Synthesis of novel halogenated cryptolepine analogues

Article abstract of DOI:10.1002/jhet.5570430126

Cryptolepine (5-N-methyl-10-H-indolo[3,2-b]quinoline) is an indoloquinoline alkaloid present in the roots of Cryptolepis Sanguinolenta. In its hydrochloride form the alkaloid presents a number of bioactivities. The alkaloid also has cytotoxic properties t

Full text of DOI:10.1002/jhet.5570430126

Jan-Feb 2006
171
Synthesis of Novel Halogenated Cryptolepine Analogues
Srinivas Reddy Gouni, S. Carrington, and C. W. Wright
School of Pharmacy, University of Bradford, Bradford, BD7 1DP, UK
Received February 22, 2005
Cryptolepine (5-N-methyl-10-H-indolo[3,2-b]quinoline) is an indoloquinoline alkaloid present in the
roots of Cryptolepis Sanguinolenta. In its hydrochloride form the alkaloid presents a number of bioactivities.
The alkaloid also has cytotoxic properties that are likely to be due to its abilities to intercalate into DNA and
inhibit the enzyme topoisomerase II, as well as the synthesis of DNA. In this research project five novel ana-
logues of cryptolepine were chosen for synthesis.
J. Heterocyclic Chem., 43, 171 (2006).
Introduction.
Cryptolepine is (5-N-methyl-10H-indolo[3,2-b]quinoline)
(Figure 1), is an indoloquinoline alkaloid obtained from
Cryptolepis Sanguinolenta, a member of the Asclepiadaceae
family and the Periplocaceae subfamily, is a shrub indige-
nous to tropical West Africa. Cryptolepine and its derivatives
present a large spectrum of biological activities which
include antimicrobial, antibacterial, anti-inflammatory, anti-
hypertensive, antipyretic, antimuscarinic, antithrombotic,
noradrenergic receptor antagonistic and vasodilative proper-
ties [1]. Cryptolepine also possesses significant antiplas-
modial activity [2] and as the major alkaloid of the plant, is a
cytotoxic DNA intercalator that has promise as an anticancer
agent [3]. Cryptolepine is a rare example of a natural product
where synthesis was reported prior to its isolation from
nature. It was first synthesized in 1906 by Fichter and co-
Figure 1. Various forms of Cryptolepine.
workers and its isolation was first reported by Clinquart in
1929 from Cryptolepis Triangularis [1,4,5]. As cryptolepine
possesses a number of biological activities many analogues
have been synthesized to identify its pharmacophoric groups.
The structure of cryptolepine was also modified in order to
enhance its potency [6]. Results of various experiments
reveal that the alkaloid tightly binds to DNA and behaves as
a typical intercalating agent. It stabilizes topoisomerase

172
S. Reddy Gouni, S. Carrington, and C. W. Wright
Vol. 43
II- DNA covalent complexes and stimulates the cutting of
DNA at pre-existing topoisomerase II-DNA cleavage sites
hence acts as a topoisomerase II poison. The drug blocks the
cell cycle in the G2 or M phases. The alkaloid is more potent
at inhibiting DNA synthesis rather than RNA and protein
synthesis [7]. Wright et al. [2], synthesized various mono-
and di-halogenated cryptolepine analogues and tested these
for antiplasmodial and cytotoxic activities. Among these
compounds, 2,7-dibromocryptolepine, 6,7- difluoro-
cryptolepines showed promising in vivo antimalarial activity.
The analogue 8,11-dichlorocryptolepine was 5 fold more
active than cryptolepine as a cytotoxic agent and these
dihalogenated cryptolepine analogues are important leads in
the search for novel potent antitumor compounds [2].
Based on the cytotoxicity activity results of 11-halocryp-
tolepine analogues synthesized by Wright et al. [2], vari-
ous 11-substituted mono and dihalogenated analogues of
cryptolepine were chosen for synthesis in an attempt to
produce these previously untested compounds. These lead
structures will be of great interest in the development of
synthetic anti-cancer drugs.
intermediates required. The general reaction scheme
involves the following five steps (Figure 2).
Setback of N-5 Alkylation with Methyl Iodide.
