Antifungal activity of resveratrol derivatives against Candida Species

Article abstract of DOI:10.1021/np5002576

trans-Resveratrol (1a) is a phytoalexin produced by plants in response to infections by pathogens. Its potential activity against clinically relevant opportunistic fungal pathogens has previously been poorly investigated. Evaluated herein are the candidacidal activities of oligomers (2a, 3-5) of 1a purified from Vitis vinifera grape canes and several analogues (1b-1j) of 1a obtained through semisynthesis using methylation and acetylation. Moreover, trans-ε-viniferin (2a), a dimer of 1a, was also subjected to methylation (2b) and acetylation (2c) under nonselective conditions. Neither the natural oligomers of 1a (2a, 3-5) nor the derivatives of 2a were active against Candida albicans SC5314. However, the dimethoxy resveratrol derivatives 1d and 1e exhibited antifungal activity against C. albicans with minimum inhibitory concentration (MIC) values of 29-37 μg/mL and against 11 other Candida species. Compound 1e inhibited the yeast-to-hyphae morphogenetic transition of C. albicans at 14 μg/mL.

Full text of DOI:10.1021/np5002576

Article
pubs.acs.org/jnp
Antifungal Activity of Resveratrol Derivatives against Candida
Species
Benjamin Houille,† Nicolas Papon,† Leslie Boudesocque,§ Eric Bourdeaud,‡ Sebastien Besseau,†
́
́
Vincent Courdavault,† Cecile Enguehard-Gueiffier,§ Guillaume Delanoue,⊥ Laurence Guerin,⊥
́
́
Jean-Philippe Bouchara,∥ Marc Clastre,† Nathalie Giglioli-Guivarc’h,† Jerome Guillard,‡
́
̂
and Arnaud Lanoue*,†
†EA 2106 “Biomolec
F-37200 Tours, France
§UMR INRA 1282 Infectiologie et Sante
́
ules et Biotechnologie Veg
́
et
́
ales”, UFR des Sciences Pharmaceutiques, Universite
́
Franco
̧
is Rabelais de Tours,
́
Publique, Equipe Recherche et Innovation en Chimie Medicinale, UFR Sciences
is Rabelais de Tours, F-37200 Tours, France
́
Pharmaceutiques, Universite
‡Equipe Synthes
e Organique, Institut Chimie Milieux et Mater
Poitiers Cedex 9, France
⊥IFV, Institut Franca
is de la Vigne et du Vin, 37400 Amboise, France
∥Universite
d’Angers Groupe d’Etude des Interactions Hote-Pathogene, EA 3142, Institut de Biologie en Sante,
Universitaire, L’UNAM Universite, 49933 Angers Cedex, France
́
Franco
̧
̀
́
iaux de Poitiers IC2MP, UMR 7285, Universite de Poitiers, F-86073
́
̧
́
̂
̀
́
Centre Hospitalier
́
S
* Supporting Information
ABSTRACT: trans-Resveratrol (1a) is a phytoalexin pro-
duced by plants in response to infections by pathogens. Its
potential activity against clinically relevant opportunistic fungal
pathogens has previously been poorly investigated. Evaluated
herein are the candidacidal activities of oligomers (2a, 3−5) of
1a purified from Vitis vinifera grape canes and several
analogues (1b−1j) of 1a obtained through semisynthesis
using methylation and acetylation. Moreover, trans-ε-viniferin (2a), a dimer of 1a, was also subjected to methylation (2b) and
acetylation (2c) under nonselective conditions. Neither the natural oligomers of 1a (2a, 3−5) nor the derivatives of 2a were
active against Candida albicans SC5314. However, the dimethoxy resveratrol derivatives 1d and 1e exhibited antifungal activity
against C. albicans with minimum inhibitory concentration (MIC) values of 29−37 μg/mL and against 11 other Candida species.
Compound 1e inhibited the yeast-to-hyphae morphogenetic transition of C. albicans at 14 μg/mL.
trans-Resveratrol (1a) is a natural stilbenoid produced by
several plants in response to pathogenic infections. Although
present in a restricted number of plant families, 1a forms the
backbone of a wide range of stilbene biosynthetic products,
leading to a spectrum of monomeric and oligomeric
compounds with diverse biological activities.1,2 Stilbenes were
first described for their fungicidal action against plant fungal
diseases by Langcake and Pryce.3 Later, antimicrobial activities
of stilbenes were reported against various phytopathogens, with
1a occurring as a major phytoalexin of the family Vitaceae.4,5
Resveratrol fully inhibits conidial germination of the gray mold
agent Botrytis cinerea6 and reduces roughly 75% sporangial
germination of the causal agent of grapevine downy mildew,
Plasmopara viticola.7 Pterostilbene, the 3,5-dimethoxyresvera-
trol (1e), and trans-ε-viniferin (2a) have been found to be 5-
fold more active than 1a, indicating the potential of resveratrol
derivatives as a source of effective antifungal agents.8,9
erties.10,11 However, little information is available concerning
the potential antifungal activity of 1a against common agents of
human mycoses such as Candida yeasts.
