Synthesis, spectroscopic studies and crystal structure of 5,5′-dimethoxy-3,3′-methanediyl-bis-indole as the inhibitor of cell proliferation of human tumors

Article abstract of DOI:10.1515/znb-2004-1010

5,5′-Dimethoxy-3,3′-methanediyl-bis-indole (3) Was synthesized in a reductive cyclisation process from (E)-5-methoxy-2-nitro-β- morpholinestyrene. The solid state structure was probed by single crystal X-ray diffraction and ¹³C CP/MAS NMR methods. The results of the X-ray analysis indicate insignificantly different structure of both methoxyindole fragments of the molecule, and this is the main reason for the appearance of the double resonances in the solid state NMR spectrum. Interesting N-H?π interactions were observed which may have a functional role in biological features of 3. 5,5′-Dimethoxy-3,3′-methanediyl-bis-indole at conc. 1·10^-4 M reduces the growth of MCF7 (breast), NCI-H460 (lung), and SF-268 (NCS) cells to 21, 0, and 48%, respectively.

Full text of DOI:10.1515/znb-2004-1010

Synthesis, Spectroscopic Studies and Crystal Structure of 5,5’-Dimethoxy-
3,3’-methanediyl-bis-indole as the Inhibitor of Cell Proliferation of
Human Tumors
Dorota Maciejewskaa, Maria Niemyjskaa, Irena Wolskab, Marek Włostowskic,
and Magdalena Rasztawickaa
a Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw,
1 Banacha Str, 02 097 Warsaw, Poland
b Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University,
6 Grunwaldzka Str, 60-780 Poznan´, Poland
c Faculty of Chemistry, Warsaw University of Technology,
75 Koszykowa Str, 00 662 Warsaw, Poland
Reprint requests to Prof. Dr. hab. D. Maciejewska. Fax: +48(22)5720643.
E-mail: domac@farm.amwaw.edu.pl
Z. Naturforsch. 59b, 1137 – 1142 (2004); received April 9, 2004
5,5’-Dimethoxy-3,3’-methanediyl-bis-indole (3) was synthesized in a reductive cyclisation process
from (E)-5-methoxy-2-nitro-β-morpholinestyrene. The solid state structure was probed by single
crystal X-ray diffraction and 13C CP/MAS NMR methods. The results of the X-ray analysis indicate
insignificantly different structure of both methoxyindole fragments of the molecule, and this is the
main reason for the appearance of the double resonances in the solid state NMR spectrum. Interesting
N-H···π interactions were observed which may have a functional role in biological features of 3. 5,5’-
Dimethoxy-3,3’-methanediyl-bis-indole at conc. 1 · 10−4 M reduces the growth of MCF7 (breast),
NCI-H460 (lung), and SF-268 (NCS) cells to 21, 0, and 48%, respectively.
Key words: 5,5’-Dimethoxy-3,3’-methanediyl-bis-indole, Anticancer Agent,
Reductive Cyclisation, X-ray Diffraction, 13C CP/MAS NMR
Introduction
The antiproliferative effect of 3,3’-diindolylme-
thane DIM (Fig. 1) on human breast and endome-
trial cancer cells was shown in papers [1 – 4]. DIM
is a major product of acid condensation of indole-3-
carbinol IC (Fig. 1), which is liberated from gluco-
brassicin by autolytic breakdown. However, IC and its
acid condensation product DIM appeared to enhance
tumor growth in some animal models, when adminis-
tered at post-initiation stage [5 – 7]. Thus, the search
for more selective 3,3’-diindolymethane derivatives
would be a fruitful synthetic direction. The first goal
of our project was 5,5’-dimethoxy-3,3’-methanediyl-
bis-indole 3 (Fig. 1). The structure of 3 in solution
Fig. 1. Chemical formulas and atom numbering.
