Synthesis and biological evaluation of indoloquinolines and pyridocarbazoles: A new example of unexpected photoreduction accompanying photocyclization

Article abstract of DOI:10.1248/cpb.55.1349

Indoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine are of great interest because in vitro and in vivo studies revealed their good cytotoxic properties. In order to obtain some biologically active analogs of these compounds, we developed a synthesis based on the photocyclization of tertiary N-substituted enaminones derived from 1,3-cyclohexandione and 3 or 6-aminoquinoline. The angular cyclized compounds thus obtained were tested in vitro on K 562 cells and A 2780 doxorubicin sensitive and resistant cells. All compounds were less effective than doxorubicin in sensitive cells but their activity wasn't decreased by MDR resistance.

Full text of DOI:10.1248/cpb.55.1349

September 2007
Chem. Pharm. Bull. 55(9) 1349—1355 (2007)
1349
Synthesis and Biological Evaluation of Indoloquinolines and
Pyridocarbazoles: A New Example of Unexpected Photoreduction
Accompanying Photocyclization
Pierre-Jean ARAGON,a,b Ange-Désiré YAPI,c Frédéric PINGUET,b Jean-Michel CHEZAL,d
d
,c
*
Jean-Claude TEULADE, and Yves BLACHE
a Laboratoire de Chimie Organique Pharmaceutique, E.A. 2414, Faculté de Pharmacie; 15 avenue Charles Flahault,
34060 Montpellier, France: b Laboratoire d’Oncopharmacologie, Centre Régional de Lutte Contre le Cancer; Val
d’Aurelle, 34298 Montpellier cedex 05, France: c Laboratoire de Chimie Organique Pharmaceutique, UMR-INSERM 484,
d
Faculté de Pharmacie; 28 Place Henry Dunant, B.P. 38, 63001 Clermont-Ferrand, France: and Laboratoire de Chimie
Organique, EA 3660, Faculté de Pharmacie; 7 Boulevard Jeanne d’Arc, 21079 Dijon, France.
Received May 23, 2007; accepted June 28, 2007
Indoloquinoline alkaloid cryptolepine and pyridocarbazole alkaloid ellipticine are of great interest because
in vitro and in vivo studies revealed their good cytotoxic properties. In order to obtain some biologically active
analogs of these compounds, we developed a synthesis based on the photocyclization of tertiary N-substituted
enaminones derived from 1,3-cyclohexandione and 3 or 6-aminoquinoline. The angular cyclized compounds thus
obtained were tested in vitro on K 562 cells and A 2780 doxorubicin sensitive and resistant cells. All compounds
were less effective than doxorubicin in sensitive cells but their activity wasn’t decreased by MDR resistance.
Key words indoloquinoline; pyridocarbazole; photochemistry; cytotoxicity
Interest in the chemistry of pyridocarbazoles and indolo- rocyclic chemistry since they can be implicated in the elabo-
quinolines has increased this last decade since these skele- ration of carbazoles,20) a-carbolines,21) b-carbolines and d-
tons are present in a large number of alkaloids of biological carbolines.22,23) The photocyclization can occur through an
interest. For example, the indoloquinoline type alkaloid cryp- electrocyclization for tertiary enaminones or through a radi-
tolepine 1 (Fig. 1) extracted from the roots of Cryptolepis cal process for halogenated enaminones.24) Furthermore, in
sanguinolenta1) has been shown to exhibit antiplasmodial,2) our recent works, we obtained N-benzylpyridocarbazoles and
antibacterial3) and cytotoxic properties.4,5) This last activity is indoloquinolines from tertiary N-benzylenaminones25) and
due to cryptolepine intercalation into DNA and subsequent non N-substituted compounds from secondary iodinated
inhibition of DNA religation by topoisomerase II.5) Another enaminones.26) In the present work, we investigate the reac-
example concerns the pyridocarbazole type alkaloid ellip- tivity of tertiary enaminones carrying an alkyl or a dialky-
ticine 2 (Fig. 1) extracted from the leaves of Ochrosia ellip- laminoalkyl side chain 3 and report the results of in vitro cy-
tica6) which has exhibited cytotoxic properties by different totoxicity studies of the obtained cyclized compounds 4.
