Synthesis and binding studies of a new DNA minor groove binder

Article abstract of DOI:10.1071/C97115

2-[2′-(4″Ethoxyphenyl)-1H-indol-6′-yl]-5-(4?- methylpiperazin-1?-yl)-1H-benzimidazole (1) has been synthesized from 2-(4′-ethoxyphenyl)-1H-indole-6-carbaldehyde (4b) and 4-(4′-methylpiperazin-1′-yl)benzene-1,2-diamine (3b). The aldehyde (4b) was prepared

Full text of DOI:10.1071/C97115

C S I R O P U B L I S H I N G
Australian Journal
of Chemistry
Volume 51, 1998
© CSIRO Australia 1998
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Aust. J. Chem., 1998, 51, 243–247
.
Short Communications
Synthesis and Binding Studies of a New
DNA Minor Groove Binder
Christopher I. Clark,A Jonathan M. White,A,B David P. Kelly,A
Roger F. Martin C and Pavel Lobachevsky C
A
School of Chemistry, The University of Melbourne, Parkville, Vic. 3052.
Author to whom correspondence should be addressed.
Trescowthick Research Laboratories, Peter MacCallum Cancer Institute,
B
C
Melbourne, Vic. 3000.
2-[20-(400-Ethoxyphenyl)-1H -indol-60-yl]-5-(4000-methylpiperazin-1000-yl)-1H -benzimidazole (1) has been
synthesized from 2-(40-ethoxyphenyl)-1H -indole-6-carbaldehyde (4b) and 4-(40-methylpiperazin-10-
yl)benzene-1,2-diamine (3b). The aldehyde (4b) was prepared in ve steps by using a modi ed
Leimgruber–Batcho indole synthesis. Evaluation of (1) as a DNA ligand is described.
Introduction
making contacts in the minor groove with hydrogen
bond acceptors on A and T sites.17 Thus, there have
been a number of attempts to modify bibenzimidazole
ligands, for example by introducing heterocyclic groups
that will act as hydrogen bond acceptors, so as to
confer GC-selectivity.16,18–20
Minor-groove-binding DNA ligands include a variety
of structural types. Classic examples1 are naturally
occurring amide-linked bis- and tris-pyrroles, namely
netropsin and distamycin A, and synthetic ligands, rst
the bibenzimidazole Hoechst 33258 (2)2 and then the
diamidino phenyl indole DAPI.3 An early interest in
these compounds was in the mode of binding to DNA,
being distinct from intercalation, and their potential
pharmacological properties, which led to the synthesis
of a number of analogues.4 However, it is their AT
selectivity that has attracted sustained attention. DNA
sequencing techniques enable discrete ligand-binding
sites to be identi ed by footprinting5 or by a nity
cleavage with ligands modi ed to include DNA cleav-
age ability by chemical,6 photolytic7,8 or radiolytic9
mechanisms, even in DNA in intact cells.10
We have also undertaken changes to the bibenz-
imidazole structure, but for quite di erent reasons.
Our interest in these ligands is in their potential
use as radiomodi ers in cancer radiotherapy. This
potential includes the use of iodinated analogues as
radiosensitizers,7 whereas the non-iodinated bibenz-
imidazoles have radioprotective activity.21–23 There is
some evidence to suggest that this radioprotective
activity may be mediated by reduction by the ligand
of radiation-induced transient oxidizing species on the
DNA.24 Accordingly, we have sought to modify the
electronic properties of the ligands, and we report here
the synthesis of a new ligand in which one of the
benzimidazoles is replaced by an indole, in order to
increase the -electron density in the molecule. Aside
from the classic case of DAPI3 there are a number
of examples of minor-groove-binding ligands including
an indole moiety,25–28 but to our knowledge this is
the rst report of a 2-(indol-6-yl)benzimidazole DNA
binding ligand.