1
was confirmed by 1D, 2D H and 13C NMR spectra in
not an easy task, but we were successful in growing
suitable crystals of 3 for X-ray diffraction measure-
ment. Geometric details of putative anticancer agents
are crucial for their biochemical activity, and we have
been analyzing them for the purpose of future synthetic
work.
DMSO-d6. In order to probe the molecular structure of
3 in solid state we took a 13C CP/MAS NMR spectrum
of the powdered sample. Double signals with intensity
ratios of 1:1 were observed in the 13C CP/MAS NMR
spectrum (Fig. 2) for the majority of C atoms. It was
c
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D. Maciejewska et al. · Synthesis, Spectroscopic Studies and Crystal Structure
Scheme 1. Reagents and conditions
for preparation of 5,5’-dimethoxy-3,3’-
methanediyl-bis-indole 3.
doles. Therefore, we modified the scheme using trip-
iperidinylmethane [9] by employing trimorpholyl-
methane in the first step. Next, we found the catalyst
10% Pd(C) to be convenient in the reductive cycli-
sation step (Scheme 1). The mechanism of the reac-
tion described herein was not studied, but it should be
related to the one suggested by the authors of [10],
in which an initial reduction of the nitro group to an
amine is followed by palladium-catalyzed cyclisation
chemical shifts of 13C in solid state, δ [ppm]
C4 C5 C6 C7 C8 C9
123.3 114.4 99.4 152.5 112.8 112.8 127.3 131.8 23.6 54.9
C2
C3
C10 C11
to the indole ring.
C2’
C3’
C4’
C5’
C6’
C7’
C8’
C9’
–
C11’
53.3
In our synthesis (E)-5-methoxy-2-nitro-β-morpho-
linestyrene 2 was originally used as reactant. It was
identified as E isomer by 1H NMR spectroscopy.
123.3 116.8 97.7 153.9 112.8 112.8 127.8 130.5
Results and Discussion
Spectroscopic study
Standard 1D and 2D hetero- and homonuclear NMR
experiments were sufficient to afford complete assign-
ment of the solution spectra of compounds 2, 2a, and 3.
In NMR spectra of 5,5’-dimethoxy-3,3’-methanediyl-
bis-indole 3 in solution we have observed a simple
pattern of signals (i.e. the number of resonances was
in agreement with the number of atoms). This means
that no hindered rotation takes place in solution, in
opposition to the situation in the solid state, where
we have observed double signals in the 13C CP/MAS
NMR spectrum of 3 (Fig. 2). This could have been
caused by the presence of two energetically similar
conformers of 3 in the solid state, or to different pack-
ing mode of both indole rings in one conformer. Crys-
tallographic atom coordinates were used for the com-
putation of shielding constants σ [ppm] of 13C atoms
to assign the resonances in solid-state NMR, employ-
Fig. 2. The 13C CP/MAS NMR spectrum of 5,5’-dimethoxy-
3,3’-methanediyl-bis-indole 3 in solid state. A linear correl-
ation between calculated shielding constants σ and experi-
mental chemical shifts δ values.
A lot of synthetic procedures towards indole have
been published [8]. Numerous reductive cyclisation
reactions of various 2-nitrostyrene derivatives can be
found in the literature [9 – 12], but some of them are
not very effective for the preparation of methoxyin-
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D. Maciejewska et al. · Synthesis, Spectroscopic Studies and Crystal Structure
1139
Table 1. Crystal data, data collection and structure refine-
ment.
Empirical formula
Formula weight
T [K]
C19H18N2O2
306.35
130(2)
˚
Wavelength [A]
0.71073
Crystal system, space group
Unit cell dimensions
orthorhombic, P212121
˚
a [A]
5.932(1)
˚
b [A]
10.892(1)
23.207(2)
1499.4(3)
4, 1.357
0.089
648
4.72 – 29.38
−4 ≤ h ≤ 8
−14 ≤ k ≤ 14
−31 ≤ l ≤ 31
˚
c [A]
3
˚
Volume [A ]
Z, Dx [Mg/m3]
µ [mm−1
F(000)
]
◦
θ Range for data collection [ ]
hkl Range
Fig. 3. The molecular structure of 3 with 50% probability
displacement ellipsoids and atom-numbering scheme.