mechanisms : intercalation into DNA,7) inhibition of topoiso-
merase II,8) formation of covalent adducts with DNA after Chemistry
bioactivation,9) stimulation of apoptosis.10) Different linear
Firtsly, the reactivity of tertiary enaminones derived from
and angular analogs of these compounds have already been 3-aminoquinoline was studied. According to previously de-
synthetized by several groups11—17) but the series of in- scribed procedures,22,23,25,26) the secondary enaminone 7 is
dolo[2,3-c]quinoline and pyrido[2,3-c]carbazole haven’t been obtained by condensation of 3-aminoquinoline 5 and 1,3-cy-
studied yet.
clohexandione 6 in toluene with catalytic amounts of p-tolue-
Therefore, as a part of our program concerning the elabo- nesulfonic acid. Then, a methyl or a diethylaminoethyl side
ration of analogs of natural products, we are interested in the chain was introduced on the enaminone nitrogen by treating
chemistry as well as in the biological activities of these angu- secondary enaminone 7 by sodium hydride, and then
lar heterocycles.18,19) Our methodology resides in the photo- by methyl iodide or by the hydrochloride salt of diethyl-
cyclization of enaminones derived from 3 or 6-aminoquino- aminoethylchloride to give 8 and 9. The dimethylamino-
line (Fig. 1). Enaminones represent convenient tools in hete- propyl side chain couldn’t be introduced following this proto-
cole. However, the tertiary enaminone 10 was obtained by
treating compound 7 with the hydrochloride salt of dimethyl-
aminopropylchloride in presence of sodium hydride in di-
methylformamide (DMF)27) (Fig. 2).
The methyl substituent was chosen because structure–
activity relationships studies realized on ellipticine and cryp-
tolepine linear or angular analogs show the contribution of
the N-methyl function to the cytotoxicity and a frequent loss
of activity with bigger alkyl chains.11,28,29) Dialkylaminoalkyl
chains were chosen because they’re often described as cyto-
toxicity enhancers, probably through a stabilisation of the
Fig. 1
drug–DNA interaction.30,31)
∗ To whom correspondence should be addressed. e-mail: Yves.blache@u-bourgogne.fr
© 2007 Pharmaceutical Society of Japan

1350
Vol. 55, No. 9
Irradiation of enaminones 8, 9, 10 to give respectively 11, 13 were retained for biological studies.
12, 13, were performed using a Pyrex well apparatus and a
Then, so as to study the influence of the position of the
medium pressure mercury UV lamp (150 W) under a set of quinolinic nitrogen on the reactivity of such enaminones, the
conditions (Fig. 3, Table 1). secondary enaminone 15 was prepared by condensation of
These photocyclizations were regioselective on the C-4 6-aminoquinoline 14 and 1,3-cyclohexandione 6 in toluene
position of the quinolinic nucleus since only angular com- with p-toluenesulfonic acid. Then, tertiary enaminones 16,
pounds were obtained. Structure of 11, 12, 13 was easily de- 17 and 18 were obtained by treatment of 15 with sodium hy-
1
termined by H-NMR, and by comparison with our previous dride in toluene and then, by methyl iodide, ethyl iodide or
1
results.25,26) More precisely the H-NMR spectrum of 11, 12, diethylaminoethyl hydrochloride. Tertiary enaminone 19 was
13 showed characteristic signals of H-1 shifted downfield due also obtained by treatment of 15 with dimethylaminopropyl-
to the proximity of the carbonyl group and appeared as dou- chloride hydrochloride in DMF in presence of sodium hy-
ble doublets (d 9.68 for 11, d 9.81 for 12, d 9.74 for 13). The dride (Fig. 4). The N-ethyl derivative 17 was prepared be-
N-substituents don’t change the regioselectivity previously cause the first biological results showed a better activity of
observed with N-benzylated enaminones25) and with second- the 6-aminoquinoline derivatives, so we wanted to test other
ary iodinated enaminones.26) Yields of photocyclization were alkyl side chains, with the hope of increasing cytotoxicity.
