Linking Flavonoids to Gold - A New Family of Gold Compounds for Potential Therapeutic Applications

Article abstract of DOI:10.1002/ejic.201500514

The flavone ligands 8-chloro-2-tetrahydrofuryl-1,4-benzopyrone and 8-chloro-2-(2-methyltetrahydrofuryl)-1,4-benzopyrone have been used to prepare the first examples of alkynyl phosphine gold compounds containing flavonoids which exhibit cytotoxicity towar

Full text of DOI:10.1002/ejic.201500514

FULL PAPER
DOI:10.1002/ejic.201500514
Linking Flavonoids to Gold – A New Family of Gold
Compounds for Potential Therapeutic Applications
Nedaossadat Mirzadeh,*[a] Steven H. Privér,[a]
Amanda Abraham,[a,b] Ravi Shukla,[a,b] Vipul Bansal,[b] and
Suresh K. Bhargava*[a]
Keywords: Gold / Flavones / Antitumor agents / Phosphine ligands / Alkyne ligands
The flavone ligands 8-chloro-2-tetrahydrofuryl-1,4-benzo-
ynyl phosphine gold compounds containing flavonoids which
pyrone and 8-chloro-2-(2-methyltetrahydrofuryl)-1,4-benzo- exhibit cytotoxicity towards human prostate cancer cells.
pyrone have been used to prepare the first examples of alk-
come the subject of attention recently due to their stable
coordinative bond (strong gold–carbon σ-bond) and there-
Introduction
fore their stability under physiological conditions.[18–21] Sur-
prisingly, however, gold compounds that contain flavonoid
ligands (Figure 1) have not been the subject of prior investi-
gation. The role of dietary flavonoids, a class of antioxi-
dants found in fruits, vegetables, tea, red wine and soy-
beans, is widely discussed in cancer prevention,[22–31] and in
vitro and in vivo studies have demonstrated their anticancer
properties.[32,33]
Worldwide there are a significant number of deaths due
to cancer;[1] however, a true medicinal cure to this disease
remains elusive. Despite the success of existing clinical
metal compounds such as cisplatin, cis-[PtCl2(NH3)2], for
the treatment of cancer,[2] there is continuing interest in new
antitumour drugs in an effort to overcome the drawbacks
of existing therapeutic agents, including high toxicity, which
cause unwanted side-effects in the human body.[2]
Since the introduction of clinically accepted auranofin in
1985 for the treatment of arthritis, gold compounds have
been the subject of investigation as a source of metal-based
drugs.[3] Among the many gold compounds that have been
tested for anticancer properties, gold(I)–phosphine deriva-
tives have offered a promising scope for the development of
gold-based drugs.[4] Initial interest concentrated on linear
two-coordinate gold complexes such as auranofin and (tri-
ethylphosphine)gold(I) chloride; this was later expanded to
include the cationic species bis[1,2-bis(diphenylphosphino)-
ethane]gold(I) chloride and bis[1,2-bis(di-n-pyridylphos-
phino)ethane]gold(I) chloride, which possess tetrahedral ge-
ometry about the metal centre.[4] Various ligands have been
used to design effective gold-based anticancer agents,[4–16]
many of which are less toxic than other metal com-
pounds.[4,5,17] Alkynyl phosphine gold complexes have be-
Figure 1. The flavone backbone.
Given our background in the synthesis of organogold
complexes,[34] we were interested to design and prepare fla-
vonoid derivatives of gold(I)–phosphine compounds, bind-
ing together two potentially anticancer-active components
(namely a gold–phosphine and a flavonoid) through a gold–
carbon σ-bond. Several factors were considered when
designing these compounds, one being the introduction of
a chlorine substituent into the phenyl ring of the flavone
moiety, which has been shown to improve the cytotoxicity
of flavone-based drugs.[35] Another factor was to incorpo-
rate a Au(PPh3) component into the structure, since it has
been reported that phenyl substituents on the phosphorus
atom cause an increase in the cellular and nuclear uptake
of AuCl(PR3) (R = Ph, Me, Et, tBu), hence an increase in
the cytotoxicity.[36,37]
[a] Centre for Advanced Materials & Industrial Chemistry,
School of Applied Sciences, RMIT University,
GPO Box 2476V, Melbourne, Victoria 3001, Australia
E-mail: nedaossadat.mirzadeh@rmit.edu.au
suresh.bhargava@rmit.edu.au
https://www.rmit.edu.au/research/research-institutes-centres-
and-groups/research-centres/camic/
[b] NanoBiotechnology Research Laboratory (NBRL),
School of Applied Sciences, RMIT University,
GPO Box 2476V, Melbourne, Victoria 3001, Australia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201500514.
We now provide a detailed account of the preparation
and biological activities of these complexes.
