New derivatives of 11-methyl-6-[2-(dimethylamino)ethyl]-6H-indolo[2,3-b] quinoline as cytotoxic DNA topoisomerase II inhibitors

Article abstract of DOI:10.1016/j.bmcl.2012.08.032

Novel indolo[2,3-b]quinoline derivatives substituted at N-6 and C-2 or C-9 positions with (dimethylamino)ethyl chains linked to heteroaromatic core by ether, amide or amine bonds, were manufactured and evaluated in vitro for their cytotoxic activity again

Full text of DOI:10.1016/j.bmcl.2012.08.032

Bioorganic & Medicinal Chemistry Letters 22 (2012) 6103–6107
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New derivatives of 11-methyl-6-[2-(dimethylamino)ethyl]-6H-
indolo[2,3-b]quinoline as cytotoxic DNA topoisomerase II inhibitors
Wojciech Luniewski a, Joanna Wietrzyk b, Joanna Godlewska b, Marta Switalska b, Malgorzata Piskozub b,
Wanda Peczynska-Czoch c, Lukasz Kaczmarek a,
⇑
a Pharmaceutical Research Institute, 8 Rydygiera St., Warszawa 01-793, Poland
b Ludwik Hirszfeld Institute of Immunology and Experimental Therapy of Polish Academy of Science, 12 Weigla St., Wroclaw 53-114, Poland
c Department of Organic Chemistry, Faculty of Chemistry, Wroclaw University of Technology, 27 Wybrzeze Wyspianskiego St., Wroclaw 50-370, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel indolo[2,3-b]quinoline derivatives substituted at N-6 and C-2 or C-9 positions with (dimethyl-
amino)ethyl chains linked to heteroaromatic core by ether, amide or amine bonds, were manufactured
and evaluated in vitro for their cytotoxic activity against several cell lines of different origin including
multidrug resistant sublines and tested for their ability to influence the cell cycle and inhibit topoisomer-
ase II activity. It was found, that all compounds show cytotoxic activity against cell lines tested, including
multidrug resistant LoVo/DX, MES-SA/DX5 and HL-60 sublines. The tested compounds induce the G2M
phase cell cycle arrest in Jurkat cells, and inhibit topoisomerase II activity.
Received 5 July 2012
Revised 6 August 2012
Accepted 8 August 2012
Available online 15 August 2012
Keywords:
Indolo[2,3-b]quinoline derivatives
Neocryptolepine
Ó 2012 Elsevier Ltd. All rights reserved.
Cytotoxic activity
Multidrug resistance
Topoisomerase II inhibition
Synthetic derivatives of indolo[2,3-b]quinolines constitute no-
vel group of compounds with potent in vitro antitumor activity
and DNA binding properties. Their structure derive from neocry-
ptolepine, a plant alkaloid isolated from roots of an African shrub
Cryptolepsis sanguinolenta. Aqueous extracts of this plant (com-
posed of a mixture of isomeric indoloquinolines) have been used
for years in folk medicine as antimicrobial and antiplasmodial
agents.1 The first synthesis of indolo[2,3-b]quinoline was per-
formed in 1897 by Gabriel and Eschenbach2 in the process of
that the presence, position, and nature of the substituent is crucial
for the activity of the derivatives. We found that 6,11-dimethyl-
6H-indolo[2,3-b]quinoline, an inactive isomer of 5,11-dimethyl-
5H-indolo[2,3-b]quinoline (DIMIQ), acquires cytotoxic activity
after the introduction of proper (alkylamino)alkyl substituents.10,11
The biological significance of (alkylamino)alkyl substituents intro-
duced into indoloquinoline isomeric cores (indolo [2,3-b] and [3,2-
b] quinolines) was also reported by other groups.12–17
In this Letter the synthesis and some biological properties of no-
vel series of 11-methyl-6-(2-dimethylamino)ethyl-6H-indolo[2,3-
b]quinoline derivatives substituted at C-2 or C-9 position with
(dimethylamino)alkyl chains linked with ether, amide or amine
bonds to heteroaromatic chromophore are presented. These
compounds bearing two (alkylamino)alkyl moieties attached to
indolo-quinoline core were evaluated in vitro for their cytotoxic
activity against several cell lines of different origin, including mul-
tidrug resistant sublines: human colon cancer, uterine sarcoma and
human promyelocytic leukemia and tested for their ability to influ-
ence the cell cycle and inhibit topoisomerase II activity.
