cyclohexyl moiety is disordered over two positions, both having a chair conformation. In solution, the ¹H NMR of [Au(Gp⁰)Cl₃] in MeOD has resonances at 2.45, 2.51, 3.05 and 3.12 ppm, that suggest that [Au(Gp⁰)Cl₃] exists as two different isomers in solution, with the - CH₂-NH ₂-AuCl₃ either axial or equatorial, and that on crystallization these isomers persist in the solid state.

Full text of DOI:10.1016/j.inoche.2011.01.017

Inorganic Chemistry Communications 14 (2011) 534–538
Contents lists available at ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
A gold(III) complex and a tetrachloroaurate salt of the neuroepileptic
drug gabapentin
⁎
Ahmed Shaikjee, Demetrius C. Levendis , Helder M. Marques, Richard Mampa
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO WITS, 2050, Johannesburg, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Gabapentin (2-[1-(aminomethyl)cyclohexyl] acetic acid, Gp), a neuroepileptic drug, has been the subject of
renewed interest in the past decade. In order to exploit the therapeutic potential of Gp several metal
complexes of Gp have been investigated. In this paper we report on the preparation of a novel, unusually
Received 5 November 2010
Accepted 18 January 2011
Available online 25 January 2011
stable Au(III)–gabapentin complex, [Au(Gp0)Cl3], with
a Au(III)―N bond, and a second product, a
gabapentin–[AuCl4]− salt, both characterized by single-crystal X-ray diffraction and 2-dimensional 15N–1H
NMR techniques. The crystal structure of [Au(Gp0)Cl3] clearly shows the Au―N coordination (Au―N bond
2.043(2) Å) in the hydrogen bonded dimer. In the crystal, the cyclohexyl moiety is disordered over two
positions, both having a chair conformation. In solution, the 1H NMR of [Au(Gp0)Cl3] in MeOD has resonances
at 2.45, 2.51, 3.05 and 3.12 ppm, that suggest that [Au(Gp0)Cl3] exists as two different isomers in solution,
with the ―CH2-NH2-AuCl3 either axial or equatorial, and that on crystallization these isomers persist in the
solid state.
Keywords:
Gabapentin
Gold-complex
Neuroepileptic drug
© 2011 Elsevier B.V. All rights reserved.
The role of γ-aminobutyric acid (GABA) as an inhibitory
neurotransmitter [1] stimulated research into the synthesis of GABA
analogs as potential central nervous system agents. One of these
analogs is gabapentin [1-(aminomethyl) cyclohexane acetic acid, Gp]
which is commercially available as Neurontin®. Gp is used as a
neuroepileptic drug in the treatment of epilepsy [2] and more
recently, neuropathic pain [3].
As active pharmaceutical ingredients (APIs) are frequently
delivered to patients as capsules or tablets, the solid-state properties
of the drug are important. Gp [4] can exist as different polymorphs
[5,6], solvates under ambient conditions, including a novel hydrate
[4], as a heptahydrate under high pressure [7], salts [8,9], co-crystals
[10] or amorphous solids. Crystal growth and nucleation mechanisms
that drive solid-state processes are still not well understood, as seen in
the emergence [11] or disappearance [12] of new polymorphic forms
as crystallization conditions are varied [11].
The first preparation and structural characterization of the Cu(II)
and Zn(II) complexes of Gp were reported by Braga et al. [13] who
used mechanochemical methods with the ZnCl2 and CuCl2 salts. In the
complexes, both Zn(II) and Cu(II) are pseudo-tetrahedral and
coordinate through the carboxylate oxygen of two gabapentin
molecules, with two Cl− ions occupying the other two sites. Zinc
and copper were noted as being important metals in neurology. This
motivated us to investigate other potentially beneficial metal
complexes of gabapentin, particularly those metals that are thought
to exhibit therapeutic potential [14,15].
Since Au(III) and Pt(II) are isoelectronic and isostructural there is
considerable interest in the potential anti-tumor activity of Au(III)
complexes. However, because of their poor kinetic and redox
stabilities under physiological conditions, their use is problematic
[16,17]. Coordination to polydentate ligands (en, dien, cyclam, terpy
and phen) does improve matters [18], and these complexes (with Cl−
occupying the other coordination sites) do display significant anti-
tumor activity against both cisplatin-sensitive and resistant human
ovarian cell line A2780; however, cytotoxicity is also significant.