N
X
N
N
H
N
N
H
X
R
Me
R
(1) CH OEt
(2) OH
N
Synthesis of the 2-(Indol-6-yl)benzimidazole (1)
The availability of synthetic oligodeoxynucleotides
has enabled ligand binding to particular sites, such as
d(AATT)2, to be examined by X-ray crystallography11–13
and solution n.m.r.14,15 To a large extent this activ-
ity is aimed at the development of the capability
to design ligands with de ned sequence selectivity.16
The AT-selectivity of many of these ligands can be
attributed to hydrogen bond donors on the ligands,
We have previously detailed the synthesis of a series
of bibenzimidazoles related to Hoechst 33258 (2).29,30
These derivatives were prepared by coupling aromatic
o-diamines with either imino ether hydrochlorides or
benzaldehyde derivatives through linear and convergent
pathways. Scheme 1 details a linear synthesis of biben-
zimidazole (5) involving the coupling of diamine (3a) to
Manuscript received 4 July 1997
᭧ CSIRO Australia 1998
0004-9425/98/030243$ 05.00

244
Short Communications
conditions32 in tetrahydrofuran35 to a ord aldehyde
(4b) in 36% yield. This was later increased to a
moderate 42%. In the nal step the coupling36 of
aromatic diamine (3b) and formylindole (4b) proceeded
smoothly to a ord (1) in 65% yield.
NH2
O
H
+
R'
R
NH2
N
R''
(4a) R' =
N
H
(3a) R =
Me
N
N
Me
N
N
(4b) R' =
N
H
Br
NO2
(6)
(3b) R =
Me
OEt
(i) dimethylformamide, pyrrolidine
Me2NCH(OMe)2
Na2S2O5
EtOH, H2O
(ii) 4-ethoxybenzoyl chloride
Et3N, benzene
O
R
N
R
X
NMe2
dioxan
N
H
N
N
N
H
X
N
R''
R''
H2O
Br
NO2
Br
NO2
(8) R = C6H4OEt
Me
(5)
variable
(7a) R = H
(1) CH 4''-OEt
(7b) R = COC6H4OEt
(i) Na2S2O4, EtOH
tetrahydrofuran, H2O
Scheme 1
(ii) tetrahydrofuran, KH
ButLi, dimethylformamide
benzaldehyde (4a). In the course of seeking a pathway
to the 2-(indol-6-yl)benzimidazole (1) we entertained
the idea that it could be produced by a convergent
synthesis between diamine (3b) and indole-substituted
aldehyde (4b).
OEt
N
R
H
(9) R = Br
(4b) R = CHO
Scheme 2
We initially proposed to synthesize 2-(40-ethoxy-
phenyl)-1H -indole-6-carbaldehyde (4b) via formylation
of an appropriately substituted indole. Given that
Vilsmeier formylation of indole and C 2 substituted
indoles has been shown to occur at C 3,31 not C 6
as required for (4b), we decided to prepare the
aldehyde via an organometallic route analogous to
that reported for indole-6-carbaldehyde by Rapoport
et al.32 This involved treating bromoindole (9) with
potassium hydride, t-butyllithium and dimethylform-
amide. We chose to synthesize (9) via a modi ed
Leimgruber–Batcho33 indole synthesis. This involves
a de novo construction of the indole nucleus with
introduction of a C 2 aryl substituent,34 and is shown
in Scheme 2.
Estimation of Dissociation Constants
The binding of the ligand (L) to DNA was studied with
thesyntheticoligoDNAd(CGCGCGAATTCGCGCG)2,
which is expected to contain a single ligand-binding
site. The expression for the dissociation equilibrium
Kd
*
DNA–Ln ) nL + DNA
(1)
can be written
Kd = L(1
)(nx L )L
(2)
Under standard conditions33 the nitrotoluene (6)
was treated with N,N -dimethylformamide dimethyl
acetal and pyrrolidine in dimethylformamide to a ord
enamine (7a). The enamine was treated with 4-
ethoxybenzoyl chloride and triethylamine in benzene
until t.l.c. indicated most of the starting material
had been consumed. Enamine (7b) was isolated
and, without puri cation, hydrolysed and deformyl-
ated in dioxan/water over 24 h to give ketone (8) in
50% overall yield from (6). Intramolecular cycliza-
tion of (8) was e ected by chemical reduction with
sodium dithionite in ethanol/tetrahydrofuran/water to
give 6-bromo-2-(40-ethoxyphenyl)-1H -indole (9) in 63%
yield. Bromoindole (9) was formylated under standard
where is the fraction of bound ligand, L is the total
ligand concentration (mol l 1), n is the number of
ligand binding sites per DNA base pair (bp), and x is
the total DNA concentration (mol bp l 1).