Although the candidacidal activity of 1a has been published
against Candida albicans TIMM 176812 and against five other
Candida species,13 these data remain somewhat controversial.14
Interestingly, it has been reported that semisynthetic
modifications of natural stilbenes can be carried out to increase
their pharmacological potential and their range of activity
against new biological targets.15−17 Considering the potential of
stilbenes as fungicidal agents against phytopathogens and taking
into account the large diversity of chemical structures exhibited
by natural and semisynthetic stilbene derivatives, the potential
of resveratrol derivatives including both natural and semi-
synthetic analogues as candidacidal agents was investigated.
In the field of human health, several investigations have been
conducted on 1a due to its multiple pharmacological activities
including cardioprotective, antiaging, anticarcinogenic, anti-
inflammatory, estrogenic/antiestrogenic, and antioxidant prop-
Received: March 31, 2014
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
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Journal of Natural Products
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Separation of 4′-methoxyresveratrol (1b), 3-methoxyresveratrol
(1c), 3,4′-dimethoxyresveratrol (1d), 3,5-dimethoxyresveratrol
(1e), and 3,5,4′-trimethoxyresveratrol (1f) was performed by
column chromatography on silica gel with petroleum ether−
ethyl acetate as the eluent. Acetyl derivatives of 1a (1g−1j)
were synthesized in one step by using acetyl chloride in a
mixture of Et3N and THF. 3-O-Acetylresveratrol (1g), 3,5-di-
O-acetylresveratrol (1h), 3,4′-di-O-acetylresveratrol (1i), and
3,5,4′-tri-O-acetylresveratrol (1j) were purified on silica gel with
light petroleum−ethyl acetate used for elution. The natural
oligomers of 1a, i.e., trans-ε-viniferin (2a), cis/trans-vitisin B
(3), ampelopsin A (4), and hopeaphenol (5), were purified
from grape cane extracts by centrifugal partition chromatog-
raphy (CPC) and semipreparative HPLC using adapted
conditions.18,19 trans-ε-Viniferin pentamethyl ether (2b) and
trans-ε-viniferin pentaacetate (2c) were obtained by treatment
of 2a with methyl iodide and acetyl chloride, respectively
(Scheme 1).
RESULTS AND DISCUSSION
Five methyl derivatives of trans-resveratrol (1b−1f; Figure 1)
were synthesized from commercial 1a in one reaction using
■
In a first series of experiments, compounds 1a−1k, 2a−2c,
and 3−5 were evaluated for their in vitro antifungal activities
against C. albicans, the most common agent in all clinical forms
of candidiasis (Table 1). At the highest test concentration (300
Table 1. Inhibition of C. albicans SC5314 by Natural and
a
Semisynthetic Stilbenoid Compounds
b
MIC95 (μg/mL)
compound
C. albicans SC5314
c
1a
na
1b
150
300
37
1c
1d
1e
29
c
1f−1k
2a−2c
3
na
c
na
300
c
4, 5
na
d
5-FC
2
Figure 1. Structures of the resveratrol analogues investigated.
a
Data are mean values of two independent experiments, each with
b
three replicates. Minimum inhibitory concentration (the lowest
compound concentration causing 95% growth inhibition). No activity
at the highest test concentration, 300 μg/mL. 5-Fluorocytosine.
c
d
methyl iodide in the presence of sodium hydride in N,N-
dimethylformamide, as described in the Experimental Section.
