3,4,2′-Trimethoxy-trans-stilbene-a potent CYP1B1 inhibitor

Article abstract of DOI:10.1039/c3md00317e

A novel series of methoxy-trans-stilbenes with 3,4-dimethoxy motifs was designed and synthesized. The inhibitory potency of 3,4-dimethoxystilbene derivatives against cytochrome P450 isozymes CYP1A1, CYP1B1 and CYP1A2 was evaluated. 3,4,2′-Trimethoxy-trans-stilbene (3,4,2′-TMS) exhibited extremely potent inhibitory action against CYP1B1 activity with an IC ₅₀ of 0.004 μM. 3,4,2′-TMS exhibited 90-fold selectivity for CYP1B1 over CYP1A1 and 830-fold selectivity for CYP1B1 over CYP1A2. However, 3,4,2′,4′-tetramethoxy-trans-stilbene appeared to be the most selective inhibitor of both CYP1B1 and CYP1A1 showing very low affinity toward CYP1A2. Complementary experimental studies and computational methods were used to explain what structural determinants decide the specific affinity of stilbene derivatives to CYP1A2 and CYP1B1 binding sites.

Full text of DOI:10.1039/c3md00317e

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3,4,20-Trimethoxy-trans-stilbene – a potent
CYP1B1 inhibitor†
Cite this: Med. Chem. Commun., 2014,
5, 496
Renata Mikstacka, a Marcin Wierzchowski,a Zbigniew Dutkiewicz,a Agnieszka Gielara-
*
Korzanska,a Artur Korzanski,b Anna Teubert,c Stanisław Sobiaka and Wanda Baer-
´
´
Dubowskad
A novel series of methoxy-trans-stilbenes with 3,4-dimethoxy motifs was designed and synthesized. The
inhibitory potency of 3,4-dimethoxystilbene derivatives against cytochrome P450 isozymes CYP1A1,
CYP1B1 and CYP1A2 was evaluated. 3,4,20-Trimethoxy-trans-stilbene (3,4,20-TMS) exhibited extremely
potent inhibitory action against CYP1B1 activity with an IC50 of 0.004 mM. 3,4,20-TMS exhibited 90-fold
selectivity for CYP1B1 over CYP1A1 and 830-fold selectivity for CYP1B1 over CYP1A2. However, 3,4,20,40-
tetramethoxy-trans-stilbene appeared to be the most selective inhibitor of both CYP1B1 and CYP1A1
showing very low affinity toward CYP1A2. Complementary experimental studies and computational
methods were used to explain what structural determinants decide the specific affinity of stilbene
derivatives to CYP1A2 and CYP1B1 binding sites.
Received 24th October 2013
Accepted 19th January 2014
DOI: 10.1039/c3md00317e
www.rsc.org/medchemcomm
17b-estradiol (4-OHE2).14 CYP1B1 is found mainly in extrahe-
patic steroidogenic tissues such as the ovary, testis, and adrenal
Introduction
trans-Resveratrol (3,40,5-trihydroxy-trans-stilbene; Fig. 1) is the
best known natural stilbene derivative that is found in grapes,
peanuts, a variety of berries and medicinal plants. Numerous
biological activities of resveratrol have been shown in studies
in vitro and on animal models in vivo.1,2 It is suggested that this
polyphenol might play a role in the prevention and treatment of
chronic diseases. This potentially chemopreventive and
chemotherapeutic agent is currently under clinical trials.3
Resveratrol analogues are designed and synthesized in order to
obtain bioactive agents as promising as the parent compounds.
In the last decade the inhibitory activity of resveratrol and its
derivatives against cytochrome P450 enzymes has been exten-
sively investigated.4–13 Cytochromes P450 of family 1, cyto-
chrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2) and
cytochrome P450 1B1 (CYP1B1), are involved in the activation of
potential carcinogens. Recently, CYP1B1 has attracted
increasing attention as a drug target. CYP1B1 is postulated to be
involved in mammary carcinogenesis responsible for 17b-
estradiol (E2) metabolism to the highly carcinogenic 4-hydroxy-
gland and in steroid-responsive tissues such as breast, uterus,
and prostate. CYP1B1 demonstrates a higher expression level in
premalignant and malignant tumors compared to normal
tissues.15 CYP1B1 up-regulation plays a crucial role in endo-
metrial carcinogenesis by targeting multiple pathways.16
A
selective inhibition of CYP1B1 is recognized as benecial for the
prevention of hormone-related cancers.