These halogenated cryptolepines were identified by the
presence of a single N-CH peak between 5.01-5.05 ppm in
3
1
the H-NMR spectrum. This confirms that the methylation
of the mono or disubstituted quindolines worked to yield the
corresponding bromoderivatives. This led to the conclusion
that despite the literature evidence, methyl iodide was not
good for N-5 alkylation of 11-bromoquindolines. The possi-
ble reason for this setback is the activation of an aromatic
nucleophilic substitution (SNAr). A bromoquindoline
should quaternize easily with methyl iodide; this quaterniza-
tion increases considerably the leaving ability of the 11-
bromine toward nucleophiles [10]. One more reason is that
the effect of aprotic solvent like sulfolane, which strongly
interacts with cations and do not solvate or stabilize the
anions well. Hence the cation-anion association in these sol-
vents is little and this further increases the reactivity of
iodide anions [11]. The best way to solve this setback would
be to use methylating agents with poor nucleophile-charac-
ter leaving groups such as methyltriflate, methyl methane-
sulfonate or dimethylsulfate [9] in a polar solvent like
methanol or the Eschweiler-Clarke procedure for alkylation
of amines with formaldehyde-formic acid [12].
Results and Discussion.
A series of 11-substituted quindoline and cryptolepine
analogues were prepared by [2,8,9] using similar reaction
schemes but with slight modifications, according to the
Figure 2. The General Reaction Scheme.

Jan-Feb 2006
Synthesis of Novel Halogenated Cryptolepine Analogues
173
+
EXPERIMENTAL
(C-7); MS. M/z (relative intensity, %): 257.6 (100) M , 241.6
(12), 213.7 (5), 193.0 (95), 142.8 (8).
Chemicals and Reagents.
Step II. Synthesis of 2-(2-Phenylamino-acetylamino)-benzoic
The chemicals and reagents were purchased from either Sigma-
Aldrich (UK), Lancaster (UK) or BDH (UK) unless otherwise
stated. All solvents were of either HPLC or laboratory grade, dou-
ble distilled water was used to prepare aqueous solutions.
acid (1b).
This compound was prepared according to the general proce-
dure for 1c and obtained in 93 % yield; mp 196.7-198.7 °C; H
1
NMR (DMSO-d , δ ppm): 3.85 (2H, s, 9-H), 6.62 (1H, t, J = 8.1,
6
Thin Layer Chromatography (TLC).
4′-H), 7.10 (1H, d, J = 5.9, 2′-H/6′-H), 7.15 (1H, d, J = 7.1, 3′-
H/5′-H), 7.59 (1H, t, J = 8.3, 4-H), 7.96 (1H, d, J = 7.9, 3-H),
Thin layer chromatography (TLC) was performed on F , 0.2
254
13
8.76 (1H, d, J = 6.9, 6-H); C NMR (CDCl , δ ppm): 40.9 (C-9),
3
mm, 20 x 20 cm, silica gel sheets (Merck). Plates were spotted
with substrate and were eluted with appropriate solvent systems,
113.0 (C-2′/C-6′), 117.6 (C-3), 116.6 (C-4′), 120.0 (C-1), 123.2
(C-5), 129.5 (C-3′/C-5′), 131.6 (C-4), 134.6 (C-6), 141.1 (C-2),
148.7 (C-10), 169.6 (C-8), 171.4 (C-7); MS M/z (relative inten-
then stained with either KMnO (1.5 g KMnO 10 g K CO , 2.5
4
4,
2
3
ml 5 % NaOH, 10 ml H O) solutions prepared in the laboratory.
2
+
sity, %): 270.8 (100) M , 268.9 (4), 142 (1) 106 (1).
The developed plates were first analysed under UV 254 nm then
stained with appropriate reagent.
Step III. Synthesis of 5,5a,10,10a-Tetrahydro-indolo[3,2-b]-
quinolin-11-one (1c).
Column Chromatography.
This compound was prepared according to the general pro-
Column chromatography was performed using silica gel with a
particle size of 50-70 µm, (BDH) or alumina STD grade CA 150
mesh (Aldrich) by preparing a slurry with the eluent mixture and
packing it into the chromatography column. The collected sample
fractions were analysed by TLC.