The spectrophotometric data from titration with
DNA was processed by regression analysis. Each
intermediate spectrum during the titration process was
represented as a combination of the spectra of free
[yf ( )] and bound [yb( )] ligand in following form:
y( ) = (1
)yf ( ) + yb( )
(3)
The regression analysis was then applied to expression
(3), to yield values for . These values were used to

Short Communications
245
build a binding curve (fraction of bound ligand against
DNA concentration) and Scatchard plot. The values
for Kd and n were calculated from the Scatchard plot.
similar to that reported previously for poly[d(A–T)],37
as shown in Table 1. Given the limited precision, the
Kd value for the 2-(indol-6-yl)benzimidazole ligand (1)
is comparable to that for Hoechst 33258 (2). However,
the value for the number of binding sites of the new
ligand per oligoDNA molecule is about twice that for
Hoechst 33258 (2). This could re ect the binding of
two molecules of the ligand, as reported for DAPI38,39
and distamycin.40
Results
The DNA binding experiments yielded a Kd value
8
1
of 2 8( 0 7) 10 mol l with n = 0 042( 0 001).
Similar experiments with Hoechst 33258 (2) gave val-
8
ues of Kd = 1 1( 0 2) 10 and n = 0 023( 0 001).
These values are averages and standard deviations of
the results of our experiments. The data from a
typical experiment are shown in Fig. 1 for (1) and
Fig. 2 for Hoechst 33258 (2). As indicated in Table 1,
the apparent binding is around 5–10-fold lower than
values reported in the Hoechst 33258 in ethanol-free
aqueous bu er.37 The ethanol was included in our
experiments to improve ligand solubility and thus
allow comparisons between a variety of new ligands,
and to minimize non-speci c binding to DNA and
glassware. The extent of the e ect of ethanol on Kd is
While the relative values of n for the 2-(indol-6-
yl)benzimidazole (1) and Hoechst 33258 (2) are close
to 2 : 1, we cannot explain why the absolute values are
less than expected.
In conclusion, (1) is the rst compound in a new
class of DNA binders, the 2-(indol-6-yl)benzimidazoles.
Work is in progress to synthesize more derivatives of
(1) and other types of compounds with increased
-electron density over (1).
Experimental
The bu er used for the DNA/ligand titration was 20 mM
phosphate bu er pH 7 4, with 100 mM NaCl, containing 20%
ethanol to minimize problems due to solubility, adsorption and
non-speci c binding of the ligand. The DNA concentration
was determined by using the extinction coe cient of the
Fig. 1. Results for ligand (1). (a) E ect of DNA on ligand
absorption. Spectra: 1, free ligand; 2,3 examples of intermediate
spectra; 4, bound ligand. Only two intermediate spectra are
shown to avoid complication of the gure. (b) Binding curve.
(c) Scatchard plot. Lb and Lf are the concentrations of bound
and free ligand respectively; x is the DNA concentration. The
closed symbols on panels (b) and (c) represent experimental
data; the solid lines are the result of regression analysis.
Fig. 2. Results for ligand (2): see caption to Fig. 1.

246
Short Communications
Table 1. Binding of ligands (1) and (2) to synthetic DNA
1
DNA
Ligand
Ethanol (%)
Kd (mol l
)
Ref.
