Quindoline Derivatives
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23 7319
Table 3. Inhibition of Quindoline and 4a-j on Telomerase
quindoline
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
TelIC50 (µM)
>138
0.55
1.12
0.44
2.35
1.55
4.38
7.11
3.29
12.3
8.12
and the organic product was extracted with chloroform,
washed with saturated NaCl solution and water, and then
dried with Na2SO4. After concentration, the product was
purified by column chromatography on silicon gel. Further
purification was carried out by recrystallization.
N′-(10H-Indolo[3,2-b]quinolin-11-yl)-(2-morpholin-4-yl-
ethyl)amine (4a). Mp 208-210 °C. ESI-MS m/z: 347 (M+).
1H NMR (300 MHz, acetone-d6): δ 8.45 (d, 1H, J ) 8.1 Hz),
8.24 (d, 1H, J ) 8.7 Hz), 8.16 (d, 1H, J ) 8.4 Hz), 7.59 (t, 2H,
J ) 8.7 Hz), 7. 53 (t, 1H, J ) 7.2 Hz), 7.43 (t, 1H, J ) 7.5 Hz),
7.22 (t, 1H, J ) 7.5 Hz), 4.07 (t, 2H, J ) 5.7 Hz), 3.68 (t, 4H,
J ) 4.2 Hz), 2.84 (t, 2H, J ) 5.7 Hz), 2.63 (m, 4H). Anal. Calcd
for C21H22N4O: C, 72.81; H, 6.40; N, 16.17. Found: C, 72.69;
H, 6.52; N, 16.24.
N′-(10H-Indolo[3,2-b]quinolin-11-yl)-N,N-dimethyl-
ethane-1,2-diamine (4b). Mp 189-191 °C. 1H NMR (300
MHz, DMSO-d6): δ 12.06 (s, 1H), 10.80 (s, 1H), 9.20 (s, 1H),
8.60 (d, 1H, J ) 8.7 Hz), 8.70 (d, 1H, J ) 7.5 Hz), 8.28 (d, 1H,
J ) 8.1 Hz), 7.89 (d, 2 H, J ) 7.8 Hz), 7.67 (t, 1H, J ) 7.5 Hz),
7.57 (t, 1H, J ) 7.5 Hz), 7.32 (t, 1H, J ) 7.5 Hz), 4.60 (m, 2H),
3.63 (t, 2H, J ) 5.4 Hz), 2.93(s, 6H). HRMS-EI m/z: calcd for
C19H20N4, 304.1688; found, 304.1680. Anal. Calcd for
C19H20N4: C, 74.97; H, 6.62; N, 18.41. Found: C, 74.92; H,
6.76; N, 18.50.
N′-(10H-Indolo[3,2-b]quinolin-11-yl)-N,N-dimethylpro-
pane-1,3-diamine (4c). Mp 197-199 °C. 1H NMR (300 MHz,
CD3OD): δ 8.37 (d, J ) 7.8 Hz 1 H), 8.18 (d, J ) 7.8 Hz 1 H),
8.03 (d, J ) 8.7 Hz 1 H), 7.54 (m H), 7.41 (m 3 H), 7.19 (t, J )
6.6 Hz 1 H), 3.89 (t, J ) 6.3 Hz 2 H), 2.58 (t, J ) 6.3 Hz 2 H),
2.31 (s, 6 H), 1.93 (m, 2 H). HRMS-EI m/z: calcd for C20H22N4,
318.1844; found, 318.1847. Anal. Calcd for C20H22N4: C, 75.44;
H, 6.96; N, 17.60. Found: C, 75.30; H, 7.15; N, 17.50.
N′-(10H-Indolo[3,2-b]quinolin-11-ylamino)ethanol (4d).
Mp 227-229 °C. 1H NMR (300 MHz, DMSO-d6): δ 8.58 (d,
1H, J ) 8.7 Hz), 8.36 (d, 1H, J ) 7.5 Hz), 8.19 (d, 1H, J ) 7.2
Hz), 7.89 (t, 1H, J ) 7.2 Hz), 7.77-7.58 (m, 3H), 7.34 (t, 1H,
J ) 6.9 Hz), 4.30 (s, 1H, OH), 4.15 (s, 2H), 3.87 (s, 2H). HRMS-
EI m/z: calcd for C17H15N3O, 277.1215; found, 277.1178. Anal.
Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.49; H, 5.67; N, 15.24.
N′-(10H-Indolo[3,2-b]quinolin-11-ylamino)propanol (4e).
Mp 232 °C. 1H NMR (500 MHz, DMSO-d6): δ 11.77 (s, 1H,
NH), 8.90 (s, 1H), 8.65 (d, 1H, J ) 5.4 Hz), 8.56 (d, 1H, J )
4.8 Hz), 8.16 (d, 1H, J ) 5.1 Hz), 7.90 (t, 1H, J ) 4.8 Hz) 7.75
(d, 1H, J ) 5.1 Hz), 7.69 (t, 1H, J ) 4.5 Hz), 7.60 (t, 1H, J )
4.5 Hz), 7.36 (t, 1H, J ) 4.8 Hz), 5.18 (s, 1H, OH), 4.19 (t, 2H,
J ) 3.9 Hz, J ) 3.9 Hz), 3.68 (t, 2H, J ) 3.3 Hz), 2.04 (m, 2H).
HRMS-FAB m/z: calcd for C18H17N3O, 291.1372; found,
291.1360. Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88; N,
14.42. Found: C, 74.06; H, 6.01; N, 14.31.
(10H-Benzofuro[3,2-b]quinolin-11-yl)-(2-morpholin-4-
ylethyl)amine (4f). Mp 216-218 °C. ESI-MS m/z: 348 (M+).
