Structure in solid state of 3,3′-diindolylmethane derivatives, potent cytotoxic agents against human tumor cells, followed X-ray diffraction and 13C CP/MAS NMR analyses

Article abstract of DOI:10.1016/j.molstruc.2005.05.035

The 5,5′-disubstituted-3,3′-diindolylmethanes 1, 2 have been prepared and their structure was analyzed by X-ray and NMR techniques. The X-ray diffraction studies revealed interesting C-H?π intermolecular interactions which may play role in characterization of their biological features. In ¹H and ¹³C NMR spectra in solution and in ¹³C CPMAS NMR spectra in solid state only a single pattern of signals was observed. Both compounds reduce the growth of MCF7 (breast), NCI-H460 (lung), and SF-268 (NCS) cells dramatically.

Full text of DOI:10.1016/j.molstruc.2005.05.035

Journal of Molecular Structure 753 (2005) 53–60
www.elsevier.com/locate/molstruc
0
Structure in solid state of 3,3 -diindolylmethane derivatives, potent
cytotoxic agents against human tumor cells, followed X-ray diffraction
1
and C CP/MAS NMR analyses
3
a,
b
a
a
˙
*
, Irena Wolska , Maria Niemyjska , Paweł Zero
Dorota Maciejewska
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 Pozna n´ , Poland
Received 4 April 2005; revised 20 May 2005; accepted 24 May 2005
Available online 21 July 2005
Abstract
0
0
The 5,5 -disubstituted-3,3 -diindolylmethanes 1, 2 have been prepared and their structure was analyzed by X-ray and NMR techniques.
The X-ray diffraction studies revealed interesting C–H/p intermolecular interactions which may play role in characterization of their
1
13
13
biological features. In H and C NMR spectra in solution and in C CPMAS NMR spectra in solid state only a single pattern of signals was
observed. Both compounds reduce the growth of MCF7 (breast), NCI–H460 (lung), and SF-268 (NCS) cells dramatically.
q 2005 Elsevier B.V. All rights reserved.
0
0
1
13
Keywords: 5,5 -disubstituted-3,3 -diindolylmethanes; X-ray data; Analysis of H; C NMR spectra in solution and in solid state; Cytotoxicity
1
. Introduction
solid state can provide useful information for further
development of our work. It is clear that determination the
nature of the interaction of drug with its macromolecular
target is most informative in drug design process, however
examinations just the structure of the designed compounds
could be essential for obtaining experimental parameters,
which can become descriptors in planned structure-activity
studies.
Clinical management of human reproductive organ
cancers still needs new chemotherapeutics. Recently,
many efforts have been made to define antiproliferative
signaling pathway of indole-3-carbinol (a natural com-
ponent of cruciferous vegetables) and its major indole
0
0
metabolite 3,3 -diindolylmethane [1–7]. Although 3,3 -
diindolylmethane greatly reduces the incidence of spon-
taneous and carcinogen induced mammary tumor formation
In the present work we report synthesis, the single crystal
13
1
X-ray diffraction measurements, the analysis of H,
C
NMR spectra in solution and C CPMAS NMR spectra in
1
3
[8–10], it also exhibits adverse promoting activity in certain
test protocol [11,12]. Therefore we decided to search for
0
solid state, as well as cytotoxicity of 3,3 -diindolylmethane
derivatives 1, 2 (Fig. 1).
0
new potent chemotherapeutics among 3,3 -diindolyl-
0
methane derivatives. Moreover, our X-ray studies of 5,5 -
0
dimethoxy-3,3 -methanediyl-bis-indole [13] revealed its
‘
2. Experimental
butterfly’ conformation, which is analogous to the one
proposed earlier for inhibitors of HIV-1 reverse transcrip-
tase, sharing the mode of action of nevirapine [14]. We are
hopeful that structural analysis of the title compounds in
2
.1. Synthesis
Melting points were determined with a Digital Melting
Point Apparatus 9001 and are uncorrected. All reported
elemental analyses were averaged from two independent
determinations. Prefabricated silica gel sheets (Merck
Kieselgel 60 F254) were used for TLC and Merck Kieselgel
*
Corresponding author. *Corresponding author. Tel.: C48 22 572 0643;
fax: C48 22 572 0643.