Reflections:
collected
unique (Rint)
10256
3820 (0.04)
2626
3820 / 0 / 210
0.834
0.0352
0.0618
0.151 / −0.171
ing DFT method with B3LYP/6–31(d,p) hybrid func-
tional using the CHF–GIAO approach [13]. The pres-
ence of a linear correlation (r = −0.993) between the
calculated shielding constants σ and the experimental
chemical shift δ values is good evidence of correct-
ness of proposed assignments (see Fig. 2). The ori-
gin of the above-mentioned double resonances is that
non-equivalent conformations of both 5-methoxy sub-
stituted indole rings are present in solid state, resulting
in diversification of the C atoms shielding constants of
rings A and B (see Fig. 3). This type of resonance pat-
tern was not observed in solution because of plausible
low-lying barriers of single C-O and C-C bonds rota-
tions.
observed (I > 2((I))
Data / restraints / parameters
Goodness-of-fit on F2
R(F)(I > 2σ(I))
wR(F2) (all data)
3
˚
Max./min. ∆ρ [e/A ]
˚
Table 2. Selected bond lengths [A] and angles [deg] and se-
lected torsion angles [deg].
C3-C10
C5-O11
O11-C11
1.503(2) C3’-C10
1.382(2) C5’-O11’
1.424(2) O11’-C11’
1.504(2)
1.388(2)
1.430(2)
C3-C10-C3’
C4’-C5’-O11’
C5’-O11’-C11’
115.8(1) C4-C5-O11
124.0(1) C5-O11-C11
117.3(1)
124.8(1)
116.4(1)
C2-C3-C10-C3’
C3-C10-C3’-C2’
−98.6(2) C4-C5-O11-C11
3.1(2)
−14.7(2)
Crystallographic study
−132.7(1) C4’-C5’-O11’-C11’
The molecular structure of 3 in the solid state was
analyzed by single crystal X-ray diffraction. Crys-
tallographic data, together with data collection and
structure refinement details are listed in Table 1. Se-
lected bond lengths, bond angles and torsion angles
are listed in Table 2. Additional crystallographic data
have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publications No
CCDC-238437. The displacement ellipsoid represen-
tation of the molecule, together with the atomic num-
bering scheme, is shown in Fig. 3 (the drawings were
performed with a Stereochemical Workstation [14]).
the five-membered and six-membered rings are 3.0(1)◦
and 3.2(1)◦ in indoles A and B, respectively. Atom
C10 is displaced from the mean plane of indole frag-
˚
˚
ments by 0.022(2) A and 0.195(2) A for indole A and
B, respectively. We have observed slightly different
conformations of the methoxy groups. The disposition
of these groups with respect to the indole fragments
can be described by torsion angles C4-C5-O11-C11
of 3.14(1)◦ and C4’-C5’-O11’-C11’ of −14.74(1)◦. In
consequence, the methyl carbon atom C11 is found to
˚
be only 0.067(2) A out of the indole A plane, the other
˚
Two methoxyindole systems (A and B, see Fig. 3) methyl carbon atom C11’ is found to be −0.346(2) A
are connected through a common C atom. Both indole out of the indole B plane. Thus, the results of the X-
moieties are quite planar and their planes make an an- ray analysis indicate an insignificantly different struc-
gle 68.10(3)◦. The small tilts between the planes of ture of both methoxyindole fragments of the molecule.
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D. Maciejewska et al. · Synthesis, Spectroscopic Studies and Crystal Structure
˚
Table 3. Hydrogen-bonding geometry [A and deg.].