8
8
d(CGCGCGAATTCGCGCG)2
d(CGCGCGAATTCGCGCG)2
d(CGCGAATTCGCG)2
poly[d(A–T)]
(2)
(1)
(2)
(2)
(2)
20
20
—
—
25
(1 1 0 2) 10
(2 8 0 7) 10
this study
this study
8
0 25 10
0 26 10
6 8 10
37
37
37
8
8
poly[d(A–T)]
1
duplex oligoDNA (286000 M
for single-stranded DNA (161600
cm 1), determined from that
(158 mg, 63%), m.p. 225–226 C (repeated trituration with
ethyl acetate/light petroleum) (Found: C, 60 9; H, 4 5; Br,
25 3; N, 4 4%; M+ 315 0133. C16H14BrNO requires C, 60 8;
1
M
cm 1) by measuring
the relative extinction of native and heat denatured DNA.
The concentration of ligand used in titration experiments was
in the range 0 4–0 2 M. The absorption spectra were mea-
sured in 50 mm cuvettes. The ultraviolet spectroscopic data
obtained for (1) (>90% pure by h.p.l.c.), in 0 1% CF3CO2H
H, 4 5; Br, 25 3; N, 4 4%; M+ 315 0259.
(CDCl3) 8 25.
H
1H, br s, NH; 7 56, 2H, d, J 8 7, H 20,60; 7 52, 1H, br s,
H 7; 7 45, 1H, d, J 8 4, H 4; 7 2, 1H, dd, J 8 3, 1 4, H 5;
6 97, 2H, d, J 8 7, H 30,50; 6 665, 1H, d, J 1 4, H 3; 4 08,
in 45% MeOH in water (v/v/v), were characterized by maxima
2H, q, J 7, OCH2CH3; 1 45, 3H, t, J 6 95, OCH2CH3.
C
1
at 385 nm (
3 98 104 mol l. cm 1) and 249 nm (
((CD3)2SO) 158 27, C 4; 138 84, C 2; 137 77, C 7; 127 85,
C 3a; 126 45, C 20,60; 124 16, C 10; 122 02, C 5; 121 25, C 4;
114 78, C 30,50; 113 44, C 6 or C 7; 113 40, C 6 or C 7; 97 36,
C 3; 63 08, OCH2CH3; 14 54, OCH2CH3). m/z 315 (M+,
98 92%), 286 (59 75), 236 (4 64), 207 (12 03).
385
1
249
2 94 104 mol l. cm 1).
Melting points are uncorrected. 1H, 13C and two-dimensional
spectra (HMBC, HMQC) were recorded on a Varian Unity 400
spectrometer operating at 399 5 MHz for 1H and 100 MHz
for 13C. J values are given in Hz. The addition of a few
drops of CF3CO2D to the CD3OD solution of (1) was found
to reduce peak broadening and enhance peak de nition in the
aromatic region of the 1H n.m.r. spectra. For the acquisition
of the carbon spectrum of (1) in CD3OD the addition of
a few drops of CH3SO3H was used to increase solubility.
Positive-ion electron ionization mass spectra were recorded on
a Micromass VG7070F instrument at an ionization potential
of 70 eV. Elemental analyses were performed by Chemical and
Micro Analytical Services Pty Ltd Melbourne, Victoria.