close to those previously obtained: Compound 11 was ob-
Then, these four tertiary enaminones were subjected to ir-
tained with the best yield (80%) with methanol as solvent, radiation in a pyrex reactor under different conditions (Fig. 5,
while the substituted indoloquinolines 12 and 13 were ob- Table 2).
tained respectively with a 60% and a 35% yield (other condi-
The results of these irradiations were quite surprising,
tions led to massive decomposition of the enaminone and since we obtained a mixture of the expected 8,9,10,11-
poor yields of cyclized compounds). Compounds 11, 12 and tetrahydropyridocarbazoles 24, 25, 26, and 27 and of
5,6,8,9,10,11-hexahydropyridocarbazoles 20, 21, 22 and 23.
In all cases, only angular compounds, identified easily thanks
to the chemical shift of proton H-1, were obtained, confirm-
ing the perfect regioselectivity of this photocyclization. The
global yields of photocyclization were smaller than those ob-
tained with 3-aminoquinoline derivatives and confirm the
lower reactivity of 6-aminoquinoline derivatives, previously
described.25,26) As the influence of solvent is a well-known
phenomenon in photochemistry, it was hypothetised that irra-
diation in another solvent such as toluene could modify the
Fig. 2
Fig. 3
Table 1. Irradiation of Tertiary Enaminones 8, 9, 19
Fig. 4
Yield (%)
of compd.
Entry
Substrate
8 RꢀCH3
8 RꢀCH3
8 RꢀCH3
Conditions
1
2
3
4
5
Pyrex, methanol, 4 h
Pyrex, toluene, 4 h
11 (80)
11 (55)
Pyrex, methanol/toluene 50/50, 4 h 11 (70)
9 Rꢀ(CH2)2N(Et)2 Pyrex, methanol, 4 h
10 Rꢀ(CH2)3N(Me)2 Pyrex, methanol, 4 h
12 (60)
13 (35)
Fig. 5
Table 2. Irradiation of Tertiary Enaminones 16, 17, 18, 19
Entry
Substrate
16 RꢀCH3
Conditions
Yield (%) of compd.
Global yield (%)
1
2
3
4
5
6
7
8
Pyrex, methanol, 4 h
Pyrex, methanol, 4 h
Pyrex, methanol, 4 h
Pyrex, methanol, 4 h
Pyrex, toluene, 4 h
Pyrex, toluene, 4 h
Pyrex, toluene, 4 h
Pyrex, toluene, 4 h
20 (56) and 24 (44)
21 (85) and 25 (15)
22 (95) and 26 (5)
23 (80) and 27 (20)
20 (40) and 24 (60)
21 (5) and 25 (95)
22 (10) and 26 (90)
23 (25) and 27 (75)
40
50
40
40
50
40
25
60
17 RꢀCH2CH3
18 Rꢀ(CH2)2N(Et)2
19 Rꢀ(CH2)3N(Et)2
16 RꢀCH3
17 RꢀCH2CH3
18 Rꢀ(CH2)2N(Et)2
19 Rꢀ(CH2)3N(Et)2

September 2007
1351
Fig. 6
Fig. 7
ratio hexahydro/terahydro compound. So, compounds 16, 17,
18 and 19 were irradiated in a pyrex reactor in toluene for
4 h. The ratios reduced/non reduced compound were reversed
and non-reduced compounds were largely predominant, ex-
cept in the case of the N-methyl derivative, whose photocy-
clization seemed to be poorly influenced by the solvent of ir-
radiation.