D-H···A
d(D-H) d(H···A) d(D···A) <(DHA)
N1-H1···O11’ i
N1’-H1’···Cgii
C2’-H2’···O11iii
C11-H11A···N1iv
C11-H11C··· O11’v
0.86
0.86
0.93
0.96
0.96
2.17
2.49
2.56
2.84
2.79
2.965(2)
3.261(2)
3.421(2)
3.591(2)
3.604(2)
153
149
154
136
144
Cg represents the centroid of the five-membered ring of indole B.
Symmetry transformations used to generate equivalent atoms:i x +
1/2, −y + 3/2, −z + 1; ii x − 1/2, −y + 5/2, −z + 1; iii −x + 1, y +
1/2, −z+1/2; iv x−1, y, z; v −x+3/2, −y+2, z−1/2.
Fig. 5. Projection of crystal structure along the a axis.
are reported as the percentage of growth of the treated
cells when compared with untreated control cells. 5,5’-
Dimethoxy-3,3’-methanediyl-bis-indole 3 at conc.
1 · 10−4 M reduces the growth of MCF7, NCI-H460,
and SF-268 cell lines to 21, 0, and 48 percent, respec-
tively.
Fig. 4. Infinite helical chains along the a axis. H atoms, ex-
cept H1 and H1’, are omitted for clarity. Cg represents the
centroid of the five-membered ring of indole B.
Experimental Section
That is probably the reason why double resonances ap-
pear in NMR spectra of 3.
Reagents and techniques
Intermolecular hydrogen bonds determine the crys-
tal packing of the molecules. Geometric parameters of
all these bonds are listed in Table 3. The most inter-
esting are shown in Fig. 4 and 5. In the crystal the
molecules are connected via intermolecular hydrogen
bonds N1-H1···O11’ and N1’-H1’···π (Fig. 4) along
the two-fold screw axis parallel to the [100] direction.
The O11 atom is involved in intermolecular hydro-
gen bonds C2’-H2’···O11 (Fig. 5), which connect the
molecules to infinite chains along the b axis. Similar
N-H···π interactions were observed for other indole
derivatives [15, 16] and for globular proteins [17]. It
has been suggested that such interactions may provide
stability and may contribute to the folding process or
have a functional role in proteins.
Melting points were determined with a Digital Melting
Point Apparatus 9001 and are uncorrected. 1H NMR and
13C NMR spectra in solution were recorded with a Varian
Unity plus-500, and standard Varian software was employed.
Chemical shifts δ [ppm] were references to TMS. The solid
state 13C CP/MAS NMR spectrum of 3 was measured us-
ing a Bruker Avance DMX 400. A powdered sample was
spun at 8 kHz. Contact time of 7 ms, repetition time of 20 s,
and spectral width of 24 kHz were used for accumulation
of 3,000 scans. All reported elemental analyses were aver-
aged from two independent determinations. Prefabricated sil-
ica gel sheets (Merck Kieselgel 60 F254) were used for TLC.
Reagents were obtained from commercial sources.
The synthesis of 3-methyl-4-nitroanisole (1a) from
3-methyl-4-nitrophenole (1) has already been described
[19, 20].
Notation used in the NMR assignments is given in
Scheme 1 and Fig. 1.
Primary anticancer prescreen
5,5’-Dimethoxy-3,3’-methanediyl-bis-indole 3 was
selected by the National Cancer Institute (NSC num-
ber 731013) [18]. As a primary anticancer assay, a 3-
cell line panel consisting of the MCF7 (Breast), NCI-
Preparation
(E)-5-Methoxy-2-nitro-β-morpholinestyrene (2)
The mixture of morpholine (7.49 g, 0.105 mol) and tri-
H460 (Lung), and SF-268 (CNS) was used. The results ethyl orthoformate (7.41 g, 0.05 mol) with 0.2 ml CH3COOH
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D. Maciejewska et al. · Synthesis, Spectroscopic Studies and Crystal Structure
1141
was stirred at 105 – 120 ◦C for 4 h. The ethanol, forming dur- MgSO4. The solvent was evaporated in vacuo and red oil
ing the reaction, and excess of orthoformate were evaporated. residue was dissolved in hot benzene (60 ml). Compound 3
The residue, white precipitate of trimorpholylmethane was
(1.52 g, 50%) precipitated when the solution was allowed
to cool. The crude precipitate was crystallized from ben-
zene under exclusion of light; 0.72 g (24%) yield. M.p.
