K. Fourmy et al. / C. R. Chimie xxx (2016) 1e6
5
at 25 ꢀC on a Bruker Avance 500, 400 Ultrashield, a DPX300
or Fourier 300 Ultrashield apparatus. 1H NMR and 13C{1H}
NMR chemical shifts are referenced to the solvent signal.
31P{1H} NMR chemical shifts are referenced to an external
standard (85% aqueous H3PO4). Multiplicity is as follows:
s ¼ singlet, d ¼ doublet, and t ¼ triplet. ESI analyses were
performed on an API-365 spectrometer.
Table 1
In vitro antiplasmodial activities of gold(I) complexes on the P. falciparum
strain FcM29-Cameroona and on FcB1-Colombiab; [n: number of inde-
pendent experiments performed].
Compound
IC50 (mM)
[Au(TMP)Cl] 1
[Au(DBP)Cl] 2
[Au(TPP)Cl] 3
[Au(DMP)Cl] 4
[Au(PPh3)Cl]
[Au(TPP)NTf2] 5
[Au(L6)Cl] 6
13 0.4 (n ¼ 4)a
9.7 2.0 (n ¼ 6)a
24 3.6 (n ¼ 7)a
18.5 3.0 (n ¼ 7)a
7.9 0.5 (n ¼ 6)a
4.2. Synthesis of gold(I) complexes
24 1.8 (n ¼ 5)a
11.5 0.9 (n ¼ 3)b
0.494 0.05 (n ¼ 4)a
0.187 0.02 (n ¼ 3)b
0.0127 0.005 (n ¼ 4)a
0.005 0.003 (n ¼ 3)b
4.2.1. Synthesis of [Au(TPP)NTf2] 5
Chloroquine
The gold chloride complex [Au(TPP)Cl] 3 (0.2 mmol) was
dissolved in CH2Cl2 (5 mL), and AgNTf2 (78 mg, 0.2 mmol)
was added resulting in the instantaneous formation of the
expected silver chloride precipitate. The mixture was stir-
red for an additional 15 min and filtrated over Celite to
remove the silver chloride salts. After evaporation to dry-
ness and drying in a vacuum, complex 5 was obtained
quantitatively as a yellow solid. NMR data were in agree-
ment with those reported in the literature [24].
Artemisinin
activity with an IC50 of24
m
M (Table 1). Incontrast, Hoffmann
and Viseux [25] showed that good cytotoxic activities on two
cancer cell lines could be achieved with [Au(PPh3)NTf2]
while [Au(PPh3)Cl] was totally inactive on the same cells.
The introduction of an amine moiety in the L-ligand
backbone was achieved through the synthesis of the pyr-
rolidinophosphole ligand L6 and its corresponding gold(I)
complex [Au(L6)Cl] 6. Unfortunately, this new structural
modulation did not lead to any significant improvement of
4.2.2. Synthesis of [Au(L6)Cl] 6
In a flamed Schlenk, (R)-2-(diphenylmethyl)pyrrolidine
6b (86.15 mg, 0.363 mmol, 1 equiv) was diluted in 5 mL of
THFand cooled down to ꢁ78 ꢀC. n-BuLi (226
mL, 0.363 mmol,
the biological activity: an IC50 of 11.5
the FcB1 strain for [Au(L6)Cl] 6, which is in the same range
as the IC50 of 13 M obtained on the FcM29-Cameroon
mM was obtained on
1 equiv) was added dropwise. The solution turned orange.
After 30 min, a solution of TMP-CN 6a [26](60 mg,
0.363 mmol, 1 equiv) in 5 mL of THF was added dropwise.
The solution was left for 1 h at ꢁ78 ꢀC and allowed to warm
up to room temperature for over 2 h. The dark red solution
was then concentrated to dryness and extracted with
approximately 3 ꢂ 8 mL of Et2O. These extracts were then
concentrated again to dryness andextracted with 3 ꢂ 8 mL of
pentane. Ligand L6 was finally obtained as a yellow oil and
was used for the complexation step without further purifi-
m
strain for the analogous [Au(TMP)Cl] 1.
Finally, the six prepared gold(I) phosphole complexes
1e6 showed IC50 in the range 9.7e24
arum chloroquino-resistant strains.
mM against P. falcip-
3. Conclusions
cation (31P{1H} NMR (121.5 MHz, Told8
) d 62.5).
In summary, a series of gold(I) complexes featuring a
monophosphole ligand has been prepared, fully charac-
terized and evaluated by the in vitro antiplasmodial refer-
ence assay.
Whatever the modulations achieved on the phosphole
skeleton or on the X-ligand, the prepared gold(I) phosphole
To a solution of the ligand L6 (80 mg, 0.21 mmol,
1.4 equiv) in dry CH2Cl2 (5 mL), was added chlor-
o(dimethylsulfide)gold(I) [Au(SMe2)Cl] (45 mg, 0.15 mmol,
1 equiv) and the reaction mixture was stirred at room
temperature for 2 h. After concentration and precipitation
with pentane, a white solid was obtained in 48% yield from
6a.
complexes showed moderate IC50 in the range 9.7e24 mM
against chloroquine-resistant strains of P. falciparum, which
precludes such as their development as antimalarial com-
pounds. The weak antiplasmodial activities of our gold(I)
phosphole complexes may be due to their incapacity of
reaching their biological target; further studies are ongoing
in our laboratory to address this issue [31]. Moreover, other
biological activities are currently investigated for these
gold complexes such as anti-cancer properties [32].
31P{1H} NMR (121.5 MHz, CDCl3)
d
79.6; 1H NMR
(300 MHz, CDCl3) 7.49e7.21 (m, 10Har), 4.76 (m, 1H, HC-
d
3
N), 3.9 (d, JHeH ¼ 12 Hz, 1H, HC(Ph)2), 2.88 (m, 1H,
HeCHeN), 2.61 (m, 1H, H′eCHeN), 1.9 (m, 4H, CH2), 1.86 (s,
3H, CH3), 1.82 (s, 3H, CH3), 1.79 (d, 3H, CH3, 3JHeP ¼ 12 Hz),
3
1.30 (d, 3H, CH3, JHeP ¼ 12 Hz).
13C{1H} NMR (75 MHz, CDCl3)
d 146.3 (C),145.9 (C),145.4
(C), 142.3 (C), 142.2 (C), 129.3 (CH), 129.2 (CH), 128.8 (CH),
126.8 (CH), 126.7 (CH), 125.6 (CH), 69.2 (CH, 2JCeP ¼ 7.5 Hz),
56.3 (CH2), 45.6 (CH), 30.9 (CH2), 24.7 (CH2), 13.6 (CH3), 11.0
4. Experimental section
(CH3, JCeP ¼ 18 Hz), 10.7 (CH3, 2JCeP ¼ 18 Hz).
2
4.1. General remarks
Mass: ESI m/z calc. for C25H30AuClNP: 607.1, found:
572.1 [MꢁCl].
All commercially available reagents were used as
received. Silver salts were stored under argon in Schlenk
tubes. Unless otherwise stated, all reactions were run under
argon using Schlenk techniques. Dichloromethane, THF,
Et2O and pentane were dried under nitrogen using a sol-
vent purification system (SPS). NMR spectra were recorded
4.3. Crystal structure determination
Diffraction data were collected at low temperature (180
K) on
a
Bruker Kappa Apex II using graphite-
Please cite this article in press as: K. Fourmy, et al., Gold(I) complexes bearing phosphole ligands: Synthesis and antimalarial
Fourmy, Kévin