Scheme 1. Substitutions of trans-ε-Viniferin
B
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Journal of Natural Products
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μg/mL) used, compounds 1a, 1f−1k, 2a−2c, 4, and 5 did not
show any activity against the C. albicans reference strain
SC5314. In contrast, five compounds displayed moderate (1b,
1c, and 3) to high (1d and 1e) antifungal activities. Of note, the
absence of biological activity of 1a observed in the present work
confirmed previous results.14 Interestingly, the methyl deriva-
tives of 1a showed varying degrees of antifungal activity
depending on the number and the position of the methyl
groups present. The highest candidacidal activities were
observed for the dimethoxy-resveratrol derivatives (1d and
1e), with minimum inhibitory concentration (MIC) values of
29−37 μg/mL, whereas two monomethoxy-resveratrol deriva-
tives (1b and 1c) showed moderate activities, with MICs of
150−300 μg/mL. In contrast, the trimethoxy-resveratrol
derivative 1f exhibited no discernible activity. In addition,
given the importance of the yeast-to-hyphae transition in the
virulence of C. albicans,20 the effect of 1e was tested on the
SC5314 strain morphogenetic transition (Figure 2). The results
activities for compounds 1b and 1e against all the tested
Candida species including C. albicans.
Therefore, the two dimethoxy-resveratrol derivatives 1d and
1e displayed interesting antifungal activities against a broad
spectrum of yeasts of the genus Candida. The pharmacomo-
dulation of 1a by selective methoxylation showed that
candidacidal activity is position-dependent, with the best
activity at the 3,5-position. Although several oligomers of 1a
have shown significant activity against various phytopathogenic
fungi,23 they were not potently active against C. albicans,
thereby suggesting the ability of this yeast to detoxify 1a
oligomers.
EXPERIMENTAL SECTION
■
General Experimental Procedures. CPC was carried out on an
FCPC Preparative 200 Kromaton Technologies apparatus (Annonay,
France). Semipreparative HPLC was conducted on a Dionex UHPLC
U3000RS system using a 3 μm column (250 × 10 mm, Multospher
120 RP-18 HP; Chromatographie Service, Langerwehe, Germany).
TLC was performed on silica gel sheets (silica gel 60 F254, Merck,
Germany). NMR experiments were performed at 300 MHz (1H) and
75 MHz (13C) on a Bruker-Avance 300 MHz spectrometer, with TMS
as internal reference. Mass spectra were obtained on a Varian MAT
311 and a Micromass ZAB SpecTOF mass spectrometer. Compounds
1b−d, 1f−j, 2a−2c, 3, 4, and 5 were identified by comparison of their
physicochemical properties (Supporting Information) with reported
values.24−32 trans-Resveratrol (1a), trans-resveratrol 5-β-monogluco-
side (piceid, 1k), and 3,5-dimethoxyresveratrol (1e) were purchased
from Sigma-Aldrich (St. Louis, MO, USA).
Purification of Resveratrol Oligomers. Grape canes of Vitis
vinifera L. variety “Malbec” (Vitaceae) were collected from vineyards in
the wine school of Amboise (France). Grape canes were ground with a
cooled analytical mill (IKA-Werke, Germany) and extracted in
ethanol−water (6:4; 24 h) in a Soxhlet apparatus. After filtration,
the solution was concentrated at 40 °C under reduced pressure and
lyophilized. Purification procedures for 2a and 3−5 were adapted from
published procedures.18,19 Dried extract (4 g) was dissolved in 20 mL
of the organic/aqueous phase mixture (1:1) of Arizona L system (n-
heptane−EtOAc−MeOH−H2O, 3:2:3:2) and injected into the CPC
apparatus. The extract was injected at 3 mL/min at low rotation speed
(600 rpm), and then the rotation speed was increased to 1300 rpm.
Separation was performed at 1300 rpm, with a 6 mL/min flow rate
(with 5% cocurrent flow) and using a step gradient procedure in the
ascending mode. The Arizona L organic phase was used as starting
mobile phase for 75 min; then the mobile phase was switched to the
organic phase of the Arizona K solvent system (n-heptane−EtOAc−
MeOH−H2O, 1:2:1:2) for an additional 75 min. Fractions were
collected every minute and combined on the basis of HPLC analysis,
providing a total of three fractions of interest. Fraction 1 (101 mg)
corresponded to 90% pure 2a as a yellow solid, mp 258 °C. Fraction 2
(55.8 mg) contained one tetramer of interest, presumed as 3, along
with other compounds, and was purified by semipreparative HPLC.