Resveratrol and its natural analogues – pterostilbene (3,5-
dimethoxy-40-hydroxy-trans-stilbene), pinostilbene (3,40-dihy-
droxy-5-methoxy-trans-stilbene), and desoxyrhapontigenin (3,5-
dihydroxy-40-methoxy-trans-stilbene)
–
inhibited CYP1B1
activity with an IC50 of 1.4, 2.1, 0.8, and 2.6 mM, respectively.4,11
Novel stilbene derivatives were designed and synthesized to
obtain more potent and selective inhibitors of CYP1 enzymes.
3,20,40,5-Tetramethoxy-trans-stilbene (3,20,40,5-TMS; Fig. 1) was
the rst synthetic resveratrol analogue that was found to be an
extremely potent inhibitor of CYP1B1 with an IC50 of 2 nM
(Chun et al., 2001; Kim et al., 2002).6,10 Moreover, a strong
cytotoxic activity of 3,20,40,5-TMS (IC50; 0.8 mg mlꢀ1) in cultured
human colon cancer cells and proapoptotic activity were
shown.17
a
´
Department of Chemical Technology of Drugs, Poznan University of Medical Sciences,
More recently, a SAR study by Chun et al. made it possible to
select a series of stilbenoids with 2,4-dimethoxy motifs as
selective inhibitors of CYP1B1 with a lead compound 2,4,20,60-
tetramethoxy-trans-stilbene (2,4,20,60-TMS; Fig. 1) showing
remarkable potency with an IC50 of 1.77 ꢁ 0.14 nM.8 Moreover,
2,4,20,60-TMS suppressed ethoxyresorun-O-deethylase (EROD)
activity and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-
induced CYP1A1 or CYP1B1 gene expression in the human
´
Grunwaldzka 6, 60-780 Poznan, Poland. E-mail: rmikstac@ump.edu.pl
bDepartment of Crystallography, Adam Mickiewicz University, Grunwaldzka 6, 60-780
´
Poznan, Poland
cInstitute of Bioorganic Chemistry, Polish Academy of Sciences, Z. Noskowskiego 12/14,
´
61-704 Poznan, Poland
d
´
Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences,
´
´
Swi˛ecickiego 4, 60-781 Poznan, Poland
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3md00317e
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Fig. 1 Structures of selective CYP1B1 inhibitors: (a) trans-resveratrol; (b) 3,5,20,40-tetramethoxy-trans-stilbene; (c) 2,4,20,60-tetramethoxy-trans-
stilbene.
hepatoma cells HepG2 and non-invasive epithelial cell line step synthesis (Scheme 1) started from 3,4-dimethoxybenzyl
MCF-10A.8 These studies have demonstrated the essential role chloride 2 preparation by converting 3,4-dimethoxybenzyl
of the 2-methoxy group linked to the stilbene scaffold; however, alcohol 1 which was next via Michaelis–Arbuzov reaction modi-
it does not seem to be the only determinant of the exceptionally ed to phosphonate 3 (diethyl (3,4-dimethoxybenzyl)phospho-
strong inhibitory action of stilbene derivatives. Molecular nate). Compound 3 was further transformed in Horner–
modeling indicates that the whole pattern of substituents is an Wadsworth–Emmons reaction with proper aromatic aldehydes
essential determinant of ligand affinity and it guarantees the (4a–4i) into nine investigated trans polymethoxystilbene
unique t of a ligand to the active site of the enzyme. By compounds. The reaction yield of compound 5a to 5i varies
searching for the most effective arrangement of substituents, between 25 and 72%. The structure of the newly synthesized
we designed and synthesized a series of stilbene derivatives with compounds was established by spectroscopic methods (1H
a 3,4-dimethoxyphenyl ring differing in the substitution pattern NMR, 13C NMR), elementary analysis and mass spectra.
of the second ring, that have never been investigated previously.
The structure of synthesized products 5a–5i was conrmed
Their inhibitory effect on cytochrome P450 family 1 enzymes using 1D and 2D NMR techniques and each H and 13C signal
CYP1A1, CYP1A2 and CYP1B1 was investigated experimentally for all compounds was annotated (ESI†). Fig. 3 shows the
by means of EROD activity determination and in silico with the exemplary structure of 5b.
use of molecular docking methods.