2-(4 0-Ethoxyphenyl)-1H-indole-6-carbaldehyde (4b)
To potassium hydride (24 mg, 0 6 mmol) in tetrahydrofuran
(0 5 ml) at 0 C was added dropwise a solution of the indole (9)
(189 mg, 0 598 mmol) in tetrahydrofuran (3 ml).32,35 When the
hydride had been consumed the solution was cooled to 100 C
and t-butyllithium (0 71 ml, 1 694 M, 1 196 mmol), at 100 C,
was added via cannula. Upon warming to 80 C, dimethyl-
formamide (46 l, 0 598 mmol) in tetrahydrofuran (1 ml) was
added and the solution was stirred at 80 C for 15 min before
being warmed to room temperature. The reaction mixture was
poured into ice-cold 1 M phosphorous acid and extracted with
ethyl acetate. Washing with saturated sodium bicarbonate,
drying with sodium sulfate and removal of the solvent gave a
residue which was subject to column chromatography on silica
gel (ethyl acetate/light petroleum (b.p. 40–60 C) (32 : 68)). The
title compound (4b) (RF 0 32) was obtained as a crystalline
solid (57 mg, 36%), m.p. 199–201 C (Found: C, 77 2; H, 5 8;
N, 5 2%; M+ 265 1254. C17H15NO2 requires C, 77 0; H,
2-(4 00-Bromo-2 00-nitrophenyl)-1-(4 0-ethoxyphenyl)ethanone (8)
To (E )-2-(4-bromo-2-nitrophenyl)-N,N -dimethylethenamine
(7a) (3 1 g, 11 57 mmol),32 prepared from 4-bromo-1-methyl-
2-nitrobenzene (6),41 was added 4-ethoxybenzoyl chloride (2 14
g, 11 57 mmol), triethylamine (1 6 ml, 11 57 mmol) and dry
benzene (15 ml). The mixture was re uxed for 7 days at which
time most of the enamine had been consumed. Upon washing
with water the organic layer was re uxed with dioxan (15 ml)
and water (5 ml) for 24 h. The solvents were removed and
the crude material in dichloromethane was ‘ ashed’ through
silica to yield (8) (2 12 g, 50 4%) as a tan crystalline solid,
m.p. 117–118 C (from dichloromethane/light petroleum (b.p.
40–60 C)) (Found: C, 52 8; H, 3 8; Br, 21 8; N, 3 8%; M+
363 0124. C16H14BrNO4 requires C, 52 7; H, 3 9; Br, 22 0;
5 7; N, 5 3%; M+ 265 1103).
((CD3)2CO) 11 15, 1H, br
H
s, NH; 9 99, 1H, s, CHO; 7 94, 1H, br s, H 7; 7 845, 2H,
d, J 8 8, H 20,60; 7 675, 1H, d, J 8 3, H 4; 7 575, 1H, dd,
J 8 2, 1 4, H 5; 7 035, 2H, d, J 8 8, H 30,50; 6 915, 1H,
d, J 1 7, H 3; 4 11, 2H, q, J 7, OCH2CH3; 1 38, 3H, t, J
6 95, OCH2CH3.
((CD3)2SO) 192 47, CHO; 158 89, C 40;
C
N, 3 9%; M+ 363 0106).
(CDCl3) 8 265. 1H, d, J 2, H 300;
142 72, C 2; 136 32, C 7a; 133 93, C 3a; 130 02, C 6; 127 09,
C 20,60; 123 72, C 10; 119 89, C 4,5; 114 92, C 30,50; 114 44,
C 7; 98 30, C 3; 63 22, OCH2CH3; 14 65, OCH2CH3. m/z
265 (M+, 89 36%), 236 (68 08), 208 (20 92), 149 (32 35), 71
(57 59), 57 (100).
H
7 97, 2H, d, J 9 1, H 20,60; 7 71, 1H, dd, J 8 1, 2, H 500; 7 205,
1H, d, J 8 1, H 600; 6 945, 2H, d, J 9, H 30,50, 4 63, 2H, s, H 2;
4 11, 2H, q, J 7, OCH2CH3; 1 45, 3H, t, J 7 1, OCH2CH3.
(CDCl3) 193 1. C 1; 163 29, C 40; 149 47, C 200; 136 26,
C
C 500; 134 82, C 600; 130 51, C 20,60; 129 87, C 100; 128 92, C 10;
128 10, C 300; 121 25, C 400; 114 28, C 30,50; 63 80, OCH2CH3;
43 21, C 2; 14 63, OCH2CH3; m/z 363 (M+, 0 31%), 149
(100), 121 (37 73), 65 (16 62), 57 (86 95).