1
cedure for 1d and obtained in 9 % yield; mp > 300 °C;
H
NMR (DMSO-d , δ ppm): 7.20 (1H, d, J = 6.6, 4-H), 7.26
6
1
(1H, d, J = 7.9, 2-H), 7.32 ( H, d, J = 7.9, 7-H), 7.42-7.54
(1H, m, 8-H), 7.68 (1H, t, J = 8.3, 3-H), 7.76 (1H, d, J = 8.3,
9-H), 8.22 (1H, d, J = 7.9, 6-H/1-H), 8.37 (1H, d, J = 8.1, 1-
Nuclear Magnetic Resonance Spectroscopy (NMR).
13
H/6-H); C NMR (CDCl , δ ppm): 113.0 (C-9), 116.0 (C-4),
3
1
13
118.5 (C-2), 119.5 (C-11a), 121.0 (C-5b), 121.5 (C-8), 122.5
(C-6), 125.0 (C-7), 127.0 (C-1), 129.0 (C-5a), 131.0 (C-7),
139.0 (C-10a), 140.0 (C-9a), 168.0 (C-4a), 174.0 (C-11); MS
H and C spectra were acquired on a JEOL GX270 FT NMR
1
13
spectrometer at 270.05 MHz for H and 67.80 MHz for C. The
samples were prepared in CDCl (deuterated chloroform),
3
+
M/z (relative intensity, %): 234.1 (100) M , 205 (11), 119 (7),
CD OD (deuterated methanol), or DMSO (deuterated dimethyl-
3
105.1 (68), 28 (12).
sulfoxide) using TMS (tetramethylsilane) as the internal stan-
dard. Chemical shifts are expressed in δ ppm (parts per million).
Coupling constants were measured in hertzs (Hz).
Step IV (b). Synthesis of 11-Bromo-10H-indolo[3,2-b]quinoline
(1d).
Mass Spectroscopy (MS).
This compound was prepared according to the general proce-
dure for 1e and obtained in 60 % yield; mp 118.4-199.6 °C; H
1
Mass spectra were acquired on an AEI (Associated Electrical
Industries Ltd.,) mass spectrometer type- MS 902 which was
operated by Mr. Andrew Healy. For accurate mass measurements
the samples were sent to university of Newcastle.
NMR (DMSO-d , δ ppm): 7.38 (1H, t, J = 8.1, 7-H), 7.69 (1H,
6
t, J = 8.1, 8-H), 7.77 (1H, t, J = 8.1, 2-H), 7.87 (1H, t, J = 8.1,
3-H), 8.01 (1H, d, J = 8.1, 9-H), 8.37 (1H, d, J = 8.1, 6-H), 8.43
13
(1H, d, J = 8.1, 4-H), 8.58 (1H, d, J = 8.1, 1-H); C NMR
Melting Point Determination,
(CDCl , δ ppm): 111.5 (C-5b), 118 (C-4), 121 (C-7), 122.5 (C-
3
Melting points of different intermediate compounds were
determined by using digital melting point apparatus (Electro
Thermal IA 9200 series) and are uncorrected.
9), 123.8 (C-2), 124.1 (C-6), 126.5 (C-11a), 127.8 (C-11), 128.8
(C-3), 129.5 (C-1), 130.5 (C-8), 130.8 (C-4a), 131.9 (C-5a),
143.5 (C-10a), 157 (C-9a); MS M/z (relative intensity, %): 296
+
(100) M , 235 (7), 202 (8), 94 (5).
General Method for the Synthesis of Various Novel Haloginated
Cryptolepine Analogues.
Step V. Synthesis of (1e).
This compound was prepared according to the general proce-
dure and obtained in 69 % yield; mp 122.6 °C; H NMR
The procedure described by [2,8,9] involves five steps (Figure
2). The same procedure was followed for the synthesis of various
novel haloginated cryptolepine analogues.
1
(CD OD-d , δ ppm): 5.00(3H, S, N-5-CH ), 7.56 (1H, t, J = 8.1,
3
4
3
7-H), 7.89 (1H, t, J = 8.1, 8-H), 7.99 (1H, t, J = 8.1, 2-H), 8.20
(1H, t, J = 8.1, 3-H), 8.52 (1H, d, J = 8.1, 9-H), 8.62 (1H, d, J =
8.1, 6-H), 8.65 (1H, d, J = 8.1, 4-H), 8.71 (1H, d, J = 8.1, 1-H);
Synthesis of 11-iodocryptolepine (1e).