1
Crystallographic data
The identication of compounds 5a, 5b, 5f, 5g, and 5i was
conrmed by X-ray crystallography. For the most active CYP1B1
inhibitor 5b, the double bond C7–C8 in the conjugated linkage
Results and discussion
Chemistry
Synthesis of a series of polymethoxystilbenes 5a–5i was per- is in the trans conguration [torsion angle C(4)–C(7)–C(8)–C(9),
formed according to the procedure described above.18 The three- 177.67(13)ꢂ]. Furthermore, the value for the observed double
Scheme 1 Synthesis of compounds 5a–5i. Reaction conditions: (i) SOCl2, CHCl3, 0–25 ꢂC, 1 h; (ii) P(OEt)3, 130 ꢂC, 24 h; (iii) NaOMe, DMF, r.t., 1 h,
next 100 ꢂC, 1.5 h.
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between the planes. Among the three methoxy substituents on
the aromatic ring, only the one at C2 is not exactly coplanar with
the benzene ring (10.54ꢂ). The other two, at C1 and C10, are
approximately coplanar with the benzene ring.20 Only for
structure 5g the aromatic rings deviate signicantly from a
coplanar arrangement, with a dihedral angle of 51.53(5)ꢂ
between the planes. This value for the other structures is
between 4.95(11) and 6.99(9) degrees.
Fig. 2 Annotated signal 1H and 13C NMR spectra according to 2D
experiments (1H–1H COSY, HSQC and HMBC). The abbreviations s, d, t
and m mean: singlet, doublet, triplet and multiplet.
Biological in vitro assay
The inhibition of CYP1A1, CYP1A2 and CYP1B1 activities.
The inhibitory effect of synthesized 3,4-dimethoxy-trans-stil-
bene derivatives was determined using the E. coli membrane
expressed human recombinant cytochromes CYP1A1, CYP1A2
and CYP1B1 with human NADPH-P450 reductase. The activities
of EROD catalyzed by CYP1A1, CYP1A2 and CYP1B1 were
measured spectrouorimetrically according to the method
described in the ESI.† The results concerning the inhibitory
potency and selectivity of the studied stilbenes (Table 1)
demonstrate variations highly dependent on the differences in
the substitution pattern.
˚
bond [C7–C8, 1.334(2) A] is longer than the normal value (1.32
˚
˚
A) and the single bonds [C(4)–C(7) – 1.465(2) A and C(8)–C(9) –
19
˚
˚
1.467(2) A] are shorter than the normal values (1.51 A), indi-
cating the formation of a weak conjugated p-electron system.
These values for all the studied structures (5a, 5b, 5f, 5g, and 5i)
are shown in the ESI.†
The aromatic rings do not deviate signicantly from a
coplanar arrangement, with a dihedral angle of 3.07(9)ꢂ
Fig. 3 A view of 5b, showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms are shown
as small spheres of arbitrary radii.
Table 1 The effect of 3,4-dimethoxy-trans-stilbene derivatives on cytochrome P450 CYP1A1, CYP1A2 and CYP1B1 activitiesa
IC50b [mM]
Compound
R
CYP1A1
CYP1A2
CYP1B1
CYP1A2/CYP1B1
CYP1A1/CYP1B1
5a
5b
5c
5d
5e
5f
5g
5h
5i
3,4-Dimethoxy
0.44 ꢁ 0.12
0.36 ꢁ 0.12
0.45 ꢁ 0.10
0.51 ꢁ 0.27
0.50 ꢁ 0.05
0.23 ꢁ 0.04
5.18 ꢁ 1.35
1.78 ꢁ 0.77
0.27 ꢁ 0.09
6.04 ꢁ 1.98
3.32 ꢁ 0.81
16.02 ꢁ 7.15
>100
0.30 ꢁ 0.04
20.1
830
43.3
>480
>160
7.5
>24
>22.5
>333
1.5
90
1.2
2.4
0.8
0.74
1.2
0.40
0.9
3,4,20-Trimethoxy
0.0040 ꢁ 0.0006
0.37 ꢁ 0.05
0.21 ꢁ 0.07
0.62 ꢁ 0.07
0.31 ꢁ 0.07
4.17 ꢁ 1.44
4.44 ꢁ 0.86
0.30 ꢁ 0.05
3,4,20,30-Tetramethoxy
3,4,20,40-Tetramethoxy
3,4,20,50-Tetramethoxy
3,4,20,60-Tetramethoxy
3,4,20,30,40-Pentamethoxy
3,4,20,40,50-Pentamethoxy
3,4,20,40,60-Pentamethoxy
>100
2.31 ꢁ 0.026
>100
>100
>100
a
CYP1A1, CYP1A2 and CYP1B1 activities were determined by the use of 7-ethoxyresorun-O-deethylation assay according to the method described
in the ESI. b IC50 values are the mean ꢁ range of three separate experiments determined using nonlinear regression methods by GraphPad Prism
soware (San Diego, CA).