E-mail address: domac@farm.amwaw.edu.pl (D. Maciejewska).
60 was used for column chromatography. Reagents were
obtained from commercial sources.
0022-2860/$ - see front matter q 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2005.05.035

54
D. Maciejewska et al. / Journal of Molecular Structure 753 (2005) 53–60
0
0
1
125.29 (C-4, C-4 ), 126.32 (C-2, C-2 ), 128.25 (C-8,
16.39 (C-3, C-3 ), 121.34 (CbN), 124.81 (C-6, C-6 ),
0 0
H 10 H
4
'
4
5
'
C
8
'
3'
3
5
X
X
8
0
0
C-8 ), 139.49 (C-9, C-9 ), ppm.-C H N (296.32):
19 12 4
calcd. C 77.01, H 4.08, N 18.91; found C 76.95, H
4.15, N 19.00.
6
6
'
2' 2
N
H
N
H
9
9
'
7
'
1'
1
7
X = F (1), CN (2)
2
.2. Crystallography
0
0
Fig. 1. Chemical formulas and atom numbering of 5,5 -difluoro-3,3 -
0
0
methanediyl-bis-indole 1 and 5,5 -dicyano-3,3 -methanediyl-bis-indole 2.
The crystals of 1 and 2 suitable for X-ray analysis were
grown from methanol solution by slow evaporation.
Diffraction data were collected on an Oxford Diffraction
KM4CCD diffractometer [18] at 150 K, using graphite-
monochromated Mo Ka radiation. A total of 532 and 588
frames were measured in four separate runs for 1 and 2,
respectively. The u-scan was used with a step of 0.758, 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 parameters
were determined by least-squares treatment of setting
angles of 1768 and 7139 highest-intensity reflections
chosen from the whole experiment for 1 and 2,
respectively. Intensity data were corrected for the Lorentz
and polarization effects [19]. The structures were solved by
direct methods with the SHELXS-97 program [20] and
Compounds 1 and 2 were synthesized from the
corresponding indoles and formaldehyde in a one-step
process according to the reported procedure [15, 16] with
slight modifications. The reaction and purification processes
were performed out of the light. It was not necessary to keep
the reaction vessel under nitrogen to obtain a sufficient yield
(
28–37%). The reactants were solved in water/ethanol
solution, vol. 225:60 ml with 2.85 ml of 0.5 M sulfuric acid.
The crude precipitate of 1 was separated chromatographi-
cally on silica gel with hexane/dichloromethane, 1:6. The
precipitate of 2 was crystallized from diluted ethanol
(
water:ethanolZ1:1). The melting points, elemental ana-
lyses, and H and C NMR data in solution are given
1
13
below. The notation used in the NMR assignments is given
0
in Fig. 1. The other method of synthesis of 5,5 -difluoro-
0
refined with full-matrix least-squares by the SHELXL-97
2
3
,3 -methanediyl-bis-indole 1, as well as its antitumorigenic
P
2 2
program [21]. The function
K1
wðjF j KjF j Þ was
o
c
activity were reported [17]. In our opinion, the physico-
chemical characterization of 1 is not sufficient, and we have
a feeling of uncertainty, if the compound examined by
authors is identical with this synthesized by us.
2
2
2
minimized with w Z½s ðF Þ Cð0:0170PÞ ꢀ for 1 and
o
wK1 Z½s ðF Þ Cð0:0574PÞ C0:2218Pꢀ for 2, where
2
2
2
o
2
o
2
c
PZðF C2F Þ=3. All non-hydrogen atoms were refined
0
0
anisotropically, positions of hydrogen atoms were gener-
ated geometrically and their positional and isotropic
displacement parameters were refined.
5
,5 -Difluoro-3,3 -methanediyl-bis-indole 1 –37% yield.
