Metallation of ligands with biological activity: Synthesis and X-ray characterization of [(SDAZ)2Au2(dppe)] (SDAZ = sulphadiazinide anion; dppe = 1,2-bis(diphenylphosphanyl)ethane)

Article abstract of DOI:10.1515/znb-2005-0314

Sulphadiazine, [4-amino-N-(2-pyrimidinyl)-benzenesulfonamide], reacts with (dppe)Au₂Cl₂ and triethylamine in methanol to produce [(SDAZ)₂Au₂(dppe)]. The structure of this novel complex was analyzed by single crystal X-ray diffraction. In [(SDAZ)₂Au ₂(dppe)] the ligands SDAZ^- and dppe have approximately the same bond distances and angles as found for the protonated and free ligand, respectively. The compound is assembled essentially of two gold atoms bonded to the phosphorus centers of one 1,2-bis(diphenylphosphanyl)ethane molecule (in an anti conformation). The coordination sphere is completed with a trans sulphadiazine ligand on each gold atom. Because of their fairly high reactivity, the two aromatic amine groups in the SDAZ ligands represent important sites for the chemical modification of the complex with biological purposes.

Full text of DOI:10.1515/znb-2005-0314

Metallation of Ligands with Biological Activity: Synthesis and X-Ray
Characterization of [(SDAZ)2Au2(dppe)] (SDAZ = Sulphadiazinide
Anion; dppe = 1,2-Bis(diphenylphosphanyl)ethane)
Lenice L. Marques, Gelson Manzoni de Oliveira, Ernesto Schulz Lang,
and Robert A. Burrow
Departamento de Qu´ımica, Laborato´rio de Materiais Inorgaˆnicos, Universidade Federal de Santa
Mar´ıa, 97105-900 Santa Maria, RS, Brazil
Reprint requests to Prof. Dr. G. Manzoni de Oliveira. E-mail: manzoni@quimica.ufsm.br
Z. Naturforsch. 60b, 318 – 321 (2005); received August 2, 2004
Sulphadiazine, [4-amino-N-(2-pyrimidinyl)-benzenesulfonamide], reacts with (dppe)Au2Cl2 and
triethylamine in methanol to produce [(SDAZ)2Au2(dppe)]. The structure of this novel complex was
analyzed by single crystal X-ray diffraction. In [(SDAZ)2Au2(dppe)] the ligands SDAZ− and dppe
have approximately the same bond distances and angles as found for the protonated and free ligand,
respectively. The compound is assembled essentially of two gold atoms bonded to the phosphorus
centers of one 1,2-bis(diphenylphosphanyl)ethane molecule (in an anti conformation). The coordina-
tion sphere is completed with a trans sulphadiazine ligand on each gold atom. Because of their fairly
high reactivity, the two aromatic amine groups in the SDAZ ligands represent important sites for the
chemical modification of the complex with biological purposes.
Key words: Sulphadiazine Complexes, Bioinorganic Chemistry of Gold, Metallation of Biological
Ligands
Introduction
idate the antiarthritic activity of its compounds, has
shown that some gold drugs seem to be also effective
in the treatment of diseases such as tumors, psoriasis
and AIDS [14, 15]. Of particularly great chemothera-
peutical potential in cancer treatment are gold(I) com-
plexes with bidentate phosphanes [16, 17], such as
[Au(dppe)2]Cl (dppe = Ph2PC2H4PPh2), which, ac-
cording to Berners-Price and co-workers [18], rep-
resent one class of lipophilic cationic antitumor
agents. Among other biological important properties,
[Au(dppe)2]Cl was shown to exhibit a spectrum of an-
titumor activity in mouse tumor models [19] in an an-
timitochondrial mode of action [20, 21]. The activity of
the complex was retained when Au(I) was substituted
by Ag(I) or Cu(I) [22, 23]. However, the replacement
of the phenyl substituents on the phosphane by other
substituents leads to a decrease or loss of antitumor ac-
tivity [24]. This is probably related to the higher re-
activity of alkyl- compared to aryl-phosphane towards
disulphide bonds, and consequent oxidation, i.e. detox-
ification, in vivo [24, 25].