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In the present study, 3,4,20-trimethoxy-trans-stilbene (5b) ring B (phenyl with the changing pattern of substituents)
inhibited CYP1B1 activity at the nanomolar level with an IC50 toward heme (Fig. 4a). Other tetramethoxy ligands – 5c, 5d and
of 4.0 nM. This compound was shown to be a particularly 5e – had signicantly lower scores (values ranging from 24.0 to
selective inhibitor of CYP1B1, exhibiting a 90-fold selectivity 34.5). The LigandFit procedure failed to dock pentamethoxy
for CYP1B1 over CYP1A1 and an 830-fold selectivity for CYP1B1 derivatives into the CYP1A2 binding site with only one excep-
over CYP1A2. The other studied compounds (listed in Table 1) tion of 5i, which was characterized by a low score and a high
possessing additional 30-, 40-, 50- or 60-methoxy substituents strain energy value.
displayed a potent inhibitory action on CYP1B1, which was,
All ligands were successfully docked to the binding site of
however, not so signicant. For example, pentamethoxy CYP1B1; however, pentamethoxy derivatives had a very low
derivatives (5g and 5h) were 1000-fold weaker CYP1B1 inhibi- score. When comparing the calculated parameters for both
tors compared to 5b. It is worth noting that among pentam- enzymes, it must be emphasized that all DockScore values for
ethoxy derivatives only 5i with methoxy groups at 20 and 60 the studied stilbenes docked to CYP1B1 were higher than the
positions was a potent inhibitor of CYP1A1 and CYP1B1
exhibiting an IC50 < 1 mM.
All 3,4-dimethoxystilbene derivatives potently inhibited
CYP1A1 activity. With the exception of pentamethoxystilbenes
5g and 5h, for the other studied compounds, the IC50 values
were less than 1 mM, and signicant differences in IC50 were not
observed. In an earlier study of a stilbene derivative, 2,3,4-tri-
methoxy-40-methylthio-trans-stilbene was reported to be a
potent and selective inhibitor of the isozymes CYP1A1 and
CYP1B1, displaying an extremely low affinity towards CYP1A2.21
Interestingly, 5g was a signicantly weaker inhibitor of CYP1A1
activity in comparison with 2,3,4-trimethoxy-40-methylthio-
trans-stilbene. It may be concluded that an additional
3-methoxy substituent in the stilbene with the 2,3,4-trimethoxy
motif inuences the localization and interaction of 5g in the
CYP1A1 cavity.
The affinity of stilbenes to the CYP1A2 binding site is
determined substantially by the size and shape of the molecule
as a binding pocket of this enzyme is recognized to be more at
and tight than those of CYP1A1 and CYP1B1.22 The relatively
small and compact molecules of stilbenes 5b and 5f were the
most active against CYP1A2 with an IC50 of 3.32 and 2.31 mM,
respectively.
The inhibitory activity of moderately strong inhibitors with
IC50 at the micromolar level may be explained and predicted on
the basis of their structure. However, in the case of very potent
inhibitors, the subtle differences in affinities to CYP1 binding
sites (IC50 < 0.1 mM) could be possibly elucidated only with
computational studies comprising molecular modeling and
docking with a detailed description of molecular interactions.
Computational study
We used a molecular docking approach to elucidate the
strong and selective affinity of 3,4,20-TMS to the CYP1B1
binding site. The analyzed molecules were docked to the
active sites of CYP1A2 (PDB: 2HI4)23 and CYP1B1 (PDB:
3PM0)24 with the use of Accelrys Discovery Studio 3.525 by the
LigandFit procedure.26 The binding energy, interaction energy
and strain energy were also estimated (values for the best
poses are presented in the ESI†).