M. p. 144.5–145.5 8C.-IR (KBr): v~ Z3470(N–H), 3120-
3
1
2
040, 2970, 2850, 1620, 1580, 1480, 1440, 1430,
K1
1
280 cm .- H NMR (500.13 MHz, CDCl ): dZ4.127 (s,
3
0
H, CH ), 6.921 (td, JZ9.5, 2.5 Hz, 2H, 6-H, 6 -H), 6.984
2
2.3. NMR spectra
0
(
dd, JZ2, 1 Hz, 2 H, 2-H, 2 -H), 7.202 (dd, JZ9.5, 2.5 Hz,
0
0
1
13
H NMR and C NMR spectra in solutions were
2
7
H, 4-H, 4 -H), 7.245 (dd, JZ9.5, 4.5 Hz, 2 H, 7-H, 7 -H),
0
13
.885 (broad s, 2 H, 1-NH, 1 -NH).- C NMR (125.68 MHz,
recorded with a Varian Unity plus-500, and standard Varian
software was employed.
0
CDCl ): dZ21.29 (C-10), 104.07 (d, JZ23.3 Hz, C-4, C-4 )
,
3
0
1
3
110.32 (d, JZ26.4 Hz, C-6, C-6 ), 111.66 (d, JZ9.1 Hz,
The solid state
C CP/MAS NMR spectra were
0
0
C-7, C-7 ), 115.41 (d, JZ4.5 Hz, C-3, C-3 ), 123.93 (C-2,
C-2 ), 127.80 (d, JZ9.5 Hz, C-8, C-8 ), 132.96 (C-9, C-9 ),
1
measured using a Bruker Avance DM!400. Powdered
samples were 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 2,500 scans. Chemical
shifts d [ppm] were references to TMS.
0
0
0
0
57.63 (d, JZ232.8 Hz, C-5, C-5 ) ppm.-C H N F
1
7
12
2
2
(
H 4.00, N 9.46.
282.28): calcd. C 72.33, H 4.29, N 9.92; found C 70.82,
0
0
5
,5 -Dicyano-3,3 -methanediyl-bis-indole
2
–28%
yield. M. p. 232.0–232.5 8C. decomp. IR (nujol)
2
.4. Molecular modeling details
:
v~ Z3340(N–H), 3050, 2800, 2240 (CbN), 1630, 1470,
K1
1
1
430, 1220 cm .- H NMR (500.13 MHz, (CD ) CO):
3 2
Crystallographic atom coordinates were used for
1
dZ4.351 (s, 2 H, CH ), 7.381 (dd, JZ8.5, 1.54 Hz, 2 H,
2
3
0
0
computation of shielding constants s [ppm] of
C
6
7
-H, 6 -H), 7.481 (dd, JZ3, 1.5 Hz, 2H, 2-H, 2 -H),
0
atoms to assign the resonances in solid-state NMR
spectra. We have employed the DFT method with
B3LYP/6-31(d,p) hybrid functional using the CHF-
GIAO approach [22].
.564 (dd, JZ8.5, 0.5 Hz, 2 H, 7-H, 7 -H), 8.037 (dd,
0
JZ1.5, 0.8 Hz, 2 H, 4-H, 4 -H), 10.612 (broad s, 2 H,
0
-NH, 1 -NH).- C NMR (125.68 MHz, (CD ) CO): dZ
3 2
13
1
2
0
0
1.37 (C-10), 102.36 (C-5, C-5 ), 113.43 (C-7, C-7 ),

D. Maciejewska et al. / Journal of Molecular Structure 753 (2005) 53–60
55
2
.5. Cytotoxicity against three cell lines
given in Experimental part 2.1. The assignments were based
1
13
on heteronuclear correlation H– C experiments. We have
observed a standard pattern of signals, i.e. the number of
peaks was equal to the number of chemically distinct sites in
the molecules. This could indicate that no steric hindrance
occurs in solution, when indole rings rotate around the
methylene linker. The protons of the NH groups in indole
rings are strongly deshielded and give the resonances above
The in vitro cell line screening utilizing three different
human tumor cell lines consisting of the MCF7 (breast),
NCI-H460 (lung), and SF-268 (CNS) was carried out in
National Institute of Health, Bethesda, USA. The results are
reported as the percentage of growth of the treated cells
when compared with the untreated control cells [23].
Additional information details concerning the NCI’s drug
discovery and development program are available at web
site http://dtp.nci.nih.gov.