This C5–C6 bond reduction had already been established
when photocyclization of secondary iodinated enaminone de-
rived from 6-aminoquinoline was conducted in a pyrex reac-
tor using acetonitrile with 4 ml of triethylamine as solvent.26)
Fig. 8
Only the hexahydro compound was obtained. Furthermore, reduced compounds when the N-substituted derivatives were
this reduction could be understood as the result of a photoin- irradiated in toluene alone. Yet we can reasonably suppose
duced electron transfer from triethylamine to the aromatic that solvent influence on the rearrangement or the dehydro-
system, followed by abstraction of a proton and an hydrogen genation is the most important phenomenon and that pho-
radical from the solvent, as described by Yang et al.32) But, in toreduction of tetrahydro cyclized compound by methanol
the present case, the reaction mixture didn’t contain any tri- may contribute to the formation of reduced compounds.
ethylamine, so this phenomenon can’t explain the photore-
Finally, we investigated the strategy which consist in treat-
duction. 6p electron mechanism is implicated in the photo- ing reduced compounds by Pd/C 10% in diphenylether.39)
cyclization of such tertiary enaminones. According to this This reaction was successful in the case of the non-N-substi-
mechanism, described by Grellman et al.33) and Chapman et tuted pyridocarbazole 3726) which gave the compound 3826)
al.,34) a zwitterionic species is initially formed, which gives a with a 30% yield. N-Methyl and N-ethyl compounds 24 and
hexahydro compound, which can eventually undergo a dehy- 25 were obtained from 20 and 21 with a 30% yield. But, un-
drogenation process to give a tetrahydro compound. Further- fortunately, compounds 22 and 23 underwent massive degra-
more, Grellman et al.35) have irradiated the N-methyl-2-anili- dation (Fig. 8).
nonaphtalene 28 in different solvents and have obtained a
mixture of 5-methylbenzo[c]carbazole 29 and 5-methyl-6,7- Biological Results
dihydrobenzo[c]carbazole 30 (2 : 1 ratio). A hypothesis was
In continuation of our previous works40,41) concerning the
proposed by the authors to explain the formation of those two antiproliferative activity of tetracyclic nitrogenous heterocy-
compounds: after the electrocyclisation, the zwitterionic in- cles, and more precisely, their activity against MDRꢁ cancer
termediate 31 undergoes a suprafacial 1,4 hydrogen shift. cells lines, the cytotoxicity of the compounds 11, 12, 13,
The resulting compound 32 can either undergo an internal re- 24, 25, 26, 37, 38 and 39, as the non N-substituted indolo-
arrangement to give 30 or undergo dehydrogenation to give quinoline previously prepared26) was evaluated by a cell
29 (Fig. 6).
growth inhibition assay against two human cell lines: K 562
This hypothesis can be applied to our compounds and (leukemia), and A 2780 (ovarian cancer) doxorubicin-sensi-
therefore may explain the results presented above: irradiation tive and resistant (MDRꢁ) and was compared to the cytotox-
of tertiary enaminones 16, 17, 18, 19 should give the inter- icity of doxorubicin. The resistant subline A 2780 R was es-
mediary hexahydro derivatives 33, 34, 35, 36. Toluene in- tablished by the continuous exposure of cells to gradually in-
duces dehydrogenation to give 24, 25, 26, 27 whereas creasing concentrations of doxorubicin. The resistant subline
methanol induces rearrangement to give 20, 21, 22, 23, as K 562 R wasn’t tested because of the poor activity of our
shown in Fig. 7.
products against K 562 S cells. IC50 (concentration inhibiting
A second phenomenon which happens after cyclization 50% of the cell proliferation) expressed in mol/l and resist-
and dehydrogenation might explain C5–C6 bond reduction. ance factor (IC50 on A2780 resistant cells/IC50 on A2780
Some authors36—38) described the reduction of one bond sensitive cells) of each compound are recapitulated in Table
of aromatic compounds when they underwent irradiation 3.
in proton donnors solvents, particularly aliphatic alcohols.
All the compounds are 10 to 1000 fold less effective than
Methanol could contribute to the reduction via this pathway. doxorubicin in all sensitive cells whereas compounds 11, 24
However, this phenomenon doesn’t explain the formation of and 26 are as active as doxorubicin on A 2780 resistant cells

1352
Vol. 55, No. 9
Table 3. IC50 and Resistance Factor of Tested Compounds and Doxorubicin
K 562 cells
(mol/l)
A 2780 sensitive cells
A 2780 resistant cells
(mol/l)
Compds.