It is well known that the sulfanilamide derivative
4-amino-N-(2-pyrimidinyl)-benzenesulfonamide (sul-
phadiazine) is an efficient antibacterial drug with
the typical sulfonamide structure [1 – 3]. Through ex-
changes of different functional groups, but with the
conservation of the structural features, sulfonamide
derivatives can display a wide variety of pharmacolog-
ical activities, such as antidiabetic, antibacterial and
also antitumor [4 – 7]. In addition, some metal com-
plexes of these ligands have been found to promote
rapid healing of burns: the Ag(I)-sulphadiazine com-
plex is used for human burn treatment [8, 9], and the
Zn(II) complex for the prevention of bacterial infection
in burned animals [10, 11]. The effectiveness of these
compounds in the treatment of skin disorders does not
depend solely on the slow release of Ag(I) or Zn(II),
but depends strongly on the nature of the material to
which the metal ion is bound [10].
Gold(I) complexes containing sulphur ligands have
been extensively used in the medical treatment of
The noteworthy chemical ability of sulphadi-
rheumatoid arthritis [12, 13]. The explosive growth of azine (1), to act as a ligand, therefore allowing the
gold chemistry in the last decade, besides to consol- synthesis of a variety of transition metal complexes,
c
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L. L. Marques et al. · Metallation of Ligands with Biological Activity
319
Table 1. Crystal data and structure refinement for [(SDAZ)2
Au2(dppe)].
Empirical formula
Formula weight
Temperature [K]
Radiation, λ [A]
Crystal system, space group
C46H38Au2N8O4P2S2
1286.84
298(2)
˚
0.71073
monoclinic, P21/n
a = 8.1606(19)
b = 25.580(6)
c = 23.536(6)
α = 90
˚
Unit cell dimensions a,b,c [A]
is based upon the acidity of the S(O)2N-H function,
allied with the presence of two vicinal pyrimidine-N
atoms as potential coordination sites.
α,β,γ [◦]
β = 97.912(4)
γ = 90
Thus, the deprotonation of the NH group yields
an anionic donor ligand, with two nitrogen atoms at
the pyrimidine ring, which provide the stereochemi-
cal requisites for the achievement of complexes with
a monodentate, chelate or bridge-forming ligand. Ear-
lier workers have reported sulphadiazine complexes
of Ag [26], Zn, Cd and Hg [27], and more recently
a sulphadiazine complex of Cu has also been de-
scribed [28]. In the past year we have reported the
first sulphadiazine complexes of gold [29, 30], with
triphenylphosphane and triphenylarsane as co-ligands.
We now report the synthesis and the X-ray structural
characterization of the first binuclear (SDAZ)-Au-
dppe complex. In this novel compound, an open (cen-
tered) Au-PPh2-C2H4-Ph2P-Au chain is linked to the
sulfonamide-N atoms of two deprotonated sulphadi-
azine molecules, both containing two aromatic amino
groups as reactive sites for the chemical modification
of the SDAZ ligands with biological aims [3, 31, 32].
3
˚
Volume [A ]
4866(2)
Z, Calculated density [g·cm−3
Absorption coefficient [mm−1
F(000)
]
]
4, 1.756
6.224
2488
Crystal size [mm]
0.57×0.11×0.05
θ Range [◦]
1.59 – 26.00
Limiting indices
−10 ≤ h ≤ 9, −31 ≤ k ≤ 26,
−29 ≤ l ≤ 27
22339
9020 [Rint = 0.1486]
94.5%
semi-empirical from equivalents
0.7460 and 0.1255
Full-matrix least-squares on F2
9020 / 0 / 307
0.891
Reflections collected
Reflections unique
Completeness to theta max.
Absorption correction
Max. and min. transmission
Refinement method
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R Indices (all data)
R1 = 0.0951, wR2 = 0.2020
R1 = 0.2744, wR2 = 0.2557
Largest diff. peak and hole [e·A−3] 3.848 and −3.466
◦
˚
Table 2. Selected bond lengths [A] and angles [ ] for
[(SDAZ)2Au2(dppe)].