The syntheses of the initial indolo[2,3-b]quinoline derivatives,
which comprise 2-methoxy-11-methyl-6H-indolo[2,3-b]quinoline
(1), 9-methoxy-11-methyl-6H-indolo[2,3-b]quinoline (2), 11-
methyl-2-nitro-6H-indolo[2,3-b]quinoline (7) and 11-methyl-9-ni-
tro-6H-indolo[2,3-b]quinoline (8) were described elsewhere.4,11,18
Compounds 5 and 6 were obtained from 2-methoxy-11-methyl-
6H-indolo[2,3-b]quinoline (1) or 9-methoxy-11-methyl-6H-indo-
lo[2,3-b]quinoline (2) which were cleaved in 48% solution of
o,o0-dinitro-
a-cyanodibenzyl reduction. Lawson, Perkin and Robin-
son3 and Holt and Petrov4 obtained some derivatives of this struc-
ture by means of Graebe–Ullman reaction (thermal decomposition
of adequate triazole). Synthetic analog of neocryptolepine that is
5,11-dimethyl-5H-indolo[2,3-b]quinoline (DIMIQ), structurally
similar to ellipticine—plant alkaloid with cytotoxic activity5—was
synthesized by our group in 1988.6 It was shown that DIMIQ has
potent cytotoxic activity in vitro and in vivo against mouse leuke-
mia P388, L1210 and B16 melanoma cell lines.6,7 However, more
advanced studies revealed impaired bioavailability of 5H-indo-
lo[2,3-b]quinoline derivatives, which brought about the need for
further work on modifications of indoloquinoline ring structure.8,9
Research on the relationship between structure and cytotoxic
activity of indolo[2,3-b]quinoline from series 5H- and 6H- revealed
⇑
Corresponding author. Tel.: +48 22 4563940; fax: +48 22 4563838.
E-mail address: l.kaczmarek@ifarm.eu (L. Kaczmarek).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.08.032

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W. Luniewski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6103–6107
hydrobromic acid in acetic acid to corresponding hydroxyderiva-
tives (3, 4) Both phenols were then substituted with two equivalents
of 2-dimethylaminoethyl chloride in phase transfer catalysis (PTC)
conditions to yield compounds 5 and 6. (Scheme 1).
The subsequent derivatives of indoloquinoline with (dimethyl-
amino)methyl side chain connected to heteroaromatic moiety via
amide group (15 and 16) were obtained in several steps. The initial
nitroderivatives 7 and 8 were substituted at the indole nitrogen
R2
Cl
CH3
R2
N
x HCl
CH3
N
CH3
CH3
R1
HBr/AcOH
R1
TBAB
N
H
N
H
N
toluene/50% NaOH
3. R1 = OH, R2 = H
4. R1 = H, R2 = OH
1. R1 = OCH3 , R2 = H
2. R1 = H, R2 = OCH3
R2
CH3
R1
N
N
N
CH3
H3C
5. R1 = O(CH2)2N(CH3)2 , R2 = H
6. R1 = H, R2 = O(CH2)2N(CH3)2
Scheme 1. Synthesis of 11-methyl-2 or 9-[2-(dimethylamino)ethoxy]-6-[(2-dimethylamino)ethyl]-6H-indolo[2,3-b]quinolines (5 and 6).