RFa)
(mol/l)
11
12
13
24
25
26
37
38
4.6ꢂ10ꢃ5ꢄ2.8ꢂ10ꢃ6
2.1ꢂ10ꢃ5ꢄ1.0ꢂ10ꢃ6
1.5ꢂ10ꢃ5ꢄ1.0ꢂ10ꢃ6
3.3ꢂ10ꢃ5ꢄ2.0ꢂ10ꢃ6
7.8ꢂ10ꢃ6ꢄ1.8ꢂ10ꢃ6
2.5ꢂ10ꢃ5ꢄ3.0ꢂ10ꢃ6
8.8ꢂ10ꢃ5ꢄ1.3ꢂ10ꢃ5
2.3ꢂ10ꢃ5ꢄ1.2ꢂ10ꢃ6
9.3ꢂ10ꢃ5ꢄ2.6ꢂ10ꢃ5
1.6ꢂ10ꢃ7ꢄ3.3ꢂ10ꢃ8
8.0ꢂ10ꢃ6ꢄ6.3ꢂ10ꢃ6
4.0ꢂ10ꢃ5ꢄ2.6ꢂ10ꢃ5
3.8ꢂ10ꢃ5ꢄ3.2ꢂ10ꢃ6
2.0ꢂ10ꢃ6ꢄ1.0ꢂ10ꢃ6
1.4ꢂ10ꢃ5ꢄ5.9ꢂ10ꢃ6
2.8ꢂ10ꢃ6ꢄ1.7ꢂ10ꢃ6
2.2ꢂ10ꢃ5ꢄ1.1ꢂ10ꢃ5
1.4ꢂ10ꢃ5ꢄ7.8ꢂ10ꢃ5
3.3ꢂ10ꢃ5ꢄ4.2ꢂ10ꢃ5
2.4ꢂ10ꢃ8ꢄ4.0ꢂ10ꢃ9
8.3ꢂ10ꢃ6ꢄ4.0ꢂ10ꢃ7
9.0ꢂ10ꢃ5ꢄ2.8ꢂ10ꢃ6
9.5ꢂ10ꢃ5ꢄ1.1ꢂ10ꢃ6
5.8ꢂ10ꢃ6ꢄ2.4ꢂ10ꢃ6
1.7ꢂ10ꢃ5ꢄ1.0ꢂ10ꢃ5
2.8ꢂ10ꢃ6ꢄ1.8ꢂ10ꢃ7
2.8ꢂ10ꢃ5ꢄ2.0ꢂ10ꢃ5
2.5ꢂ10ꢃ5ꢄ4.6ꢂ10ꢃ6
4.2ꢂ10ꢃ5ꢄ5.5ꢂ10ꢃ6
2.9ꢂ10ꢃ6ꢄ4.9ꢂ10ꢃ7
1
2.3
2.5
2.9
1.2
1
1.3
1.8
1.3
39
Doxb)
121
a) resistance factor, b) doxꢀdoxorubicin.
with IC50 varying between 2.8 and 8.3ꢂ10ꢃ6 mol/l. The other
compounds are only 10 fold less active than doxorubicin on
A 2780 R cells. The resistance factor of all those compounds
varies between 1 and 2.9 (doxorubicin: 121), which indicates
that these compounds, as most synthetic compounds, are not
concerned by the multidrug resistance phenomenon.