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Results and Discussion
To bind a gold–phosphine moiety to a flavonoid, a prop-
argyl ether group was employed,[18] which conveniently en-
abled the formation of the desired gold–carbon σ-bond by
deprotonation of the alkyne. Thus, reaction of 3-hydroxy-
benzopyrans 1a and 1b with propargyl bromide gave aryl
propargyl ethers 2a and 2b (Scheme 1).[38,39] Treatment of
2a and 2b with [AuCl(PPh3)] in the presence of CuI and
iPr2NEt afforded the desired gold(I) compounds 3a and 3b
(Scheme 1) as air-stable solids in good yields (85–90%).
Scheme 1. Linking flavonoids to gold.
Complexes 3a and 3b were characterized by elemental
analysis and spectroscopic techniques. The H NMR spec-
troscopic data of 3a and 3b are generally similar to those
of 2a and 2b,[39] respectively, with additional aromatic mul-
tiplets due to the phenyl protons of the PPh3 ligand. The
31P NMR spectra of 3a and 3b each showed a singlet reso-
1
Figure 2. Molecular structure of 2a (top) and 2b (bottom). Ellip-
soids show 50% probability levels. Hydrogen atoms have been
omitted for clarity. The disordered benzene of crystallization in 2b
has been omitted.
nance at δ = 41.8 ppm. The ESI mass spectra of 3a and 3b high dosage is required for chemotherapy, which generally
both show the expected [M + H]+ peak at m/z 759.08 and leads to adverse side effects, we chose to investigate PC-3
773.09, respectively, and elemental analyses are consistent cells for our experiments.[40,41] Another reason for choosing
with the proposed structures. The structures of 2a, 2b, 3a PC-3 cells is the fact that the activity of this cell line, when
and 3b were also confirmed by X-ray diffraction. The mo- challenged with flavone compounds, has been well estab-
lecular structures of 2a and 2b are shown in Figure 2 and lished.[35,42,43] In particular, chlorine substitution on the
those of 3a and 3b in Figure 3. Selected bond lengths and phenyl ring of flavones has been shown to change the steric
angles for 2a, 2b, 3a and 3b are listed in Tables 1 and 2.
and electronic characteristics of anticancer flavone-based
The bond lengths and angles in the flavonoid compounds drugs and favourably enhances their anticancer properties
2a and 2b are unexceptional (Tables 1 and 2). In general, against PC-3 cells.[35]
the metrical parameters of gold complexes 3a and 3b are
Actively growing PC-3 cells in the log phase of their cell
similar to those in the corresponding precursors 2a and 2b. cycle were treated with increasing concentrations of com-
Upon coordination of the Au(PPh3) fragment, there is a pounds 1–3 for a period of 24 h, and the toxicity was as-
slight lengthening of the CϵC bond by about 0.02 Å. As sessed by using the 3-(4,5-dimethylazol-2-yl)-2,5-diphenyl-
expected, the gold atom in 3a and 3b displays linear coordi- tetrazolium bromide (MTT) assay.[44] The MTT assay esti-
nation.
mates cellular viability by measuring the mitochondrial de-
The cytotoxicity of gold compounds 3a and 3b, flavonoid hydrogenase activity as indicated by the reduction of yellow
precursors 1a, 2a, 1b, 2b and gold precursor [AuCl(PPh3)] tetrazolium MTT to purple needle-like formazan crystals,
were tested against human prostate cancer (PC-3) cells. which, on solubilization, can be measured with a UV/Vis
Given the fact that androgen-independent prostate cancer multiwell plate reader. The cell viability percentages were
is resistant to the common anticancer drug cisplatin, and a calculated for 1–3 and [AuCl(PPh3)] and are shown in the
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compounds react with MTT to form formazan crystals,
which lead to false positive results,[45] compounds 1–3 were
tested with MTT through cell-free controls. The results
showed no formazan crystal formation, indicating that
MTT was a suitable assay for testing the viability of these
compounds. Vehicle control (1% DMSO) was tested with
PC-3 cells and resulted in 97% viability, indicating that the
highest concentration of DMSO used was not toxic to the
cells.
Table 3. Cytotoxicity of compounds 1a–3a, 1b–3b and
[AuCl(PPh3)] against human prostate cancer (PC-3) cells.
Compound
EC50 [μm][a]
Compound
EC50 [μm][a]
1a
2a, 2b
3a
84.69
NA[b]
37.73
1b
155.81
27.99
43.36
[AuCl(PPh3)]
3b
[a] The concentration of compound that gives half-maximum re-
sponse. [b] Compounds 2a and 2b show no activity.