R2
R2
Cl
CH3
N
CH3
N
x HCl
CH3
N
SnCl2/HCl
R1
CH3
R1
N
H
TBAB
N
toluene/50% NaOH
N
9. R1 = NO2, R2 = H
10. R1 = H, R2 = NO2
CH3
7. R1 = NO2, R2 = H
8. R1 = H, R2 = NO2
H3C
R2
R2
CH3
N
CH3
Cl
Cl
HN(CH3)2
R1
R1
O
NEt3
N
N
N
N
N
CH3
CH3
H3C
H3C
13. R1 = NHCOCH2Cl, R2 = H
14. R1 = H, R2 = NHCOCH2Cl
11. R1 = NH2, R2 = H
12. R1 = H, R2 = NH2
R2
CH3
R1
N
N
N
CH3
H3C
15. R1 = NHCOCH2N(CH3)2, R2 = H
1
2
NHCOCH N(CH )
16. R = H, R =
2
3 2
Scheme 2. Synthesis of N-{11-methyl-6-[(2-(dimethylamino)ethyl]-6H-indolo[2,3-b]quinolin-2 or 9-yl}-2-(dimethylamino)acetamides (15 and 16).

W. Luniewski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6103–6107
6105
atom with 2-dimethylaminoethyl chain by the reaction with 2-
dimethylaminoethyl chloride in PTC conditions, and then the re-
sulted compounds 9 and 10 were reduced with tin (II) chloride
in HCl/ethanol. The formed aminoderivatives 11 and 12 were used
in the syntheses of amides 15 and 16 (Scheme 2) as well as substi-
tuted amine derivatives 21 and 22 (Scheme 3). At first, the amino
R2
R2
CH3
N
Cl
CH3
CH3
N
x HCl
R1
TsCl
R1
CH3
N
N
N
N
N
CH3
CH3
H3C
H3C
17. R1 = NHTs, R2 = H
18. R1 = H, R2 = NHTs
11. R1 = NH2, R2 = H
12. R1 = H, R2 = NH2
R2
R2
CH3
N
CH3
N
R1
H2SO4
R1
N
N
N
N
CH3
CH3
H3C
H3C
21. R1 = NH(CH2)2N(CH3)2, R2 = H
19. R1 = N(Ts)(CH2)2N(CH3)2, R2 = H
1
2
1
2
NH(CH ) N(CH )
3 2
22. R = H, R =
N(Ts)(CH ) N(CH )
20. R = H, R =
2 2
2 2
3 2
Scheme 3. Synthesis of 11-methyl-6-[(2-dimethylamino)ethyl]-2 or 9-[2-(dimethylamino)ethylamino]-6H-indolo[2,3-b]quinolines (21 and 22).
Table 1
Structures of double substituted indolo[2,3-b]quinoline derivatives
Indolo[2,3-b]quinoline derivatives
C-2
C-9
CH3
N
CH3
O
N
N
H3C
O
CH3
N
N
CH3
CH3
N
N
N
CH3
H3C
CH3
H3C
x
2 (COOH)2 x H2O
5 (m.wt. 390.53)
6 (m.wt. 588.61)
CH3
H
O
CH3
HN
N
H3C
N
N
CH3
N
CH3
O
CH3
N
N
N
N
CH3
H3C
N
CH3
H3C
15 (m.wt. 403.53)
16 (m.wt. 403.53)
CH3
H
CH3
CH3
HN
N
N
H3C
CH3
N
CH3
N
N
N
N
N
CH3
H3C
N
CH3
H3C
x
2 (COOH)2 x H2O
21 (m.wt. 389,54)
22 (m.w. 587.64)

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W. Luniewski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6103–6107
groups of compounds 11 or 12 were transformed into correspond-
ing chloroamides by reactions with chloroacetyl chloride in the
presence of sodium carbonate. Then the side chain chlorine atom
of the obtained compound (13) or (14) was substituted with
dimethylamine in the presence of triethylamine as an acid scaven-
ger (Scheme 2).
All tested compounds were cytotoxic against human cancer cell
lines, such as KB (nasopharynx carcinoma), MCF-7 (breast cancer),
A549 (lung cancer) and Hs294T(melanoma), but also against nor-
mal mice fibroblast BALB/3T3. The IC50 were lower than 1 lM
and these derivatives were more potent than the referential com-
pound, that is 5,11-dimethyl-indolo[2,3-b]quinoline [DiMIQ] (IC50
The third group of derivatives was obtained in the three step
synthesis. The amino groups of compounds 9 or 10 were trans-
formed into sulfonamides 17 and 18, then active hydrogen atoms
at sulfamoyl functional groups were substituted with 2-dimethyl-
aminoethyl chloride at PTC conditions (compounds 19, 20). Finally,
both sulfonamides were cleaved in the mixture of concentrated
sulfuric acid and glacial acetic acid to give the desired compounds
21 and 22 (Scheme 3).