Bond lengths
Au(1)-N(11)
Au(1)-P(3)
Au(2)-N(21)
Au(2)-P(4)
S(1)-O(12)
S(1)-O(11)
S(1)-N(11)
S(2)-O(22)
S(2)-O(21)
S(2)-N(21)
P(3)-C(3)
O(12)-S(1)-O(11)
O(12)-S(1)-N(11)
O(11)-S(1)-N(11)
O(12)-S(1)-C(121) 108.3(12)
O(11)-S(1)-C(121) 107.4(12)
N(11)-S(1)-C(121) 109.3(12)
O(22)-S(2)-O(21)
O(22)-S(2)-N(21)
O(21)-S(2)-N(21)
O(22)-S(2)-C(221) 107.1(12)
O(21)-S(2)-C(221) 107.2(11)
N(21)-S(2)-C(221) 109.1(11)
116.1(12)
103.9(11)
111.7(13)
Results and Discussion
2.05(2)
2.228(8)
2.08(2)
2.211(7)
1.377(17)
1.42(2)
[(SDAZ)2Au2(dppe)] (1) crystallizes in the mono-
clinic, centrosymmetric space group P21/n. The crys-
tal data and experimental conditions are given in Ta-
ble 1. Fig. 1 shows the contents of the asymmetric
115.5(11)
113.2(12)
104.4(11)
1.63(2)
1.430(18)
1.467(18)
1.63(2)
1.86(3)
P(4)-C(4)
C(3)-C(4)
1.85(2)
1.55(3)
C(3)-P(3)-Au(1)
C(4)-P(4)-Au(2)
S(1)-N(11)-Au(1)
S(2)-N(21)-Au(2)
C(4)-C(3)-P(3)
C(3)-C(4)-P(4)
106.3(9)
110.0(8)
116.7(12)
115.6(12)
110.4(17)
109.0(17)
Bond angles
N(11)-Au(1)-P(3) 169.8(6)
N(21)-Au(2)-P(4) 169.2(6)
unit. Selected bond distances and angles are listed in
Table 2.
In [(SDAZ)2Au2(dppe)], the ligands SDAZ and
Fig. 1. Molecular structure (asymmetric unit) of dppe have approximately the same bond distances and
[(SDAZ)2Au2(dppe)].
angles as found for the protonated and free ligand [33],
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320
L. L. Marques et al. · Metallation of Ligands with Biological Activity
respectively. The compound is assembled essentially lated by filtration. The product was dried under vacuum and
recrystallized from a mixture (1:1) of dichloromethane and
petroleum ether: 0.21 g (80% based on sulphadiazine) of air-
stable gray crystals, m. p. 312 ◦C.
of two gold atoms bonded to the phosphorus centers of
one 1,2-bis(diphenylphosphanyl)ethane molecule (in
an anti conformation). The coordination sphere is com-
pleted with a trans sulphadiazine ligand on each gold
atom. The pairs of P-Au and N-Au distances are iden-
tical considering the standard deviations, Au(1)-P(3) /
IR (KBr): ν = 3459 (m, νas(NH2)), 3364 (s, νs(NH2)),
3246 (m, δ(NH2)), 3056 (s, (C-H)aryl), 2907 cm−1
(s, (C-H)alkyl); the ν(SO2) absorptions between 1300 –
1100 cm−1 could not be detached from the bands of
the aromatic rings (1300 – 1000 cm−1). Analysis for
C46H38Au2N8O4P2S2 (1286.84): calcd. C 39.13, H 3.14;
found C 42.80, H 3.28. Highly divergent N values were not
considered.
˚
Au(2)-P(4) at 2.228(8) / 2.211(7) A, Au(1)-N(11) /
˚
Au(2)-N(21) at 2.05(2) / 2.08(2) A respectively (see
Table 2). The bond angles surrounding the gold atoms
are also identical, 169.8(6)◦ [N(11)-Au(1)-P(3)] and
169.2(6)◦ [N(21)-Au(2)-P(4)].
The simple architecture of the molecule should be
considered a major plus regarding its biological activ-
ity, since many biologically active metal complexes of
sulphadiazine or dppe are also not highly structured.
Finally, the two aromatic amino groups are suitably
distant of the core of the molecule, so that chemical
transformations of these sites for biological purposes
should not be difficult.
Structural determination
Data were collected on a Bruker SMART CCD diffrac-
tometer. The structure of [(SDAZ)2Au2(dppe)] was solved
by direct methods (SHELXS-97 [34]). Refinements were
carried out with the SHELXL-97 [35] package. All refine-
ments were made by full-matrix least-squares on F2 with
anisotropic displacement parameters for all non-hydrogen
atoms. Hydrogen atoms were included in the refinement in
calculated positions. The carbon atoms were refined with
isotropic parameters. Crystallographic data for the struc-
ture have been deposited with the Cambridge Crystallo-
graphic Data Centre, CCDC-246335 (1). Copies of the data
can be obtained free of charge on application to The Di-
rector, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(Fax: int. code +(1223)336-033; e-mail for inquiry: file-
serv@ccdc.cam.ac.uk).
Experimental Section
Preparation of [(SDAZ)2Au2(dppe)] (1)
After dissolving 0.05 g (0.2 mmol) of sulphadiazine in
5 ml of methanol a few drops of triethylamine were added.
Under stirring the solution was slowly added to 0.063 g
(0.1 mmol) of (dppe)Au2Cl2 previously dissolved in 5 ml
of hot methanol. After 3 h a rose-colored precipitate was iso-
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