8
signals in 1 resulting from the presence of F atoms at C5 and
ppm. We have observed additional splittings of NMR
0
C5 positions. The J
coupling constants through one, two
C–F
three and four bonds are equal to 233, 25, 9, 5 Hz,
respectively.
3
. Results and discussion
1
3
The C CP/MAS NMR spectroscopy in solid state is a
complementary tool to X-ray diffraction method. Of
special interest is the application of solid state NMR to
the investigation of polymorphism and dynamic events of
3
.1. NMR spectra
1 13
The H and C chemical shift d [ppm] and coupling
1
3
constants J [Hz} in CDCl for 1 and in (CD ) CO for 2 are
3 3 2
biologically active substances in solid state. The
C
1
3
0
0
0
0
Fig. 2. The C CP/MAS NMR spectra of 5,5 -difluoro-3,3 -methanediyl-bis-indole 1 and 5,5 -dicyano-3,3 -methanediyl-bis-indole 2 in solid state. Sidebands
are marked with an asterix.

56
D. Maciejewska et al. / Journal of Molecular Structure 753 (2005) 53–60
Table 1
1
3
13
Assignments of resonances in C CP/MAS NMR spectra of compounds 1 and 2. chemical shifts of C in solid state, d [ppm]
1
3
comp
chemical shifts of C in solid state, d [ppm]
0
0
0
0
0
0
0
0
0
0
0
0
0
1
C2;C2
25.3
C2;C2
24.1
C3;C3
115.0
C3;C3
113.9
C4;C4
103.8
C4;C4
123.6
C5;C5
157.4
C5;C5
110.8
C6;C6
110.0
C6;C6
125.6
C7;C7
113.4
C7;C7
99.5
C8;C8
128.0
C8;C8
125.6
C9;C9
133.6
C9;C9
138.5
C1017.5
1
0
0
0
2
C10
18.9
CbN
117.8
1
CP/MAS NMR spectra of 1 and 2 are shown in Fig. 2 and
the most probable assignments of signals are given in
Table 1. Surprisingly, the number of resonances in both
spectra was consistent with solution spectra (or even less),
carbon atoms in both indole rings differ insignificantly
from each other; it results in broad, overlapped
resonances.
0
0
contrary to our findings for 5,5 -dimethoxy-3,3 -methane-
diyl-bis-indole, where we observed double signals of C
atoms [13]. Then we decided to compute the shielding
constants for appropriate assignment of resonances.
The calculated shielding constants, based on crystallo-
3
.2. X-ray diffraction study
The crystal and molecular structures of 1 and 2 were
determined by single crystal X-ray diffraction. The -
crystallographic data, together with data collection and
structure refinement details are listed in Table 2. Selected
bond lengths, bond angles and torsion angles are listed in
Table 3 and hydrogen bonding parameters in Table 4.
Additional crystallographic data have been deposited with
the Cambridge Crystallographic Data Centre as supplemen-
tary publications No CCDC 272 415 for 1, and 272 416 for
2. The displacement ellipsoid representation of the
0
0
graphic coordinates, of carbon atoms in 5,5 -difluoro-3,3 -
methanediyl-bis-indole 1 are pairwise equal, which
explains the observed pattern of resonances. It is not the
0
0
case of 5,5 -dicyano-3,3 -methanediyl-bis-indole 2. The
signals are poorly resolved. Some splitting could be
1
3
14
explained in terms of C- N residual dipolar coupling,
but not all. The calculated shielding constants for relevant
Table 2
Crystal data, data collection and structure refinement for compounds 1 and 2
Compound
1
2
Empirical formula
Formula weight
T (K)
C
17
H
12
F
2
N
2
19 12 4
C H N
282.29
150(2)
296.33
150(2)
˚
Wavelength (A)
0.71073
0.71073
Crystal system, space group
orthorhombic, I ba2
1
monoclinic, P 2 /c
Unit cell dimensions
˚
a (A)
˚
b (A)
11.611(1)
13.005(1)
8.672(1)
11.543(2)
13.546(3)
9.633(2)
˚
c (A)
o
b ( )
90.63(3)
3
˚
Volume (A )
1309.5 (2)
4, 1.432
1506.2(5)
4, 1.307
3
(Mg/m )
K1
Z, D
x
m (mm
F(000)
)
0.105
0.081
584
616
o