Step I. Synthesis of 2-(2-Bromo-acetylamino)-benzoic acid (1a).
13
C NMR (CDCl , δ ppm): 44.9 (C-12), 105.8 (C-11), 111.0 (C-
3
This compound was prepared according to the general proce-
dure and obtained in 91 % yield; mp 162.8-163.4 °C. This was
the common intermediate in step I for all the synthesised novel
9), 119.6 (C-8), 120.5 (C-6), 121.7 (C-7), 126.5 (C-4), 127.6 (C-
5b), 128.3 (C-2), 129.1 (C-11a), 130.3 (C-3), 132.3 (C-1), 133.7
(C-10a), 135.5 (C-9a), 148.3 (C-4a), 152.2 (C-5a); HRMS
1
cryptolepine analogues; H NMR (DMSO-d , δ ppm): 4.24 (2H,
6
Found: m/z 357.9967 Calcd for C
H N I: M 358.
16 15 2
s, 9-H), 7.18 (1H, t, J = 7.9, 5-H), 7.60 (1H, t, J = 8.1, 4-H), 8.00
Anal. Calcd. for C
H N I: C, 53.68; H, 4.24; N, 7.82. Found:
16 15 2
13
(1H, d, J = 7.9, 3-H), 8.45 (1H, d, J = 8.3, 6-H); C NMR
C, 53.76; H, 4.27; N, 7.93.
(CDCl , δ ppm): 39.7 (C-9), 117.6 (C-3), 120.5 (C-1), 123.9
3
Synthesis of 9,11-Dichlorocryptolepine (2d).
(C-5), 131.6 (C-4), 134.5 (C-6), 140.5 (C-2), 165.5 (C-8), 169.7

174
S. Reddy Gouni, S. Carrington, and C. W. Wright
Vol. 43
Step II. Synthesis of 2-[2-(2-Chloro-phenylamino)-acetylamino]-
benzoic acid (2a).
4), 121 (C-7), 121.7 (C-9), 124.2 (C-2), 125.1 (C-6), 125.7 (C-
11a), 126.9 (C-11), 127.6 (C-3), 129.4 (C-1), 129.7 (C-8), 132
(C-4a), 140 (C-5a), 145.1 (C-10a), 145.4 (C-9a) MS M/z (relative
intensity, %): 332.1 (100) M , 251 (10), 215 (22), 166 (13), 107.5
(12), 28 (21).
This compound was prepared according to the general proce-
+
dure for 2b and obtained in 92 % yield. This was also the com-
1
mon intermediate for 3b in Step II; mp 206.7-208.4 °C; H NMR
(DMSO-d , δ ppm): 4.01 (2H, s, 9-H), 6.30 (1H, t, J = 5.6, 3′-H),
Step V. Synthesis of (3b).
6
6.57 (1H, d, J = 8.1, 2′-H), 6.66 (1H, t, J = 7.5, 4′-H), 7.13 (1H,
This compound was prepared according to the general proce-
dure and obtained in 90 % yield; mp 113.8 °C; H NMR
m, 5′-H), 7.30 (1H, d, J = 7.9, 5-H), 7.59 (1H, t, J = 8.3, 4-H),
1
13
7.96 (1H, d, J = 7.9, 3-H), 8.75 (1H, d, J = 8.3, 6-H); C NMR
(CD OD-d δ ppm): 5.05(3H, S, N-5-CH ), 7.55(1H, t, J = 8.2,
3
4,
3
(CDCl , δ ppm): 49.1 (C-9), 111.7 (C-2′), 116.5 (C-6′), 118.2 (C-
3
7-H), 8.00 (1H, d, J = 7.9, 8-H), 8.02 (1H, t, J = 7.8, 2-H), 8.23
(1H, t, J = 7.1, 3-H), 8.59 (1H, d, J = 8.8, 6-H), 8.66 (1H, d, J =
4′), 119.0 (C-3), 120.0 (C-1), 123.3 (C-5), 128.6 (C-3′), 129.6 (C-
5′), 131.7 (C-4), 134.7 (C-6), 141.1 (C-2), 144.2 (C-1′), 169.7 (C-
13
8.8, 4-H), 8.72 (1H, d, J = 8.2, 1-H); C NMR (CDCl , δ ppm):
3
+
8), 170.6 (C-7); MS M/z (relative intensity, %): 304.8 (100) M ,
44.9 (C-12), 105.8 (C-11), 116.3 (C-9), 118.6 (C-6), 120.0 (C-8),
123.1 (C-7), 126.5 (C-4), 128.3 (C-2), 129.0 (C-5b), 129.1
(C11a), 130.6 (C-3), 132.3 (C-1), 133.7 (C-10a), 135.9 (C-9a),
148.3 (C-4a), 152.2 (C-5a); HRMS Found: m/z 391.9577 Calcd
226.8 (12), 213.7 (7), 142.7 (8), 139.8 (11), 87.8 (11).