172 – 172.5 ◦C. Colorless crystals, suitable for X-ray analy-
mixed with 3-methyl-4-nitroanisole (1a) (2.68 g, 0.016 mol)
◦
at 110 C. Next, the mixture was heated at 148 – 150 ◦C for
◦
7 h and cooled to 70 C. The ethanol (2.5 ml) was added
and the red solution was then allowed to cool to room tem-
perature. After 24 h at 4 C the red crystals were formed.
˜
sis, were formed from methanol. – IR (KBr): ν = 3420, 3410,
◦
3380 (NH), 3150 – 3000, 3000 – 2800, 1620, 1590, 1480,
1450, 1440, 1300, 1210, 1060 (C-O-C), 1180 (CN) cm−1. –
1H NMR (500.13 MHz, DMSO-d6): δ = 3.71 (s, 6 H, OMe),
4.08 (s, 2 H, 10-CH2), 6.73 (d, J = 9 Hz, 2 H, 6-H, 6’-H),
7.04 (d, J = 2 Hz, 2 H, 4-H, 4’-H), 7.10 (d, J = 1 Hz,
2 H, 2-H, 2’-H), 7.30 (d, J = 9 Hz, 2 H, 7-H, 7’-H), 10.60
(s, broad, 2 H, 1-NH, 1’-NH). – 13C NMR (125.68 MHz,
DMSO-d6): δ = 20.81 (C-10), 55.18 (OMe), 100.56 (C-4,
C-4’), 110.64 (C-6, C-6’), 111.84 (C-7, C-7’), 113.87 (C-3,
C-3’), 123.39 (C-2, C-2’), 127.43 (C-8, C-8’), 131.46 (C-9,
C-9’), 152.68 (C-5, C-5’) ppm. – C19H18N2O2 (306.35):
calcd. C 74.49, H 5.92, N 9.14; found C 74.44, H 5.92,
N 9.13.
They were suction-filtered, washed twice with ethanol and
recrystallized from ethanol; 2.89 g, (68%) yield. M.p. 107.1 –
◦
˜
107.4 C. – IR (KBr): ν = 3150 − 3000, 300 – 2800, 1610,
1600, 1570 (NO2), 1490, 1420, 1320 (NO2), 1230, 1170,
1030 cm−1. – 1H NMR (500.13 MHz, CDCl3): δ = 3.14
(t, J = 5 Hz, 4 H, 9-CH2, 11-CH2), 3.75 (t, J = 5 Hz, 4 H,
10-CH2, 12-CH2), 3.86 (s, 3 H, OMe), 6.26 (d, J = 14 Hz,
1 H, 7-H), 6.60 (dd, J1 = 2 Hz, J2 = 9 Hz, 1 H, 4-H), 6.73
(d, J = 14 Hz, 1 H, 8-H), 6.84 (d, J = 2 Hz, 1H, 6-H), 7.97
(d, J = 9 Hz, 1 H, 3-H) ppm. – 13C NMR (125.68 MHz,
CDCl3): δ = 48.74 (C-10, C-12), 55.63 (3 H, OMe), 66.24
(C-9, C-11), 95.31 (C-7),108.96 (C-6), 110.11 (C-4), 128.09
(C-3), 137.92 (C-1) 139.38 (C-2), 143.90 (C-8), 162.85
(C-1) ppm.