q range for data collection ( )
hkl range
5.26–29.34
K15%h%15
K17%k%17
K5%l%11
3.13–29.26
K15%h%15
K18%k%15
K13%l%13
Reflections
Collected
4253
10524
unique (Rint
)
1049 (0.053)
706
3769 (0.031)
3183
observed (IO2s(I))
Data/restraints/parameters
2
Goodness-of-fit on F
1049/1/120
0.855
3769/0/256
1.089
R(F) (IO2s(I))
0.0352
0.0388
2
wR(F ) (all data)
0.0524
0.1069
3
Max/min. Dr (e/A )
˚
0.171/–0.157
0.220/–0.217

D. Maciejewska et al. / Journal of Molecular Structure 753 (2005) 53–60
57
Table 3
Selected bond lengths [A] and angles [deg] and selected torsional angles
deg] for compounds 1 and 2
˚
fragments are essentially planar to within 0.026(2)A (for
˚
˚
) and 0.021(1)A (for 2) with the dihedral angle between
1
[
o
o
their mean planes of 72.98(4) and 88.53(4) for 1 and 2,
respectively. However the molecular structures of 1 and 2
differ in the arrangement of these fragments (the appropriate
torsion angles are given in Table 3). The other non-H atoms
are nearly coplanar with that two-ring framework. The
disposition of the CbN groups in 2 with respect to the indole
fragments can be described by the torsion angles C4–C5–
1
2
N1–C9
0
1.373(2)
1.373(2)
1.373(3)
1.373(3)
1.358(3)
1.358(3)
1.413(2)
1.413(2)
108.9(2)
108.9(2)
114.3(3)
78.2(2)
1.369(1)
1.366(1)
1.380(1)
1.382(1)
1.370(1)
1.366(1)
1.422(1)
1.427(1)
108.7(1)
108.8(1)
112.7(1)
K87.7(1)
K174.8(1)
K177.8(1)
K179.2(1)
0
0
N1 –C9
N1–C2
0
N1 –C2
C2–C3
0
0
C2 –C3
0
0
0
0
C11–N12 of –171(3)8 and C4 –C5 –C11 –N12 of 35(3)8.
So, these results indicate that there are insignificant
differences between the structures of these fragments. This
may be the reason why the calculated shielding constants for
relevant carbon atoms in both indole rings of 2 are slightly
different.
C8–C9
0
0
C8 –C9
C9–N1–C2
0
0
0
0
C9 –N1 –C2
C3–C10–C3
C8–C3–C10–C3
0
0
0
C8 –C3 –C10–C3
N1–C2–C3–C10
78.2(2)
In the crystals of 1 and 2 the packing of the molecules is
stabilized by different weak intermolecular contacts. The
geometric parameters of all hydrogen bonds are given in
Table 4. The crystal structure of 1 is built of folded layers
perpendicular to the c axis (Fig. 4). Cohesion between these
layers results from the CKH/p intermolecular inter-
actions. Within the layer the molecules are linked by NK
H/F and CKH/F hydrogen bonds (Fig. 5, Table 4). In the
crystal of 2, there is a three-dimensional network of NKH/
N, CKH/N and CKH/p interactions (Fig. 6, Table 4).
The molecules are connected via NKH/N intermolecular
hydrogen bonds along the two-fold screw b axis. Addition-
ally the CKH/p interactions link the molecules to infinite
179.2(2)
179.2(2)
0
0
0
N1 –C2 –C3 –C10
molecules, together with the atomic numbering scheme, is
shown in Fig. 3 (the drawings were performed with a
Stereochemical Workstation [24]).
Compound 1 crystallizes in the orthorhombic space
group I ba2 with a half of the ordered molecule in the
asymmetric unit (the molecule occupies a special position:
the C10 atom is located at two-fold axis) and compound 2
crystallizes in the monoclinic space group P 2 /c with a
1
single ordered molecule in the asymmetric unit. The
structures consist of two indole systems connected by a
common C atom (C10). Bond lengths observed in the
molecules are in good agreement with the corresponding
distances in the related compounds [13, 25]. X-ray results
indicate that studied bis-indoles adopt a butterfly confor-
0
chains along the c axis. The N12 and N12 atoms are also
involved in weak intermolecular CKH/N interactions,
which results from the crystal packing of the molecules.