Step III. Synthesis of 9-Chloro-5,5a,10,10a-tetrahydro-
indolo[3,2-b]quinolin-11-one (2b).
for C
Anal. Calcd. for C
Found: C, 53.57; H, 4.72; N, 7.95.
H N ClI: M 392.
16 14 2
This compound was prepared according to the general proce-
dure for 2c and obtained in 13 % yield. This was also the common
intermediate for 3b in Step III; mp > 300 °C; MS M/z (relative
H N ClI: C, 53.68; H, 4.67; N, 7.82.
16 14 2
+
Synthesis of 8-Chloro-11-iodocryptolepine (4d).
intensity, %): 268.7 (100) M , 199 (1), 139.8 (5), 121 (1), 100 (1).
Step II. Synthesis of 2-[2-(3-Chloro-phenylamino)-acetylamino]-
benzoic acid (4a).
Step IV (a). Synthesis of 9,11-Dichloro-10H-indolo[3,2-b]-
quinoline (2c).
This compound was prepared according to the general proce-
dure for 4b and obtained in 80 % yield; mp 201.3-202.6 °C; H
This compound was prepared according to the general proce-
dure for 2d and obtained in 31 % yield; mp 106.8- 107.3 °C; H
1
1
NMR (DMSO-d , δ ppm): 3.94 (2H, s, 9-H), 6.59- 6.60 (1H, m,
NMR (CDCl , δ ppm): 7.28 (1H, t, J = 7.8, 7-H), 7.57 (1H, d, J =
6
3
2′-H/6′-H), 6.63 (1H, t, J = 7.9, 4′-H), 6.70 (1H, d, J = 4.1, 3′-H),
7.10 (1H, t, J = 8.1, 5-H), 7.57 (1H, t, J = 8.1, 4-H), 7.98 (1H, d,
7.62, 8-H), 7.65 (1H, t, J = 6.8, 2-H), 7.71 (1H, t, J = 8.3, 3-H),
8.26 (1H, d, J = 8.4, 6-H), 8.31 (1H, d, J = 8.3, 4-H), 8.37 (1H, d,
13
13
J = 7.9, 3-H), 8.78 (1H, d, J = 8.3, 6-H); C NMR (CDCl , δ
J = 7.8, 1-H); C NMR (CDCl , δ ppm): 116.8 (C-5b), 120.4 (C-
3
3
ppm): 49.0 (C-9), 111.3 (C-2′), 112.6 (C-6′), 116.5 (C-4′), 117.1
(C-3), 120.0 (C-1), 123.2 (C-5), 131 (C-3′), 131.7 (C-5′), 134.2
(C-4), 134.6 (C-6), 141.1 (C-2), 150.1 (C-1′), 169.8 (C-8), 170.7
4), 120.8 (C-7), 121.7 (C-9), 122.7 (C-2), 124.1 (C-6), 124.5 (C-
11a), 126.7 (C-11), 127.6 (C-3), 129.4 (C-1), 129.6 (C-8), 129.9
(C-4a), 140.1 (C-5a), 145.2 (C-10a), 145.9 (C-9a). MS M/z (rela-
+
+
(C-7); MS M/z (relative intensity, %): 304.7 (100) M , 226.8 (2),
tive intensity, %): 286 (100) M , 253 (12), 215 (25), 188 (6), 142
213.9 (3), 142.8 (4), 117.8 (2), 87.9 (5).