X-ray diffraction measurements
Crystals suitable for X-ray analysis were grown from
methanol solution by slow evaporation. Diffraction data were
collected on an Oxford Diffraction KM4CCD diffractome-
ter [21] at 130 K, using graphite-monochromated Mo-Kα ra-
diation. A total of 532 frames were measured in four sep-
arate runs in order to cover the symmetry-independent part
of reciprocal space. The ω-scan was used with a step of
0.75◦, two reference frames were measured after every 50
frames, they did not show any systematic changes either in
peaks positions or in their intensities. The unit-cell param-
eters were determined by least-squares treatment of setting
angles of 3809 highest-intensity reflections, chosen from the
whole experiment. Intensity data were corrected for Lorentz
and polarization effects [22]. The structure was solved by di-
rect methods with the SHELXS-97 program [23] and refined
with full-matrix least-squares by the SHELXL-97 [24] pro-
gram. The function Σw(|Fo| − |Fc| ) was minimized with
w−1 = [σ2(Fo)2 + (0.0246P)2], where P = (Fo2 + 2Fc2)/3.
All non-hydrogen atoms were refined anisotropically, the
positions of hydrogen atoms were generated geometrically
and these atoms were included in the refinement as a “rid-
ing model” with Uiso parameters set at 1.2 (1.5 for methyl
groups) times Ueq of the appropriate carrier atom.
5-Methoxyindole (2a)
Compound (2) (4.92 g, 0.02 m) was dissolved in benzene
(150 ml) and 2 g of 10% Pd/C was added. The mixture was
◦
kept for 8 h at 50 C and at a pressure of 6 atm in an au-
toclave. Finally, the catalyst was removed from light yellow
solution by filtration. After evaporation of the solvent, the
residue was separated chromatographically on silica gel with
chloroform/methanol/diethyl ether, 3:1:1. The oily residue of
(2a) crystallized after several hours at 4 ◦C. It was recrystal-
lized from ethanol; 2.12 g (72%) yield. M.p. 51.1 – 52.1 ◦C. –
˜
IR (KBr): ν = 3400 (NH), 3150 – 3000, 300 – 2800, 1620,
1590, 1490, 1450, 1440, 1350, 1230, 1040 cm−1. – 1H NMR
(500.13 MHz, CDCl3): δ = 3.82 (s, 3 H, OMe), 6.45 (td,
J1 = 1 Hz, J2 = J3 = 2 Hz, 1 H, 4-H), 6.85 (dd, J1 = 2 Hz,
J2 = 9 Hz, 1 H, 6-H), 7.06 (t, J1 = J2 = 2 Hz, 1 H, 2-H), 7.10
(d, J = 2 Hz, 1 H, 3-H), 7.17 (d, J = 9 Hz, 1 H, 7-H). 7.98 (s,
broad, 1 H, NH) ppm. – 13C NMR (125.68 MHz, CDCl3):
δ = 55.82 (OMe), 102.19 (C-4), 102.27 (C-3), 111.78 (C-7),
112.24 (C-6), 124,97 (C-2), 128.21 (C-8), 130.94 (C-9),
154.06 (C-5) ppm.
2
2 2
5,5’-Dimethoxy-3,3’-methanediyl-bis-indole (3)
Crystallographic data for the structure have been de-
posited with the Cambridge Crystallographic Data Centre,
CCDC-238437. Copies of the data can be obtained free of
charge on application to The Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Fax: int.code+(1223)336-
033; e-mail for inquiry: fileserv@ccdc.cam.ac.uk).
Compound (2a) (2.94 g, 0.02 m) was dissolved in water
(100 ml) and formalin (0.81 g, 0.01 mol) was added. The
◦
mixture was kept out of light and stirred at 80 – 85 C for
7 h, and then the solution was allowed to cool to room tem-
perature. The water phase was extracted three times with di-
ethyl ether (15 ml each). The organic phase was dried with
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D. Maciejewska et al. · Synthesis, Spectroscopic Studies and Crystal Structure
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