2-[2 0-(4 00-Ethoxyphenyl)-1H-indol-6 0-yl)]-5-(4 000
methylpiperazin-1 000-yl)-1H-benzimidazole (1)
-
To freshly prepared 4-(40-methylpiperazin-10-yl)benzene-1,2-
diamine (3b)29 (44 mg, 0 21 mmol) in dry ethanol (2 ml) was
added a solution of thiosulfate aldehyde complex (prepared
by adding sodium metabisul te (39 5 mg, 0 208 mmol) in
ethanol/water (0 5 : 0 5 ml) to a re uxing solution of (4b)
(55 mg, 0 208 mmol) in ethanol (5 ml)). The resultant solution
was heated at re ux for 12 h. The solution was cooled, basi ed
with ammonium hydroxide and put in a freezer for several
hours. The solid obtained via ltration was washed with water,
diethyl ether and dried in vacuum to give (1) as a yellow
solid (65 mg, 69%), m.p. 294 C (dec.) (Found: C, 74 0; H,
6 7; N, 15 6; O, 3 3%; M+ 451 2343. C28H29N5O requires
6-Bromo-2-(4 0-ethoxyphenyl)-1H-indole (9)
The ketone (8) (284 mg, 0 780 mmol) and sodium dithionite
(313 mg, 1 80 mmol) in tetrahydrofuran (2 ml), ethanol (2 ml)
and water (1 3 ml) were re uxed for 20 min. The reaction
was monitored by silica t.l.c. (benzene; RF 0 4 for (8), RF
0 64 for (9)). Additional sodium dithionite and tetrahydrofu-
ran/ethanol/water were added and the solution was reheated if
required. Upon completion the organic solvents were removed
and (9) was isolated by ltration. The ltrate was acidi ed
with dilute HCl and heated and further product was obtained.
Upon drying the title compound was obtained as a beige solid
C, 74 5; H, 6 5; N, 15 5; O, 3 5%; M+ 451 2372).
H

Short Communications
247
16
17
(CD3OD+CF3CO2D) 8 055, 1H, d, J 1 5, H 70; 7 745, 2H, d, J
8 7, H 200,600; 7 73, 1H, d, J 8 8, H 40; 7 620, 1H, d, J 8 7,
H 7; 7 619, 1H, dd, J 8 7, 1 8, H 50; 7 305, 1H, dd, J 9, 2 2,
H 6; 7 21, 1H, d, J 2 1, H 4; 6 98, 2H, d, J 8 8, H 300,500; 6 78,
1H, br s, H 30, exchangeable; 4 065, 2H, q, J 7, OCH2CH3;
3 885 2H, br d, J 13 4, piperazinyl H; 3 655, 2H, br d, J
12 1, piperazinyl H; 3 29, 2H, br t, J 9 7, piperazinyl H; 3 15,
2H, br t, J 11 9, piperazinyl H; 2 98, 3H, s, NCH3; 1 41,
Dervan, P. B., Science, 1986, 232, 464.
Mikhailov, M. V., Zasedatelev, A. S., Krylov, A. S., and
Gursky, G. V., Mol. Biol. SSSR, 1981, 15, 690.
Lown, J. W., Krowicki, K., Bhat, U. G., Skorobogaty, A.,
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18
19
20
3H, t, J 7 05, OCH2CH3.
(CD3OD+CH3SO3H) 160 49,
C
C 400; 150 42, C 2 or C 3a0; 149 51, C 3a or C 5; 143 98, C 20;
137 41, C 60 or C 7a0; 134 15, C 2 or C 3a0; 133 31, C 3a or
C 5; 127 88, C 2,600; 126 75, C 7a; 124 68, C 100, 121 55, C 40;
118 66, C 50; 117 86, C 6; 115 66, C 3,500; 114 74, C 7; 113 99,
C 60 or C 7a0; 111 10, C 70; 100 26, C 4; 99 3, C 30; 64 47,
OCH2CH3; 54 41, piperazinyl C; 47 99, piperazinyl C; 43 57,
(NCH3; 15 19, OCH2CH3. m/z 451 (M+, 100%), 381 (12 32),
253 (14 59), 157 (13 27), 71 (17 21).
21
22
23
24
25
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1996, 74, S99.
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Acknowledgments
We are grateful for the nancial support of a grant
from the Australian Research Council.
26
27
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Chem., 1996, 39, 1049.
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