The obtained compounds 5, 6, 15, 16, 21 and 22 were tested for
their biological activity. Compounds 6 and 22 were obtained as
oils, which are inconvenient for biological testing. Therefore, prior
to tests, they were transformed into crystalline oxalic acid salts.
Structures of compounds tested are given in Table 1.
All compounds are substituted with 2-(dimethylamino)ethyl
substituents at N-6 and also at C-2 or C-9 positions, where this
substituent is connected to a heterocyclic chromophore with an
ether (5, 6) or amine (21, 22) linker. However, compounds 15
and 16 are substituted at C-2 or C-9 with (dimethylamino)methyl
carbamoyl moiety. The aim of this study was to find whether a
character of the linker between chromophore and dial-
kylaminoalkyl moiety has any impact on the biological activity.
Moreover, it was expected that the cytotoxicity in C-2 and C-9
substituted compounds would be higher than in N-6 mono-substi-
tuted derivatives.11 The results of the studies on antiproliferative
activity of disubstituted indolo[2,3-b]quinoline derivatives are
summarized in Table 2.
between 1.0 and 9.7 lM). In general, derivatives substituted in
position C-2: 21, 15 and 5, exhibited higher cytotoxicity than their
C-9 substituted isomers.
Multidrug resistance (MDR) is one of the most important factors
affecting the therapy of tumors, and there is still a demand for
seeking the novel, anticancer drugs that may overcome this phe-
nomenon. Therefore we examined novel, disubstituted indoloquin-
olines for their ability to overcome the drug resistance of
neoplastic cells. In our research we used three various human can-
cer cell lines and their drug-resistant sublines: human colon cancer
(LoVo) and doxorubicin-resistant LoVo/DX, uterine sarcoma (MES-
SA) and MES-SA/DX5 (both showing P-gp-dependent resistance to
doxorubicin), human promyelocytic leukemia cell line (HL-60) and
HL-60/MX2 (P-gp-independent and topoisomerase II-dependent
resistance). The results of these studies are summarized in Table 3.
The results of our investigations showed that—in contrary to the
known chemotherapeutics such as doxorubicine and mitoxan-
tron—all indoloquinoline derivatives were active against drug
resistant cells and their activity was higher than that of DIMIQ.
We calculated the resistance indexes (RI) by dividing the IC50 val-
ues of the compounds tested against the cells of drug resistant cell
subline by the respective values obtained against the cells of drug
sensitive cell line. All compounds were capable of overcoming the
barrier of drug P-gp-dependent resistance (RI 0.2–1.6). With the
exception of the compound 21, the tested compounds did not
overcome the barrier of topoisomerase II-dependent (reduced
Table 2
Antiproliferative activity of disubstituted indolo[2,3-b]quinoline derivatives against human cancer cell lines and normal mice fibroblast (BALB/3T3)
Compound tested
Cell line/IC50 SD (
KB
lM)
A-549
MCF-7
Hs294T
BALB/3T3
5
0.08 0.02
0.31 0.10
0.15 0.07
0.15 0.05
0.64 0.08
0.36 0.13
1.14 0.61
0.19 0.07
0.32 0.03
0.24 0.07
0.81 0.10
0.17 0.05
0.29 0.05
2.19 0.48
0.66 0.05
0.81 0.07
0.38 0.047
0.79 0.10
0.47 0.00
0.99 0.05
1.50 0.52
0.76 0.14
0.91 0.12
0.62 0.07
0.64 0.07
0.35 0.05
0.72 0.09
9.70 1.42
0.57 0.05
0.74 0.05
0.31 0.05
0.67 0.05
0.34 0.02
0.60 0.02
5.70 0.93
6a
15
16
21
22a
DIMIQb
IC50—compound concentration leading to 50% inhibition of cell proliferation.
a
Tested as dioxalate hydrates.