Molecular docking to the CYP1A2 cavity was performed for
all synthesized compounds. The highest values of the Dock-
Score function were obtained for 5a, 5b and 5f (52.6, 53.0 and
Fig. 4 The highest scored pose of 5b in (a) CYP1A2 and (b) CYP1B1
binding sites. Solid blue lines represent p–p interactions; heme is
42.2, respectively). The ligands were preferably oriented with represented as a stick model in red.
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Fig. 5 The amino acid residues surrounding 5b in the CYP1B1 binding site. Residues involved in van der Waals and polar interactions are colored
in green and magenta, respectively. Solid blue lines represent p–p interactions.
respective values in the case of CYP1A2. Strain energies, with
the exceptions of 5a and 5e, were signicantly lower for stil-
Conclusions
benes in the CYP1B1 binding site. Moreover, binding free
energies for all compounds docked to CYP1B1 are considerably
higher than that of CYP1A2; it may be suggested that complexes
of CYP1B1 with ligands are much more stable in comparison
with complexes of CYP1A2.
CYP1B1 inhibition is extremely sensitive to the substitution
pattern of trans-stilbene. In the present study, 5b inhibited
CYP1B1 activity in the nanomolar range with an IC50 value of 4.0
nM. Moreover, 5b displayed a 90-fold selectivity for CYP1B1 over
CYP1A1 and an 830-fold selectivity for CYP1B1 over CYP1A2.
With the use of in silico methods, the favorite pose of ligands
with 3,4-dimethoxyphenyl directed toward heme in the CYP1B1
binding site was identied. The methoxy group in the 20 posi-
tion appeared to be a crucial substituent; however, other
determinants of 5b inhibitory potency toward CYP1B1 remain
to be identied on the molecular level. Experimental studies of
the inhibitory activity of stilbene derivatives supported by
computational screening may be helpful in the design of
molecules targeting the enzymes involved in the biotransfor-
mation of potential carcinogens. However, further improve-
ments of analyzing functions would be expected to better
estimate ligand-binding site interactions. On the other hand,
nding a new very selective CYP1B1 inhibitor opens up an
opportunity for further studies on 17beta-estradiol metabolism
pathways in terms of inhibition of carcinogenic 4-OHE2
generation.
The extremely strong affinity of 5b to CYP1B1 was reected in
the highest value of binding free energy, ꢀ443.1 kcal molꢀ1
,
when ring A (3,4-dimethoxyphenyl) was directed to the heme
(Fig. 4b). This pose seems to be more favorable because 17 of
the 20 poses analyzed for 5b docked to CYP1B1 were directed
with 3,4-dimethoxyphenyl to the heme. For the opposite
orientation the binding energy was signicantly lower (ꢀ403.0
kcal molꢀ1). Additionally, the interaction energy for the orien-
tation of ring A or B towards heme differs considerably, with
values of ꢀ59.0 and ꢀ47.2 kcal molꢀ1, respectively. It is worth
adding that according to the nding of Chun,6 the more ener-
getically favorable orientation enables demethylation of 3,4-
dimethoxy stilbene derivatives.
Interestingly, in the energetically favorable orientation of 5b
docked to the CYP1B1 pocket, there were no hydrogen bonds
formed. Most interactions were attributed to van der Waals forces
and only p–p stacking interaction occurred for Phe231 (Fig. 5),
whereas in the opposite orientation of 5b (with a 20-methoxy-
phenyl ring directed to the heme), hydrogen bonding between a
3-methoxy group and an amino acid residue Gln332 occurred.
Hydrogen bonds were not observed, either, when the tested
ligands were docked to the CYP1A2 active site. The binding
specicity of polymethoxystilbenes was supposed to be based on
the hydrophobic interactions between the methoxy groups and
the specic CYP1 residues (Fig. 5), as it was observed when
methoxyavonoids were docked to CYP1A2 and CYP1B1.27
However, itseems that inthe case ofthe studied series of stilbenes
spatial tting plays an important role besides molecular interac-
tions between the ligand and the binding site environment.
Acknowledgements
´
This study was supported by Poznan University of Medical
Sciences, grant no. 502-01-03313427-08870, Polish National
Science Centre, grant 2012/05/B/NZ7/03048 and the European
Fund for Regional Development no. UDA-POIG.02.01.00-30-182/09.
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