Comparison of IC50 values of the hexahydro compound 37
and the tetrahydro compound 38 shows this reduction doesn’t
seem to influence the biological activity, in spite of the
twisted structure of the reduced compound. Whatever the N-
substituent is, IC50 of 3-aminoquinoline derivatives are, in
most cases, equal or higher than IC50 of 6-aminoquinoline
derivatives, proving that 6-aminoquinoline series gives more
active compounds. About the influence of the N-substituent,
it appears that the N-methyl compound 11 is the most active
of the 3-aminoquinoline derivatives and that N-methyl and N-
diethylaminoethyl compounds 24 and 26 are the most active
pressure mercury UV lamp (Heraeus TQ 150). Total volume of solvent(s)
was about 350—400 ml. In order to remove oxygen, the reaction mixture
was submitted to ultrasound waves for 10 min before irradiation. Besides,
during the irradiation, the reaction mixture was flushed with a stream of
nitrogen.
3-[(3ꢀ-Quinolinyl)methylamino]cyclohex-2-en-1-one 8 Compound 7
(1 g, 4.2 mmol) was added to a suspension of sodium hydride (1 g, 25 mmol,
60% in mineral oil) in anhydrous toluene (50 ml). The mixture was refluxed
under nitrogen for 2 h and cooled to room temperature. Methyl iodide (5 ml,
80 mmol) was then added and the mixture was refluxed for 3 h. After cool-
ing, toluene was washed with water and the insoluble residue was dissolved
in dichloromethane and washed with water. The organic layers were dried
over sodium sulfate and evaporated in vacuo. The crude product was chro-
matographed on silica gel with dichloromethane and a gradient of methanol
as eluent to give 8 as a white powder: 45%, mp 128—130 °C. 1H-NMR
(CDCl3) d: 1.91 (2H, m), 2.28 (4H, m), 3.32 (3H, s), 5.37 (1H, s), 7.58 (1H,
m), 7.76 (2H, m), 7.90 (1H, d, Jꢀ2.2 Hz), 8.11 (1H, d, Jꢀ8.1 Hz), 8.71 (1H,
d, Jꢀ2.3 Hz); 13C-NMR (CDCl3) d: 22.2, 29.3, 35.8, 40.7, 101.7, 127.4
(3C), 129.0, 129.7, 132.5, 138.4, 146.3, 149.4, 164.2, 197.3; Anal. Calcd for
C16H16N2O: C, 76.19; H, 6.35; N, 11.11. Found: C, 76.30; H, 6.35; N, 11.08.
3-[(3ꢀ-Quinolinyl)diethylaminoethylamino]cyclohex-2-en-1-one 9
of the 6-aminoquinoline derivatives, thus proving the role of Compound 7 (0.5 g, 2.1 mmol) was added to a suspension of sodium hydride
(1 g, 25 mmol, 60% in mineral oil) in anhydrous toluene (50 ml). The mix-
ture was refluxed under nitrogen for 2 h and cooled to room temperature. Di-
ethylaminoethylchloride hydrochloride (0.4 g, 2.3 mmol) was then added and
the mixture was refluxed for 2 h. After cooling, toluene was washed with
the N-methyl group in the cytotoxic activity and the role of
dialkylaminoalkyl side chains in cytotoxicity enhancement.
Compounds 11, 24 and 26, the most active ones, are good
candidates for further in vivo studies.
water and the insoluble residue was dissolved in dichloromethane and
washed with water. The organic layers were dried over sodium sulfate and
evaporated in vacuo. The crude product was chromatographed on alumina
gel with ether and a gradient of methanol as eluent to give 9 as a yellow oil:
Conclusion
In this paper, we have reported the synthesis of N-substi-
tuted tetracyclic nitrogen heterocycles: indoloquinolines
and pyridocarbazoles. The photochemical key step which
provides cyclized compounds from N-alkyl or N-dialkyl-
aminoalkyl enaminones occures with a total regioselectivity,
since only angular compounds are obtained. An unexpected
photoreduction phenomenon occured during irradiation and
was shown to be greatly influenced by the solvent. The first
in vitro studies reveal that the main interest of these com-
pounds resides in their activity toward resistant cells. Further
studies on the pharmacomodulation of such compounds are
now in progress and should lead to an interesting class of
1
35%. H-NMR (CDCl3) d: 0.88 (6H, t, Jꢀ7.0 Hz), 1.89 (2H, m), 2.26 (4H,
m), 2.42 (q, 4H, Jꢀ7.0 Hz), 2.67 (2H, t, Jꢀ6.9 Hz), 3.73 (2H, t, Jꢀ6.9 Hz),
5.35 (1H, s), 7.69 (3H, m), 8.1 (2H, m), 8.75 (1H, d, Jꢀ2.3 Hz); 13C-NMR
(CDCl3) d: 11.3 (2C), 22.0, 29.1, 35.6, 46.7 (2C), 49.6, 51.3, 101.1, 127.0,
127.2, 128.8, 129.4, 133.3, 137.5, 146.1, 150.2, 163.5, 196.8. Anal. Calcd
for C21H27N3O: C, 74.78; H, 8.01; N, 12.46. Found: C, 74.61; H, 8.02; N,
12.37.