(12), 125 (12), 64 (5), 28 (4).
Step III. Synthesis of 8-Chloro-5,5a,10,10a-tetrahydro-indolo-
[3,2-b]quinolin-11-one (4b).
Step V. Synthesis of (2d).
This compound was prepared according to the general proce-
dure and obtained in 34 % yield; mp 118.4 °C; H NMR
1
This compound was prepared according to the general proce-
dure for 4c and obtained in 13.2 % yield; mp > 300 °C; MS M/z
(CD OD-d δ ppm): 5.09 (3H, S, N-5-CH ), 7.57 (1H, t, J = 8.1,
3
4,
3
+
(relative intensity, %): 268.7 (100) M , 197.8 (2), 139.8 (5),
7-H), 7.97 (1H, d, J = 8.1, 8-H), 8.03 (1H, t, J = 8.1, 2-H), 8.08
(1H, t, J = 8.1, 3-H), 8.21 (1H, d, J = 8.1, 6-H), 8.75 (1H, d, J =
117.8 (4), 99.9 (5).
13
8.1, 4-H), 8.80 (1H, d, J = 8.1, 1-H); C NMR (CDCl , δ ppm):
3
Step IV (b). Synthesis of 11-Bromo-8-chloro-10H-indolo[3,2-
b]quinoline (4c).
44.9 (C-12), 116.3 (C-9), 118.6 (C-6), 120.0 (C-8), 121.6 (C-
10a), 123.1 (C-7), 124.3 (C-1), 125.0 (C-11a), 125.3 (C-4), 126.3
(C-2), 129.0 (C-5b), 131.8 (C-3), 135.9 (C-9a), 137.8 (C-11),
148.0 (C-4a), 150.3 (C-5a); HRMS Found: m/z 302.0431 Calcd
This compound was prepared according to the general proce-
1
dure for 4d and obtained in 42 % yield; mp 108.7-109.2 °C; H
NMR (DMSO-d , δ ppm): 6.76 (1H, d, J = 9.1, 7-H), 7.38 (1H, d,
6
for C
H N Cl : M 302.
16 14 2 2
J = 9.1, 9-H/6-H), 7.65 (1H, t, J = 7.5, 2-H), 7.79 (1H, t, J = 8.9,
3-H), 7.8-7.9 (1H, m, 6-H/9-H), 8.28 (1H, m, J = 7.0, 4-H), 8.37
Anal. Calcd. for C
H N Cl : C, 53.68; H, 4.67; N, 7.82.
16 14 2 2
Found: C, 53.73; H, 4.59; N, 7.88.
13
(1H, d, J = 8, 1-H); C NMR (CDCl , δ ppm): 109.6 (C-5b),
3
Synthesis of 9-Chloro-11-iodocryptolepine (3b).
111.6 (C-4), 121.7 (C-7), 122.2 (C-9), 123.5 (C-2), 124.7 (C-6),
125.1 (C-11a), 126.8 (C-11), 127 (C-3), 127.1 (C-1), 130.3 (C-
4a), 130.5 (C-5a), 144 (C-10a), 145.2 (C-9a); MS M/z (relative
Step IV (b). Synthesis of 11-Bromo-9-chloro-10H-indolo[3,2-b]-
Quinoline (3a).
+
intensity, %): 331.9 (100) M , 251 (11), 215 (22), 165.9 (10),
This compound was prepared according to the general proce-
dure for 3b and obtained in 41 % yield; mp 106.2-107.4 °C; H
94.5 (6), 39 (3).
1
Step V. Synthesis of (4d).