The mobile phase consisted of aqueous trifluoroacetic acid (0.1% w/v;
eluent A) and acetonitrile (eluent B) pumped at 3.5 mL/min into the
HPLC system. The elution program was as follows: 10% to 40% B
(from 0 to 15 min), 40% to 42% B (from 15 to 50 min), followed by
washing and reconditioning the column. The isolated compound was
identified by HPLC-DAD and 1H and 13C NMR spectroscopy analysis
in acetone-d6. However, it was possible to obtain only a mixture of the
70% cis and 30% trans forms because 3 was subject to isomerization
during purification. Fraction 3 (264.3 mg) was fractionated with a
second CPC step using the Arizona H solvent system (n-heptane−
EtOAc−MeOH−H2O, 1:3:1:3) in the ascending mode, at 1300 rpm at
a flow rate of 6 mL/min. Fraction 3 was injected at 3 mL/min, at low
rotation speed (600 rpm), in a mixture of 10 mL of organic and
aqueous phase (1:1, v/v). Fractions were collected every 30 s and
combined on the basis of HPLC analyses, providing a total of two
fractions of interest. Fraction 3A (60.4 mg) corresponded to 90% pure
Figure 2. Effect of different concentrations of 3,5-dimethoxyresveratrol
(1e) on the yeast-to-hyphae morphogenetic transition of C. albicans
SC5314 after 48 h of incubation at 32 °C in RPMI medium; untreated
control cells (A) and 7 (B), 14 (C), and 28 μg/mL (D) 3,5-
dimethoxyresveratrol (1e).
showed that 1e is able to inhibit hyphal formation for this strain
at 14 μg/mL. The antifungal activity of 1e and its capacity to
disrupt hyphal formation of C. albicans SC5314 are in
agreement with recent results.21
Although C. albicans remains the most frequent agent of
candidiasis, non-albicans Candida (NAC) species now account
for a substantial proportion of clinical isolates collected
worldwide. NAC species of particular clinical importance
include C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei,
as well as the emerging species C. guilliermondii, C. lusitaniae, C.
kefyr, C. famata, C. inconspicua, C. dubliniensis, and C.
norvegensis.22 In a second series of experiments, the antifungal
activity was tested for compounds 1b−1e and 3 against these
11 NAC species (Table 2). The results showed antifungal
C
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Journal of Natural Products
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a
Table 2. Antifungal Activity (MIC95 μg/mL) of Selected Stilbenoid Compounds against Candida Species
b
MIC95 (μg/mL)
c
Candida sp.
strain
5-FC
1b
1c
1d
1e
3
C. albicans
ATCC MYA-2876 (SC5314)
ATCC MYA-646
VKMY-9
2
2
2
4
2
4
4
4
2
4
4
4
150
150
18
300
150
18
37
18
9
28
14
7
300
150
18
C. dubliniensis
C. famata
C. glabrata
C. guilliermondii
C. inconspicua
C. kefyr
ATCC 90030
150
150
300
150
150
300
75
300
150
300
150
300
300
300
300
na
37
18
37
18
37
37
37
18
27
28
7
300
150
300
150
300
300
300
300
ATCC 6260
clinical isolate
clinical isolate
ATCC 6258
28
14
28
28
28
14
28
C. krusei
C. lusitaniae
C. norvegensis
C. parapsilopsis
C. tropicalis
CBS 6936
clinical isolate
ATCC 22019
300
300
d
d
ATCC MYA-3404/T1
na
a
b
Data are mean values of two independent experiments, each with three replicates. Minimum inhibitory concentration (the lowest compound
c
d
concentration causing 95% growth inhibition). No activity at the highest test concentration, 300 μg/mL. 5-Fluorocytosine.
4. Fraction 3B (12.8 mg), containing one tetramer of interest with
other compounds, was purified by semipreparative TLC. The TLC
plates were developed with CHCl3−MeOH−acetic acid (80:20:3, v/
v). The detection was achieved at 254 nm. The eluted compound (8.7
mg) corresponded to 90% pure 5.
column chromatography (light petroleum−EtOAc, 70:30), giving 2c
(55 mg) in 63% yield as a white solid.
In Vitro Antifungal Assays. Minimum inhibitory concentration
values (Tables 1 and 2) were determined using the broth
microdilution method (serial 2-fold dilutions) as recommended by
the Clinical Laboratory Standards Institute.33 Strains were grown in
RPMI AutoMod medium (Sigma). Yeasts were added by inoculation a
0.5 McFarland standard solution (106 cfu/mL) in a final volume of 0.3
mL. After incubation for 48 h at 32 °C, the MIC was read following
the OD at 630 nm at the lowest compound concentration causing 95%
growth inhibition compared to the control. The C. lusitaniae strain was
from Centraalbureau voor Schimmelcultures (CBS, Utrecht, The
Netherlands), and Candida guilliermondii, C. parapsilopsis, C. glabrata,
C. krusei, C. tropicalis, C. dubliniensis, and C. albicans strains were from
the American Type Culture Collection (ATCC, Manassas, VA, USA).