3-[(3ꢀ-Quinolinyl)dimethylaminopropylamino]cyclohex-2-en-1-one 10
Compound 7 (0.5 g, 2.1 mmol) and dimethylaminopropylchloride hydrochlo-
ride (0.4 g, 2.53 mmol) were added to a suspension of sodium hydride (1 g,
25 mmol, 60% in mineral oil) in dimethylformamide (10 ml). The mixture
was refluxed under nitrogen for 3 h and cooled to room temperature. Then,
methanol was added to neutralize sodium hydride excess, followed by water
(30 ml). After extraction with dichloromethane (3ꢂ50 ml), the organic layers
new potential anticancer agents with no multidrug resistance were dried over sodium sulfate and evaporated in vacuo. The crude product
was chromatographed on silica gel with ether and a gradient of methanol as
phenomena.
1
eluent to give 10 as a yellow oil: 34%. H-NMR (CDCl3) d: 1.87 (4H, m),
Experimental
2.11 (6H, s), 2.26 (6H, m), 3.70 (2H, t, Jꢀ7.3 Hz), 5.35 (1H, s), 7.71 (4H,
1H- and 13C-NMR spectra were recorded on a Brüker AC 100 or EM 400 m), 8.11 (1H, d, Jꢀ8.3 Hz), 8.67 (1H, d, Jꢀ2.2 Hz); 13C-NMR (CDCl3) d:
22.7, 25.4, 29.0, 36.4, 45.6, 51.6, 56.7, 101.9, 128.0, 128.0, 128.2 (3C),
WB. Chemical shift data are reported in ppm downfield d from TMS. Cou-
pling constants J are given in Hz. s, d, dd, t, q, and m mean respectively sin- 129.6, 130.4, 134.2, 137.6, 147.0, 150.6, 164.5, 197.8. Anal. Calcd for
glet, doublet, double doublet, triplet, quadruplet and multiplet. Melting C20H25N3O: C, 74.30; H, 7.74; N, 13.0. Found: C, 74.50; H, 7.76; N, 12.89.
points were determined on a Büchi capillary melting point apparatus and are
not corrected. Elemental analysis was performed by Microanalytical center, pound 8 (0.4 g, 1.6 mmol) underwent irradiation under different conditions
ENSCM, Montpellier.
see Table 1). Then, the solvents were evaporated under reduced pressure. The
Irradiations were conducted in a pyrex well apparatus using a medium crude product was chromatographed on silica gel using dichloromethane and
7-Methyl-8,9,10,11-tetrahydroindolo[2,3-c]quinolin-11-one 11 Com-
(

September 2007
1353
a gradient of methanol as eluent to give 11 as a white powder: 80% (best over sodium sulfate and evaporated in vacuo. The crude product was chro-
1
yield), mp 238—240 °C. H-NMR (CDCl3) d: 2.08 (2H, m), 2.35 (2H, t, matographed on alumina gel with ether and a gradient of methanol as eluent
Jꢀ6.2 Hz), 2.54 (2H, t, Jꢀ6.3 Hz), 3.16 (3H, s), 7.63 (2H, m), 8.12 (1H, dd, to give 18 as a yellow oil: 28%. 1H-NMR (CDCl3) d: 0.87 (6H, t, Jꢀ7.1 Hz,
Jꢀ6.7, 1.5 Hz), 8.52 (1H, s), 9.68 (1H, dd, Jꢀ6.6, 1.5 Hz); 13C-NMR
(CDCl3) d: 22.2, 22.5, 29.9, 39.0, 114.7, 123.3, 125.9, 126.2, 127.4, 128.6,
129.5, 129.9, 135.3, 144.3, 152.7, 193.4. Anal. Calcd for C16H14N2O: C,
76.80; H, 5.60; N, 11.20. Found: C, 76.75; H, 5.62; N, 11.17.