NMR (CDCl , δ ppm): 7.31(1H, t, J = 7.9, 7-H), 7.58 (1H, d, J =
3
1
7.9, 8-H), 7.65 ( H, t, J = 8.1, 2-H), 7.69 (1H, t, J = 8.1, 3-H),
This compound was prepared according to the general proce-
1
8.22 (1H, d, J = 8.3, 6-H), 8.28 (1H, d, J = 8.1, 4-H), 8.35 (1H, d,
dure and obtained in 25% yield; mp 121.7 °C; H NMR
13
J = 7.6, 1-H); C NMR (CDCl , δ ppm): 111.5 (C-5b), 116.8 (C-
(CD OD-d , δ ppm): 5.01(3H, S, N-5-CH ), 7.53 (1H, dd, J = 9,
3
3
4
3

Jan-Feb 2006
Synthesis of Novel Halogenated Cryptolepine Analogues
175
8.9, 7-H), 7.90 (1H, d, J = 8.6, 9-H/6-H), 8.00 (1H, t, J = 8.6, 2-
H), 8.22 (1H, t, J = 7.4, 3-H), 8.60 (1H, d, J = 4.6, 6-H/9-H), 8.64
(1H, d, J = 4.8, 4-H), 8.70 (1H, d, J = 8.8, 1-H); C NMR
Step V. Synthesis of (5d).
This compound was prepared according to the general proce-
dure and obtained in 33 % yield; mp 124.2 °C; H NMR
13
1
(CDCl , δ ppm): 44.9 (C-12), 105.8 (C-11), 111.4 (C-9), 121.9
3
(CD OD-d , δ ppm): 5.02 (3H, S, N-5-CH ), 7.87 (1H, d, J = 8.3,
3
4
3
(C-6), 122.1 (C-7), 124.9 (C-8), 125.7 (C-5b), 126.5 (C-4), 128.6
(C-2), 129.1 (C-11a), 130.3 (C-3), 132.3 (C-1), 133.7 (C-10a),
136.9 (C-9a), 148.3 (C-4a), 152.2 (C-5a); HRMS Found: m/z
8-H), 7.93 (1H, d, J = 8.9, 9-H/6-H), 8.02 (1H, t, J = 8.3, 2-H),
8.24 (1H, t, J = 6.8, 3-H), 8.62 (1H, d, J = 8.5 6-H/9-H), 8.64
(1H, d, J = 9.1, 4-H/1-H), 8.77 (1H, d, J = 8, 1-H/ 4-H);
13
C
391.9577 Calcd. for C
H N ClI: M 392.
16 14 2
NMR (CDCl , δ ppm): 44.9 (C-12), 105.8 (C-11), 112.4 (C-9),
3
Anal. Calcd. for C
H N ClI: C, 53.68; H, 4.67; N, 7.82.
16 14 2
120.9 (C-6), 127.0 (C-7), 120.0 (C-8), 129 (C-5b), 126.5 (C-4),
128.6 (C-2), 129.1 (C-11a), 130.3 (C-3), 132.3 (C-1), 133.7
(C-10a), 136.9 (C-9a), 148.3 (C-4a), 152.2 (C-5a); HRMS
Found: C, 53.68; H, 4.77; N, 7.84.
Synthesis of 7-Chloro-11-iodocryptolepine (5d).
Found: m/z 391.9577 Calcd for C
H N ClI: M 392.
16 14 2
Step II. Synthesis of 2-[2-(4-Chloro-phenylamino)-acetylamino]-
benzoic acid (5a).
Anal. Calcd. for C
H N ClI: C, 53.68; H, 4.67; N, 7.82.
16 14 2
Found: C, 53.76; H, 4.71; N, 7.82.
This compound was prepared according to the general proce-
1
Acknowledgements.
dure for 5b and obtained in 88 % yield; mp 215.5-217.8 °C; H
NMR (DMSO-d , δ ppm): 3.89 (2H, s, 9-H), 6.65 (1H, d, J = 8.8,
6
I gratefully acknowledge my supervisors S. Carrington and C. W.
Wright.