Square planar Au(III) complexes with di- and tripeptides are
known, with coordination through some or all of Nδ of His, the N- and
C-terminal amino and carboxylate groups and deprotonated amide N
atoms [19–21,24]. Au(III) also coordinates to amino acids. Au(III)
forms a bis–histidine complex with coordination through the amino
group and a histidine Nδ [27]. It causes the deamination and
subsequent decarboxylation of glycine with the formation of glyoxylic
acid, NH+4 , formic acid and CO2, accompanied by the reduction of Au
(III) to Au(0) [22]. This may be the reason why colloidal gold is often
seen in the reactions of Au(III) with peptides [22]. Amino and
carboxylate functionalities in alfalfa biomass reduce Au(III) to Au(0)
through a Au(I) intermediate [23]. Amines, including Lys, complex
with gold nanoparticles; the capping stabilizes the particles in
solution and renders them water-dispersible [25]. Tyr, Arg and Gly-
Tyr have been used as reductants of [AuBr4]− to produce water-
soluble dispersions of gold nanoparticles [26].
⁎
Corresponding author. Tel./fax: +27 11 7176742/7176749.
E-mail address: demetrius.levendis@wits.ac.za (D.C. Levendis).
1387-7003/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2011.01.017

A. Shaikjee et al. / Inorganic Chemistry Communications 14 (2011) 534–538
535
Thus, Au(III) has a fairly rich biological chemistry: it is redox-
active; it can be coordinated by amino acids (especially Cys and Met)
and proteins; it is able to deprotonate and bind to the amide N of
peptides; and it is capable of cross-linking histidine imidazole rings
[28].
Given the medical importance of GABA and related neurotrans-
mitters on the one hand, and coordination complexes of Au(III) on the
other, we have initiated a study into the complexes of Au(III) with a
number of natural and synthetic neurotransmitters and their analogs.
We report here the crystal structure of a Au(III) complex of Gp in
which Au(III) is coordinated by Gp's amino group, and use NMR to
indicate that this structure is likely to persist in solution. We report
also the structure of the salt GpH[AuCl4]. (See note [29(b)] for an
explanation of the abbreviations used.)
the crystallographic data. The cyclohexyl in the second molecule in
the asymmetric unit is similarly disordered over two positions with
site occupancies of 0.70(1) and 0.30(1) for the axial and equatorial
geometries, respectively.
The observation of two possible chair conformations in crystals of
[Au(Gp0)Cl3] suggests that these conformations may not be signifi-
cantly different in energy, resulting in an appreciable population of
The reaction of Gp with auric acid [29] leads to two distinct
crystalline products, pale yellow needles (I) and orange blocks (II),
which we have characterized crystallographically [30]. [Au(Gp0)Cl3]
(I) was found to be a gold–Gp0 complex involving an Au(III)―N bond
in which the amine group has been deprotonated (Scheme 1(a)). GpH
[AuCl4] (II) is the salt (Scheme 1(b)).
[Au(Gp0)Cl3] (I) has two molecules in the asymmetric unit. One of
the [Au(Gp0)Cl3] molecules is shown in Scheme 1(a). The two
molecules in the asymmetric unit are hydrogen bonded via the
carboxylic acid. The two [Au(Gp0)Cl3] molecules are almost identical
but are not related by crystallographic symmetry. In one of the
molecules there is an intramolecular hydrogen bond between N1 and
O1 (2.903 Å) resulting in small conformational differences between
the two molecules. The cyclohexyl of each of the Gp0 molecules is
disordered over two possible chair conformations with the methyl-
amine group axial in one and equatorial in the other. This disorder can
be correlated to the solution 1H NMR spectra as discussed below.
Diagrams showing the cyclohexane conformations in each of the
disordered forms are given in Figs. 1 and 2 for the two molecules in
the asymmetric unit.
The relative occupancies of each of the disordered positions of the
cyclohexane chair for this molecule, axial or equatorial, are 0.67(1)
and 0.33(1), respectively, as found by least squares refinement against
Fig. 1. (a) Molecular structure of the axial conformation of the ―CH2-NH2-AuCl3 moiety
in [Au(Gp0)Cl3] showing the atom labeling scheme with 50% probability displacement
ellipsoids. Dashed lines indicate N―H···O intramolecular hydrogen bonding interac-
tions. (b) Molecular structure of the equatorial conformation of the ―CH2-NH2-AuCl3
moiety in [Au(Gp0)Cl3] showing the atom labeling scheme with 50% probability
displacement ellipsoids. Open dashed lines indicate N―H···O intramolecular hydro-
gen bonding interactions. Solid dashed lines are covalent bonds indicating the
alternative (equatorial) position of the Gp0 cyclohexane.