The results revealed that the presence of the hydroxyl
group in compounds 1a and 1b is essential for their effec-
tiveness as cytotoxic agents. The toxicities of 1a and 1b are
diminished when the hydroxyl group is converted to a prop-
argyl ether; compounds 2a and 2b exhibit no toxicity, lead-
ing to 100% viability of PC-3 cells under the conditions
used. This may be explained by the fact that the hydroxyl
group, due to its electron-donating capability, is able to dis-
rupt the balance of reactive oxygen species (ROS) in the
cells, leading to apoptosis.[46]
Figure 3. Molecular structure of 3a (top) and 3b (bottom). Ellip-
soids show 50% probability levels. Hydrogen atoms and the
CH2Cl2 of crystallization have been omitted for clarity. Only the
ipso carbon atoms of the PPh3 group are shown.
Upon coordination of the Au(PPh3) moiety to 2a and 2b,
an increase in toxicity was observed (3a, EC50 = 37.73 μm;
3b, EC50 = 43.36 μm). The toxicities of 3a and 3b are greater
than those of their precursors 2a and 2b and even those of
1a and 1b. The presence of a methyl group in the furan ring
resulted in a slight decrease in the cytotoxic potency of gold
compound 3b compared to that of 3a; a similar trend was
also observed between 1b and 1a. These observations high-
light the importance of substituents in the furan ring for
fine-tuning the activity profiles of these compounds. The
toxicity of [AuCl(PPh3)] was also tested against PC-3 cells
to determine the extent the gold moiety contributes to
the cytotoxicity of 3a and 3b. The results show that
[AuCl(PPh3)] has even greater activity than 1a–3a and 1b–
3b at all concentrations tested (see Figure S1 in the Sup-
porting Information), suggesting that the activities of 3a
and 3b are mainly derived from the presence of the
Au(PPh3) fragment. The results also indicate that the effec-
tiveness of gold compounds 3a and 3b approaches that of
[AuCl(PPh3)] at higher concentrations. The exact mecha-
nism of action of these gold compounds remains to be in-
vestigated. It is also important to determine whether the
cellular responses elicited by 3a and 3b arise from a syner-
gistic effect of the flavone and Au(PPh3) moieties or are
solely due to one or the other.
Table 1. Selected bond lengths [Å] and angles [°] in 2a and 3a.
2a
3a
Au1–P1
Au1–C16
C15–C16
C14–C15
–
–
2.2795(6)
1.998(2)
1.202(3)
1.463(3)
1.467(3)
179.23(7)
113.15(19)
114.71(19)
178.2(3)
1.180(2)
1.459(2)
1.4532(18)
–
108.88(12)
112.42(11)
177.10(17)
C14–O2
P1–Au1–C16
C15–C14–O2
C14–O2–C2
C14–C15–C16
Table 2. Selected bond lengths [Å] and angles [°] in 2b and 3b.
2b
3b
Au1–P1
Au1–C17
C16–C17
C15–C16
–
–
2.2829(6)
2.001(2)
1.206(3)
1.459(3)
1.467(3)
178.54(7)
112.98(18)
114.75(19)
176.7(3)
1.161(3)
1.447(3)
1.438(2)
–
108.61(15)
115.46(13)
177.3(2)
C15–O2
P1–Au1–C17
C16–C15–O2
C15–O2–C2
C15–C16–C17
Conclusions
Supporting Information, while the EC50 values are listed
We have demonstrated the successful preparation of the
in Table 3. Since studies have shown that many flavonoid first representatives of a family of organometallic gold com-
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ness and the solid was washed with Et2O. Recrystallization from
CH2Cl2/MeOH gave a pale yellow solid, which was isolated by fil-
tration, washed with MeOH and dried in vacuo (252 mg, 91%). 1H
NMR: δ = 5.23 (s, 2 H, methylene), 6.61 (dd, J = 1.7, 3.6 Hz, 1 H,
furan), 7.38–7.54 (m, 16 H, aromatics, furan), 7.57 (dd, J = 2.5,
8.9 Hz, 1 H, aromatic), 7.64 (d, J = 1.1 Hz, 1 H, furan), 7.74 (d, J
pounds containing flavone ligands that exhibit cytotoxicity
against human prostate cancer (PC-3) cells. Growing evi-
dence increasingly supports the role of flavonoids in cancer
therapy alongside its prevention, wherein different flavono-
ids are found to selectively influence different proinflamma-
tory signalling pathways.[47,48] Although the cytotoxicity of
gold complexes 3a and 3b towards PC-3 cells was less than
we had hoped, the results have provided further insights
into the structural features that are important for activity.
For example, the inactivity of compounds 2a and 2b com-
pared to 1a and 1b highlights the importance that the
phenol group plays in the cytotoxicity of these compounds.