So, we have observed the interactions between the CH
groups and the p-electron system of indole rings.
0
0
mation (see Fig. 4) similar to that observed for 5,5 -
0
Analogous NKH/p contacts were observed for 5,5 -
dimethoxy-3,3 -methanediyl-bis-indole [13], other indole
derivatives [26, 27] and for globular proteins [28].
0
dimethoxy-3,3 -methanediyl-bis-indole [13]. The indole
Table 4
˚
Hydrogen-bonding geometry [A and deg.] for compounds 1 and 2
3.3. Primary anticancer assay
Compound 1
0
0
0
5
,5 -Difluoro-3,3 -methanediyl-bis-indole 1 and 5,5 -
D–H/A
d(D–H)
d(H$ $$$A) d(D$$$$A)
!(DHA)
0
i
dicyano-3,3 -methanediyl-bis-indole 2 were examined
against the MCF7 (breast), NCI-H460 (lung), and SF-
268 (CNS) tumor cell lines. The results are reported as the
percentage of growth of the treated cells when compared
N1–H1/F
0.86(2)
0.95(2)
0.86(2)
0.95(2)
2.35(2)
2.64(2)
2.49(2)
2.75(2)
3.055(2)
3.320(3)
3.236(2)
3.593(2)
139(2)
129(2)
147(2)
148(2)
i
C7–H7/F
ii
N1–H1/
iii
C6–H6/Cg
Cg represents the centroid of five-membered ring of the indole;
symmetry codes: (i) 0.5Cx, 0.5Ky, z; (ii) 0.5Kx, K0.5Cy, z; (iii) 0.5Kx,
with untreated control cells. The derivative 1 at conc.
K4
.10 M reduces the growth of MCF7, NCI-H460, and
1
SF-268 cell lines to 1, 0, and 2 percent, whereas
0.5Ky, K0.5Cz
Compound 2
K5
the derivative 2 at conc. 5.10 M- to 4, 1, and 9
0
i
N1–H1/N12
0.91(1)
0.90(2)
1.00(1)
0.99(1)
0.97(2)
2.16(1)
2.15(2)
2.54(1)
2.55(2)
2.47(2)
2.949(1)
2.984(1)
3.532(2)
3.398(2)
3.430(2)
143(1)
153(1)
172(1)
144(1)
171(2)
percent, respectively. Both compounds are highly cyto-
toxic in vitro against those tumor lines.
0
0
ii
N1 –H1 /N12
0
iii
C6–H6/N12
C7–H7/N12
iv
0
0
v
C7 –H7 /Cg
4. Conclusions
Cg represents the centroid of five-membered ring (N1/C2/C3/C8/C9) of the
indole; symmetry codes: (i) 1Kx, 0.5Cy, K0.5Kz; (ii) 2Kx, 0.5Cy, K0.
0
0
X-ray analysis of 5,5 -difluoro-3,3 -methanediyl-bis-
0
0
5Kz; (iii) 1Cx, y, 1Cz; (iv) 2Kx, 0.5Cy, 0.5Kz; (v) x, y, K1Cz.
indole 1 and 5,5 -dicyano-3,3 -methanediyl-bis-indole 2

58
D. Maciejewska et al. / Journal of Molecular Structure 753 (2005) 53–60
Fig. 3. Molecular structure of 1 and 2 with 50% probability displacement ellipsoids and atom-numbering scheme.
Fig. 4. Projection of the crystal structure of 1 along the a axis with CKH/p intermolecular hydrogen-bonding interactions. H atoms are omitted for clarity.
revealed interesting interactions between the CH groups and
the p-electron system of indole rings. They adopt a butterfly
conformation which may have a functional role in their
biological features. Their cytotoxicity indicates that they
could be interesting as potential antitumoral
chemotherapeutics.
Acknowledgements
The computational results discussed in this work were
obtained using the resources of Interdisciplinary Centre for
Mathematical and Computational Modelling (ICM) War-
saw University.
1
13
According to H and C NMR data no hindered
1
3
rotation phenomena are observed in solution. In
C
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