Scheme 1. Schematic representation of (a) I [Au(Gp0)Cl3], the gold–gabapentin Au–N
complex and (b) II GpH[AuCl4] the gold–Gp salt.

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A. Shaikjee et al. / Inorganic Chemistry Communications 14 (2011) 534–538
both conformers in solution. One of these pairs is shown in Fig. 3.
Crystallization may thus be kinetically controlled by nucleation
events; moreover, packing forces may determine the conformation
selected in the crystals. It is reasonable to assume that in the case of
[Au(Gp0)Cl3] both conformations of the cyclohexyl group exist in
solution at room temperature, but they do not rapidly interconvert,
possibly due to the intra-molecular ―NH2–O=C− and NH2–Cl
hydrogen bonds. These two conformational forms of [Au(Gp0)Cl3]
are retained in the resulting disordered crystal, a consequence of the
rapid precipitation of [Au(Gp0)Cl3] due to the presence of the ethanol
in the solvent. The persistence of the two conformations in a methanol
solution was investigated further using 1H and 15N NMR as described
later.
The orange salt, GpH[AuCl4], is shown in Fig. 4. The geometry of the
methylamine group is equatorial with no apparent disorder. The
geometry of the GpH cation in GpH[AuCl4] is similar to that observed
in the GpH chloride salt [8,9]. The [AuCl4]− ion has the typical square
planar geometry.
In GpH[AuCl4] pairs of GpH cations are hydrogen bonded to each
other via the protonated carboxylate groups. The negatively charged
[AuCl4]− ions occur in chains separating the GpH dimeric pairs
(Fig. 5). This type of packing arrangement is similar to that found in
several organic–inorganic hybrid materials in which layers of the
organic moiety are separated by layers of inorganic anions.
To determine whether the [Au(Gp0)Cl3] complex is retained in
solution the CD3OD 1H and 15N NMR spectra of Gp, the Gp–gold
complex [Au(Gp0)Cl3] and the gold salt, GpH[AuCl4] were recorded
[31]. At room temperature the two cyclohexyl conformers of pure Gp
inter-convert rapidly on the NMR timescale and only one signal is
observed for each of the aminomethyl (2.880 δ) and carboxymethyl
(2.448 δ) protons. The methylene signals associated with ―CH2-NH3+
and CH2-COOH were unequivocally assigned by using 2-dimensional
1H {15N} NMR. These are in agreement with previous observations
made by Ananda et al. [8], who also found that two distinct resonances
are observed for each of the methylene groups in Gp on cooling to
−80 °C. They attribute this observation to an equilibrium between
the axial and equatorial conformations of the methylamine groups in
solution at low temperature.
The only significant differences apparent in the Gp, [Au(Gp0)Cl3]
and GpH[AuCl4] NMR spectra relate to the methylene groups, and so
only these peaks are discussed further (see Fig. 6 and Supplementary
material).
[Au(Gp0)Cl3] in solution shows four sharp singlets. In view of the
nature of the disordered crystals obtained from this solution and the
observations made by Ananda et al. for pure Gp [8], it would be
reasonable to assume that two of these peaks (at 2.513 δ and 3.048 δ)
correspond to the chair conformation of cyclohexyl with the
methylamine group in the equatorial position, and the other two
peaks (at 2.473 δ and 3.199 δ) correspond to the chair conformation of
cyclohexane with the methylamine group in the axial position. The
peaks at 2.513 δ and 3.048 δ integrate for 1.27 protons each. The peaks
at 2.473 δ and 3.199 δ integrate for 0.67 protons each. The peak
Fig. 2. (a) Molecular structure of the equatorial conformation of the second molecule in
the asymmetric unit in [Au(Gp0)Cl3] showing the atom labeling scheme with 50%
probability displacement ellipsoids. (b) Molecular structure of the axial conformation
of the second molecule in the asymmetric unit in [Au(Gp0)Cl3] showing the atom
labeling scheme with 50% probability displacement ellipsoids. Solid dashed lines are
covalent bonds indicating the alternative (axial) position of the Gp0 cyclohexane.
Fig. 3. The two molecules of gold(III) gabapentin complex [Au(Gp0)Cl3] in the
asymmetric unit with only one of the disordered cyclohexane rings shown. Dotted lines
indicate N―H···O intramolecular or O―H···O intermolecular hydrogen bonding
interactions and also indicate N···H·O and C···H.O intermolecular hydrogen bonds
which form R22 [8] graph-set motifs.