1H NMR (500 MHz, DMSO-d6): δ 8.32 (d, 1H, J ) 8.5 Hz),
8.20 (d, 1H, J ) 7.5 Hz), 7.99 (d, 1H, J ) 8.5 Hz), 7.72 (d, 1H,
J ) 8.0 Hz), 7.64-7.69 (m, 2H), 7.45-7.49 (m, 2H), 7.22 (brs,
1H), 4.05 (t, 2H, J ) 10.5 Hz, J ) 6.5 Hz), 3.59 (s, 4H), 2.74
(brs, 2H), 2.54 (s, 4 H). HRMS-EI m/z: calcd for C16H11N2O
[M+ - O(C2H4)2NCH2], 247.0871; found, 247.0839. Anal. Calcd
for C21H21N3O2: C, 72.60; H, 6.09; N, 12.10. Found: C, 72.45;
H, 6.21; N, 11.95.
(10H-Benzofuro[3,2-b]quinolin-11-yl)-N,N-dimethyl-
ethane-1,2-diamine (4g). Mp 208-210 °C. 1H NMR (500
MHz, DMSO-d6): δ 8.30 (d, 1H, J ) 8.5 Hz), 8.19 (dt, 1H, J )
7.0, 1.0 Hz), 7.99 (dd, 1H, J ) 8.5, 1.0 Hz), 7.63-7.71 (m, 3H),
7.46 (tt, 1H, J ) 8.0, 2.0 Hz), 7.13 (t, 1H, J ) 6.0 Hz), 4.02 (q,
2 H, J ) 6.5 Hz), 2.66 (t, 2H, J ) 6.5 Hz), 2.28 (s, 6H). HRMS-
EI m/z: calcd for C19H19N3O, 305.1528; found, 305.1518. Anal.
Calcd for C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C,
74.56; H, 6.38; N, 13.51.
binding affinity to G-quadruplex. Furthermore, the 11-
substituted quindoline derivatives with the same aro-
matic core but different side chains demonstrated
different abilities in inducing and stabilizing the telo-
meric G-quadruplex structures. Obviously, the electro-
static interactions between the ligand side chains and
telomeric G-quadruplex structures play an important
role in their recognition of each other.
4. Conclusions
Several quindoline derivatives (4b-j) were designed
and synthesized, and their interaction with the telom-
eric G-quadruplex has been studied. Introducing an
electron-donating group such as a substituted amino
group to the 11-position of quindoline significantly
increased the electron density at the 5-N atom, resulting
in easy protonation under physiological pH. EMSA and
CD spectra studies clearly showed that these compounds
were capable of inducing the formation and stabilization
of the G-quadruplex and thus exhibited inhibitory effect
on the telomerase. The competition dialysis experiment
showed that 4a interacted preferentially with G-qua-
druplexes and had comparatively weak affinity for
duplex DNA. The inhibitory effect of these compounds
on telomerase was also investigated through the utiliza-
tion of a modified telomerase repeat amplification
protocol (TRAP) assay. This study suggested that the
quindoline derivatives might be potential lead com-
pounds for the development of new telomerase inhibi-
tors.
5. Experimental Section
Synthetic Chemistry. Melting points were recorded on a
Leica Galen III hot-stage melting point apparatus and were
uncorrected. 1H NMR spectra were recorded on a 500 MHz
Varian Unity INOVA spectrometer or a 300 MHz Mercury-
Plus spectrometer using TMS as an internal standard in
DMSO-d6, CDCl3, CD3OD. Mass spectra were recorded on
either a VG ZAB-HS (fast atom bombardment) or a Finnigan
LCQ Deca XP (Electrospray) instrument. High-resolution mass
spectra were obtained with a GCT-TOF. Elemental analyses
were carried out on an Elementar Vario EL CHNS elemental
analyzer. All compounds were routinely checked by TLC with
Merck silica gel 60F-254 glass plates.
11-Chloro-10H-indolo[3,2-b]quinoline (3a). Compound
3a was synthesized by using a literature procedure.6b Mp 219-
221 °C (219-221 °C in ref 6c). 1H NMR (300 MHz, DMSO-d6):
δ 11.86 (brs, NH), 8.37 (d, 1H, J ) 7.8 Hz), 8.28 (t, 2H, J )
8.4 Hz), 7.80-7.62 (m, 4H), 7.35 (t, 1H, J ) 7.5 Hz). HRMS-
EI m/z: calcd for C15H9N2Cl, 252.0454; found, 252.0453.
11-Chlorobenzofuro[3,2-b]quinoline (3b). Compound 3b
was synthesized by a literature procedure.6d Mp 158-160 °C
(157-158 °C in ref 6c). FAB-MS m/z: 254 (M+ + 1). 1H NMR
(500 MHz, DMSO-d6): δ 8.35 (d, 1H, J ) 8.0 Hz), 8.22 (d, 1H,
J ) 8.0 Hz), 7.80 (d, 1H, J ) 8.0 Hz), 7.75 (d, 2H, J ) 8.5 Hz),
7.70 (td, 1H, J ) 8.0, 7.0, 1.5 Hz), 7.51 (td, 1H, J ) 8.0, 7.0,
1.5 Hz), 7.38 (m, 1H).
General Method for the Preparation of the 11-Ami-
noquindoline Derivatives (4). A mixture of 3 (5 mmol) and
10 g of phenol was heated at 60 °C for half an hour, then 10
mmol of N,N-dialkylalkylamine was added and the mixture
was heated at 120 °C for 4 h. The mixture was cooled to room
temperature and was poured to 50 mL of water. The pH of
the mixture was adjusted to 10 with a 40% NaOH solution,