DiMIQ—referential compound—5,11-dimethyl-5H- indolo[2,3-b]quinoline.
b
Table 3
Antiproliferative activity of disubstituted indolo[2,3-b]quinoline derivatives against human cancer cell lines and its sublines resistant to chemotherapeutic agents
Compound tested
Cell line/IC50 SD (lM)
LoVo
LoVo/DX
RILoVo
MESSA
MESSA/DX5
RIMESSA
HL-60
HL-60/MX2
RIHL-60
5
0.64 0.07
0.64 0.10
0.33 0.10
0.60 0.19
0.12 0.02
0.27 0.05
0.27 0.40
0.04 0.01
n.t.
0.15 0.05
0.21 003
0.11 0.02
0.14 0.00
0.10 0.01
0.39 0.02
0.80 0.12
5.27 0.02
n.t.
0.2
0.3
0.4
0.2
0.8
1.5
3.0
131.8
—
0.08 0.01
0.13 0.07
0.10 0.01
0.09 0.10
0.05 0.01
0.10 0.01
0.31 0.08
0.01 0.002
n.t.
0.07 0.02
0.08 0.03
0.07 0.01
0.09 0.02
0.08 0.01
0.09 0.02
0.15 0.28
0.25 0.05
n.t.
0.9
0.6
0.7
1.0
1.6
0.9
0.5
25.0
—
0.04 0.02
0.13 0.02
0.06 0.002
0.215 0.012
0.09 0.02
0,13 0,01
1.30 0.04
n.t.
0.32 0.07
0.51 0.03
0.57 0.14
0.47 0.14
0.05 0.01
0,61 0,15
1.30 0.20
n.t.
8.0
3.9
9.5
2.2
0.6
4.7
1.0
—
6a
15
16
21
22a
DIMIQ
Doxorubicin
Mitoxantron
0.0025 0.0008
0.561 0.213
224.4
n.t. not tested.
RI—the resistance indexes were calculated by dividing the ID50 values of the compounds tested against the cells of drug resistant cell subline by respective values obtained
against the cells of drug sensitive cell line. According to Harker et al.23 three categories of the cells could be distinguished: (a) the cells are drug-sensitive—if the ratio
approaches 0–2; (b) the cells are moderately drug-resistant—if the ratio ranges from 2 to 10; (c) the cells are markedly drug-resistant—if the ratio is higher than 1.
a
Tested as dioxalate hydrates.

W. Luniewski et al. / Bioorg. Med. Chem. Lett. 22 (2012) 6103–6107
6107
expression of this enzyme19) resistance represented by the HL-60/
MX2 cells (RI ranged from 2 to 10).
compounds to inhibit the human topoisomerase II activity con-
firmed that they are potent inhibitors of this enzyme, comparable
to m-AMSA (aminoacridine derivative) and much more active than
daunorubicin (anthracycline aminoglycoside antibiotic), both
known as intercalating and inhibiting topoisomerase II antineo-
plastic agents. On the other hand, the presented results show that
the tested compounds are not able to overcome the topoisomerase
II-dependent resistance barrier in HL-60/MX2 cells, which supports
our earlier observations that their mechanism of action involves
more than the inhibition of topoisomerase II activity.22 Although
all tested compounds revealed promising antiproliferative activity
against human tumor cell lines and also were able to overcome the
barrier of drug resistance, their cytotoxicity to normal cells (mice
fibroblast BALB/3T3) is comparable with antineoplastic activity.
As we also found, there is no clear structure–activity relationship
among the tested indoloquinolines. These results show that further
extensive study among indolo[2,3-b]-quinoline derivatives are
needed. The aim of the further work is to elucidate their mecha-
nism of action as well as the rational design and manufacturing
of the compounds with pronounced bioavailability and reduced
toxicity to the normal cells.