A. Shaikjee et al. / Inorganic Chemistry Communications 14 (2011) 534–538
537
Fig. 4. Molecular structure of GpH[AuCl4] showing the atom labeling scheme with 50% probability displacement ellipsoids.
integration is in reasonable agreement with the site occupancies of
the two conformers observed crystallographically. We tentatively
conclude that both of the chair conformations are present in solution
at 293 K, stabilized at room temperature by the intramolecular
hydrogen bonds. However, we cannot rule out the possibility that
some of the [Au(Gp0)Cl3] complex dissociates to form the GpH[AuCl4]
salt on dissolving in methanol since the 1H NMR spectrum of the salt
peaks (2.513 δ and 3.055 δ) are close to those of the central peaks of
the [Au(Gp0)Cl3] spectrum. The deduction that both axial and
equatorial conformations exist in solution, together with our
observation that under certain conditions [Au(Gp0)Cl3] is reduced to
metallic gold and as yet unidentified products, is under investigation
and will be reported elsewhere.
(III) has been trapped as a result of rapid crystallization. The [Au(Gp0)
Cl3] complex could have important biological and pharmaceutical
significance.
Acknowledgements
The University of the Witwatersrand, Johannesburg, and the
National Research Foundation, Pretoria, is acknowledged for funding;
Dr Manuel Fernandes is also acknowledged for X-ray data collection
and advice on the disorder refinements.
This work has shown, for the first time, the formation of a stable
complex between Au(III) and Gp in the solid state, in which the Au(III)
is coordinated to the amino nitrogen. This complex persists in
solution. Thus an intermediate in the oxidation of gabapentin by Au
Appendix A. Supplementary data
Supplementary data to this article can be found online at
doi:10.1016/j.inoche.2011.01.017.
Fig. 5. Packing diagram of the GpH[AuCl4] salt showing layers of hydrogen bonded GpH molecules separated by chains of Cl···Cl interacting AuCl−4 ions. Dotted lines indicate
N―H···Cl, O―H···O or C―H···O intermolecular interactions and also indicate N···H·O and C···H·O intermolecular hydrogen bonds which form R22 [8] graph-set motifs.

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A. Shaikjee et al. / Inorganic Chemistry Communications 14 (2011) 534–538
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[29] (a) Suitable crystals for X-ray diffraction were obtained by the dissolution of
equimolar amounts of Gp (0.1711 g gabapentin, 1.0 mmol) and auric acid
(0.3938 g of AuCl3.6H2O, 1.0 mmol) in a mixture of 1:1 distilled water (5.0 ml)
and ethanol (5.0 ml) in a sample vial (40mmx10mm diameter) at 293 K. The pale
yellow crystals appear within 1–2 days and can be filtered off. On allowing the
solution to stand longer, for up to two weeks, the orange form crystallizes
concomitantly with the pale yellow crystals. These were separated by hand under
an optical microscope.(b) A note on the abbreviations used: by Gb we mean the
common zwitterionic form; by Gb0 we mean the neutral form; by GbH we mean
the cationic form. Therefore the abbreviation [Au(Gb0)Cl3] refers to the Au(III)
complex with the neutral Gp0 (as shown in Scheme 1(a)) and GpH[AuCl4] refers
to the salt as shown in Scheme 1.(b).
Fig. 6. The 1H NMR of (a) Gp, (b) the [Au(Gp0)Cl3] complex (c) the GpH[AuCl4] salt in
[30] CCDC 799398 & 799399 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Crystal
data for I. CCDC deposition number 799398. Empirical formula C9H17AuCl3NO2,
Mr =474.55, monoclinic space group P21/n, a=14.8729(3), b=7.0060(1),
c=26.4622(5) Å, β=93.355(1)°, V=2752.62(9) Å3, T=173(2) K, Z=8,
Dc =2.290 Mg/m3, μ (Mo Kα)=11.257 mm−1, F(000)=1792, 42829 reflections
measured, 5978 unique [R(int)=0.083] which were used in all calculations.
Refinement converged as a final R1 =0.0376 (wR2 =0.0896) for 5978 observed
reflections [IN2σ(I)]. Crystal data for II. CCDC deposition number 799399.
C9H18AuCl4NO2, Mr = 511.01, triclinic space group P-1, a = 6.6890(2),
b=7.6819(2), c=14.4134(3) Å, α=79.526(2)°, β=89.864(1)°, γ=81.248
CD3OD.
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