Similarly, the slightly greater activity of 3a compared to that
of 3b illustrates the effect that relatively minor structural
= 3.5 Hz, 1 H, furan), 8.20 (d, J = 2.5 Hz, 1 H, aromatic) ppm. 31
P
NMR: δ = 41.8 (s) ppm. ESI-MS: m/z = 759.08 [M + H]+, 781.05
[M + Na]+. C34H23AuClO4P (758.95): calcd. C 53.81, H 3.05, Cl
4.67; found C 53.41, H 2.76, Cl 4.73.
Complex 3b: A procedure similar to that described above using alk-
yne 2b (105 mg, 0.33 mmol) and [AuCl(PPh3)] (165 mg, 0.33 mmol)
1
gave the desired product as a pale yellow solid (217 mg, 84%). H
NMR: δ = 2.43 (s, 3 H, methyl), 5.20 (s, 2 H, methylene), 6.22 (d,
J = 2.8 Hz, 1 H, furan), 7.37–7.68 (m, 18 H, aromatics, furan), 7.65
changes can play on anticancer activity. Nevertheless, given (d, J = 3.4 Hz, 1 H, furan), 8.18 (d, J = 2.4 Hz, 1 H, aromatic)
ppm. 31P NMR: δ = 41.8 (s) ppm. ESI-MS: m/z = 773.09
the results reported here, further investigations into the
modification or functionalization of the furan ring, phos-
phine ligand or aryl halide group may lead to complexes
[M + H]+, 795.07 [M + Na]+. C35H25AuClO4P (772.97): calcd. C
54.39, H 3.26, Cl 4.59; found C 54.02, H 3.08, Cl 4.71.
that show even greater activity towards PC-3 cells.
Cell Viability Assay: The cytotoxicity of the gold compounds and
their precursors towards prostate cancer (PC-3) cells under in vitro
conditions was examined by using the MTT assay. Briefly, 1ϫ104
cells were seeded into each well of a flat-bottomed 96-well poly-
styrene-coated plate and incubated for 24 h in a CO2 incubator at
5% CO2 and 37 °C. 100X stock solutions of the compounds were
prepared in DMSO, and the cells were treated with increasing con-
centrations of compounds ranging from 0 to 100 μm. Each concen-
Experimental Section
Compounds 2a and 2b, their starting materials[38,49] and
[AuCl(PPh3)][50] were prepared according to literature methods; all
other reagents were commercially available and used as received.
1H (300 MHz) and 31P (121 MHz) NMR spectra were measured tration was run in triplicate and 1% DMSO, the highest DMSO
with a Bruker Avance 300 spectrometer at room temperature in
CDCl3. Coupling constants (J) are given in Hz and chemical shifts
(δ) in ppm, internally referenced to residual solvent signals (1H) or
external 85% H3PO4 (31P). Electrospray (ESI) mass spectra were
measured with HP 5970 MSD and Waters spectrometers in the
Mass Spectrometry Unit of the Research School of Chemistry, Aus-
tralian National University (ANU). Elemental analyses were car-
ried out by the Microanalytical Unit at the same school.
concentration used for treatment, used as a vehicle control, was
found to be nontoxic to the cells. After 24 h of incubation, 10 μL
per well of MTT solution (stock solution of 5 mg/mL in phosphate
buffered saline) was added and incubated for 4 h at 37 °C. The
formazan crystals thus formed were dissolved in acidified 2-prop-
anol (100 μL), and the intensity of the colour progression was mea-
sured with a microplate reader at 595 and 630 nm. The absorbance
readings from the two wavelengths were subtracted and the percen-
tage viability and EC50 were determined. The viability of untreated
cells was comparable to those treated with the vehicle control, and
untreated cells were considered to be 100% viable.
X-ray Crystallography
Crystals suitable for X-ray crystallography were obtained from
methanol (for 2a), benzene layered with hexane (for 2b) or di-
chloromethane layered with hexane (for 3a and 3b). X-ray diffrac-
tion data were collected at 200 K with a D8 Bruker diffractometer
with an APEX2 area detector using graphite-monochromated Mo-
Kα radiation (λ = 0.71073 Å) from a 1 μS microsource. Geometric
and intensity data were collected by using SMART software.[51] The
data were processed with SAINT,[52] and corrections for absorption
were applied by using SADABS.[53] The structures were solved by
direct methods and refined with full-matrix least-squares methods
on F2 by using the SHELX-TL package.[54] OLEX2 was used to
refine the structure of 3b and to produce the molecular graphics.[55]
Selected crystal data and details of data collection and structure
refinement are listed in Table S1 (Supporting Information).
Acknowledgments
The authors thank the Platform Technologies Research Institute
for an inter-institute seed grant. V. B. acknowledges the Australian
Research Council for the award of
(FT140101285).
a Future Fellowship
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