2′-H/6′-H), 7.14 (1H, t, J = 8.3, 5-H), 7.47 (1H, s, 3′-H/5′-H),
7.57 (1H, t, J = 8.1, 4-H), 7.97 (1H, d, J = 7.9, 3-H), 8.77 (1H, d,
13
J = 8.3, 6-H); C NMR (CDCl , δ ppm): 114.4 (C-2′/C-6′),
3
REFERENCES AND NOTES
116.5 (C-4′), 120.0 (C-3), 121.0 (C-1), 123.2 (C-5), 129.2 (C-
3′/C-5′), 131.7 (C-4), 134.6 (C-6), 141.1 (C-2), 147.6 (C-1′),
169.7 (C-8), 170.9 (C-7); MS M/z (relative intensity, %): 304.8
[1] D. E. Bierer, D. M. Fort, C. D. Mendez, J. Luo, P. A. Imbach,
L. G. Dubenko, S. D. Jolad, R. E. Gerber, J. Litvak, Q. Lu, P. S. Zhang,
M. J. Reed, N. Waldeck, R. C. Bruening, B. K. Noamesi, R. F. Hector, T.
J. Carlson, S. R. King, J. Med. Chem., 41, 894 (1998).
[2] C. W. Wright, J. Addae-Kyereme, A. G. Breen, J. E. Brown,
M. F. Cox, S. L. Croft, Y. Gokcek, H. Kendrick, R. M. Phillips, P. L.
Pollet, J. Med. Chem., 44, 3187 (2001).
[3] C. Ansah, N. J. Gooderham, Toxico. Sci., 70, 245 (2002).
[4] Fichter, Boehringer, Chem. Ber., 39, 3932 (1906).
[5] Clinquart, Bull. Acad. Rev. Med., Belgium., 12, 627 (1929).
[6] G. M. Leroy, P. C. Fan, S. Y. Ablordeppy, Med. Chem. Res., 9,
118 (1999).
+
(100) M , 226.8 (18), 213.7 (11), 150.7 (3), 142.8 (5), 117.8 (4),
87.8 (25).
Step III. Synthesis of 7-Chloro-5,5a,10,10a-tetrahydro-indolo-
[3,2-b]quinolin-11-one (5b).
This compound was prepared according to the general proce-
dure for 5c and obtained in 6 % yield; mp > 300 °C; MS M/z (rel-
+
ative intensity, %): 268.7 (100) M , 139.7 (5), 121 (3), 100 (2),
88 (2).
Step IV (b). Synthesis of 11-Bromo-7-chloro-10H-indolo[3,2-b]-
quinoline (5c).
[7] J. N. Lisgarten, M. Coll, J. Portugal, C. W. Wright, J. Aymami,
Nat. Struct. Biol., 9, 57 (2002).
[8] M. Yamato, Y. Takeuchi, M. Chang, K. Hashigaki, T. Tsuruo,
T. Tashiro, S. Tsukagoshi, Chem. Pharm. Bull., 38, 3048 (1990).
[9] D. E. Bierer, L. G. Dubenko, P. S. Zhang, Q. Lu, P. A. Imbach,
A. W. Garofalo, P. W. Phuan, D. M. Fort, J. Litvak, R. E. Gerber, B.
Sloan, J. Luo, R. Cooper, G. M. Reaven, J. Med. Chem., 41, 2754 (1998).
[10] J. March, Advanced organic chemistry reactions, mecha-
nisms, and structure, John Wiley & Sons, New York, NY, 1992, pp 649-
650.
This compound was prepared according to the general procedure
for 5d and obtained in 48 % yield; mp 111.6-113.2 °C; H NMR
1
(CDCl , δ ppm): 7.39 (1H, d, J = 8.6, 8-H), 7.49 (1H, t, J = 9.1, 2-
3
H), 7.65 (1H, d, J = 8.3, 9-H), 7.71 (1H, d, J = 8.1, 6-H/1-H), 7.81
(1H, t, J =8.1 3-H), 8.19 (1H, d, J = 8.1, 6-H/1-H), 8.27 (1H, d, J
13
=8, 4-H); C NMR (CDCl , δ ppm): 111.5 (C-5b), 112.4 (C-4),
3
122.2 (C-7), 123.7 (C-9), 125 (C-2), 125.7 (C-6), 126.5 (C-11a),
126.9 (C-11), 127.4 (C-3), 129.6 (C-1), 130.2 (C-8) 132.7 (C-4a),
134.8 (C-5a), 141.3 (C-10a), 145 (C-9a); MS M/z (relative inten-
[11] J. Miller, Aromatic nucleophilic substitution, Elsevier, New
York, NY, 1968, pp 61-136.
+
sity, %): 332 (100) M , 251 (12), 215 (28), 166 (9), 94.5 (6), 28 (8).
[12] M. L. Moore, Org. Reactions, 5, 309 (1949).