The C. famata strain was kindly provided by Prof. Andriy Sibirny
(National Academy of Sciences, Kiev, Ukraine). Candida kefyr, C.
norvegensis, and C. inconspicua clinical isolates were from the Angers
University Hospital (Angers, France). The antifungal agent flucytosine
(5-fluorocytosine, Sigma-Aldrich, St. Louis, MO, USA) was used as
positive control.
Synthesis of Methyl Derivatives of trans-Resveratrol (1b−
1f). To a suspension of 1a (1g, 4.38 mmol) in anhydrous DMF (20
mL) under an inert atmosphere was added portionwise NaH (157 mg,
1.5 × 4.38 mmol) at −5 to 0 °C. The mixture was stirred for 30 min
under continued cooling. CH3I (0.4 mL, 1.5 × 4.38 mmol) was then
added, and the mixture was warmed to ambient temperature naturally.
After 18 h, the mixture was diluted with EtOAc (40 mL), washed with
brine (3 × 30 mL), dried, filtered, concentrated under vacuum, and
purified by flash column chromatography (light petroleum−EtOAc,
95:5 to 70:30), giving 1f (176 mg) in 24.5% yield as a white solid, 1e
(345 mg) in 48% yield as a white solid, 1d (97 mg) in 13.5% yield as a
white solid, 1c (30 mg) in 4.5% yield as a white solid, and 1b (68 mg)
in 9.5% yield as a white solid.
Synthesis of Acetyl Derivatives of trans-Resveratrol (1g−1j).
A solution of 1a (1 g, 4.38 mmol) in a mixture of Et3N−THF (10 mL)
under an inert atmosphere was added to a solution of acetyl chloride
(0.47 mL, 1.5 × 4.38 mmol) in anhydrous THF (5 mL) at 0 °C. The
mixture was then stirred for 18 h under continued cooling, basified
using aqueous 10% NaOH until pH 9, and extracted with EtOAc (3 ×
20 mL). The combined organic layers were washed with brine (3 × 30
mL), dried, filtered, concentrated under vacuum, and then separated
by flash column chromatography (light petroleum−EtOAc, 90:10 to
70:30), affording 1j (103 mg) in 17.3% yield as a white solid, 1i (290
mg) in 48.8% yield as a white solid, 1h (40 mg) in 6.7% yield as a
white solid, and 1g (119 mg) in 20.8% yield as a white solid.
Synthesis of trans-ε-Viniferin Pentamethyl Ether (2b). NaH
(78 mg, 6 × 0.33 mmol) was added dropwise at −5 to 0 °C to a
magnetically stirred solution of 2a (150 mg, 0.33 mmol) in anhydrous
DMF (5 mL) under an inert atmosphere. Then, CH3I (120 μL, 6 ×
0.33 mmol) was added, and the mixture was warmed to ambient
temperature naturally. After 18 h, the mixture was diluted with EtOAc
(20 mL), washed with brine (3 × 20 mL), dried, filtered, concentrated
under a vacuum, and purified by flash column chromatography (light
petroleum−EtOAc, 80:20), giving 2b (100 mg) in 58% yield as a white
solid.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectroscopic data of compounds 1b−d, 1f−
j, 2a−2c, and 3−5. 1H NMR spectra of 3 and 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +33-2-47-36-72-14. Fax: +33-2-47-36-72-32. E-mail:
arnaud.lanoue@univ-tours.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Synthesis of trans-ε-Viniferin Pentaacetate (2c). A solution of
acetyl chloride (60 μL, 6 × 0.13 mmol) in anhydrous THF (5 mL) at
0 °C was added dropwise to a solution of 2a (60 mg, 0.13 mmol) in a
mixture of Et3N−THF (2 mL) under an inert atmosphere. The
mixture was then stirred for 18 h under continued cooling, basified
using aqueous 10% NaOH until pH 9, and extracted with EtOAc (3 ×
10 mL). The combined organic layers were washed with brine (3 × 10
mL), dried, filtered, concentrated under vacuum, and purified by flash
■
This work was supported by the Reg
́
ion Centre grants
ACTISARM 201100068678 and VITITERROIR
201300083172. The authors wish to thank A. Mancois and F.
Fourmont (Lycee Viticole d’Amboise, France) for providing
̧
́
the grape canes. We acknowledge A. J. Simkin for critical
reading of the manuscript.
D
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