In order to verify the hypothetic mechanism of cytotoxicity of
disubstituted indoloquinolines, we studied the ability of the tested
compounds to inhibit the human topoisomerase II activity. It was
found that these indolo[2,3-b]quinoline derivatives are potent
inhibitors of the said enzyme, similar to m-AMSA (aminoacridine
derivative) and much more active than daunorubicin (anthracy-
cline aminoglycoside antibiotic), both known as intercalating and
inhibiting topoisomerase II antineoplastic agents. However, there
was no clear structure–activity relationship among the tested
indoloquinolines. (Table 4). In order to find how the novel indolo-
quinoline derivatives affect the cell cycle, we also performed a cell
cycle analysis of the Jurkat cells. The results are summarized in
Table 4.
All of disubstituted indolo[2,3-b]quinoline derivatives showed
the ability to inhibit the cell cycle in G2/M phase. The lowest influ-
ence on cell cycle inhibition in G2/M phase was exhibited by the
compound 6 substituted with 2-(dimethylamino)ethoxy chain at
C-2 position, and the highest one was revealed by the compound
15 substituted with carbamoyl chain at C-2. The rest of the
derivatives had activity similar to that of the referential compound
DIMIQ, with lower sub-toxic concentrations.
Supplementary data
In conclusion, the tested 11-methyl-6-(2-dimethylamino)ethyl-
6H-indolo[2,3-b]quinolines bearing (dimethylamino)alkyl chain at
C-2 or C-9 positions, connected to heterocyclic chromophore with
ether (5 and 6), amine (15 and 16) or amide (21 and 22) linker, re-
vealed antiproliferative activity against human cancer cell lines KB
(nasopharynx carcinoma), A-549 (lung carcinoma), MCF-7 (breast
cancer) and Hs294T (melanoma). This activity was considerably
higher than that of the reference DIMIQ and, in general, the C-2
substituted derivatives were more active than C-9 ones. Com-
pounds 5, 6, 15, 16, 21 and 22 were also tested for their antiprolif-
erative activity against human cancer cell lines and their sublines,
resistant to chemotherapeutic agents, that is LoVo versus LoVo/DX,
MESSA versus MESSA/DX5 and HL-60 versus HL-60 /MX2. All com-
pounds showed pronounced ability to overcome the barrier of drug
P-gp-dependent resistance (RI 0.2–1.6), however (with the excep-
tion of the compound 21) they did not overcome the barrier of
topoisomerase II-dependent resistance represented by the HL-60/
MX2 cells (RI ranged from 2 to 10). The presented data suggest that
the mechanism of action of these compounds is strongly related to
topoisomerase II activity, as it is known for many other indolo[2,3-
b]quinoline derivatives.11,20,21 The study of the ability of the tested
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.
08.032. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
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Table 4
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Inhibition of topoisomerase II activity and the effect on cell cycle of Jurkat cells
revealed by disubstituted indolo[2,3-b]quinoline derivatives
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Compound
tested
Total topoisomerase
II inhibition [mM]
Cell cycle inhibiton
Degree of
Subtoxic
concentration
M]
inhibition in G2M
phase
[l
17. Lavrado, J.; Cabal, G. G.; Prudencio, M.; Mota, M. M.; Gut, J.; Rosenthal, P. J.;
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A.; Boratynski, J.; Marcinkowska, E.; Glazman-Kusnierczyk, H.; Radzikowski, C.
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5
0.025
0.025
0.05
0.025
0.025
0.05
0.38
0.17
0.10
0.37
0.26
0.26
++
+
+++
++
++
++
6*
15
16
21
22a
DIMIQb
0.5
0.05
1.02
++
m-AMSAc
Daunorubicind 0.5
a
b
c
Tested as dioxalate hydrates; referential compounds.
DiMIQ—5,11-dimethyl-5H-indolo[2,3-b]quinoline.
m-AMSA—aminoacridine derivative.
23. Harker, W. G.; Slade, D. L.; Dalton, W. S.; Meltzer, P. S.; Trent, J. M. Cancer Res.
1989, 49, 4542.
d
Daunorubicin—anthracycline aminoglycoside antibiotic; both are
a potent
intercalating and inhibiting topoisomerase II antineoplastic agents.