CH3 4ꢆ), 1.84 (2H, m), 2.21 (2H, t, Jꢀ6.2 Hz), 2.24 (2H, t, Jꢀ6.3 Hz), 2.40
(4H, q, Jꢀ7.1 Hz), 2.63 (2H, t, Jꢀ7.3 Hz), 3.70 (2H, t, Jꢀ7.1 Hz), 5.30 (1H,
s), 7.38 (1H, m), 7.49 (1H, dd, Jꢀ8.9, 2.4 Hz), 7.62 (1H, d, Jꢀ2.2 Hz), 8.07
(2H, m), 8.87 (1H, dd, Jꢀ4.2, 1.6 Hz); 13C-NMR (CDCl3) d: 12.2 (2C),
7-(N,N-Diethylaminoethyl)-8,9,10,11-tetrahydroindolo[2,3-c]quinolin- 22.9, 29.7, 36.4, 47.6 (2C), 50.3, 52.0, 101.4, 122.2, 126.6, 128.8, 130.2,
11-one 12 Compound 9 (0.3 g, 0.9 mmol) underwent irradiation for 2 h in 131.5, 136.2, 142.6, 147.3, 151.4, 164.7, 197.9. Anal. Calcd for C21H27N3O:
a pyrex reactor using methanol as solvent. Then, the solvents were evapo- C, 74.78; H, 8.01; N, 12.46. Found: C, 74.84; H, 8.03; N, 12.49.
rated under reduced pressure. The crude product was chromatographed on 3-[(6ꢀ-Quinolinyl)dimethylaminopropylamino]cyclohex-2-en-1-one 19
silica gel using dichloromethane and a gradient of methanol as eluent to give Compound 15 (0.5 g, 2.1 mmol) and dimethylaminopropylchloride hy-
12 as a yellow oil: 60% (best yield). 1H-NMR (CDCl3) d: 0.86 (6H, t, drochloride (0.4 g, 2.53 mmol) were added to a suspension of sodium hy-
Jꢀ6.7 Hz), 2.24 (2H, m), 2.47 (4H, q, Jꢀ6.7 Hz), 2.74 (4H, m), 2.99 (2H, t,
Jꢀ6.1 Hz), 4.19 (2H, t, Jꢀ6.8 Hz), 7.64 (2H, m), 8.15 (1H, m), 8.95 (1H, s),
dride (1 g, 25 mmol, 60% in mineral oil) in dimethylformamide (10 ml). The
mixture was refluxed under nitrogen for 3 h and cooled to room temperature.
9.81 (1H, m); 13C-NMR (CDCl3) d: 11.60 (2C, CH3 4ꢅ), 22.39 (2C, C8, C9), Then, methanol was added to neutralize sodium hydride excess, followed by
38.80 (C10), 43.09 (CH2 1ꢅ), 47.55 (2C, CH2 3ꢅ), 52.55 (CH2 2ꢅ), 114.49 water (30 ml). After extraction with dichloromethane (3ꢂ50 ml), the organic
(C11a), 123.19 (C11b), 125.71 (C3), 125.95 (C11c), 126.63 (C2), 128.22 layers were dried over sodium sulfate and evaporated in vacuo. The crude
(C1), 129.00 (C4), 129.27 (C6a), 135.38 (C6), 144.09 (C4a), 152.58 (C7a), product was chromatographed on alumina gel with ether and a gradient of
1
193.00 (C11). Anal. Calcd for C21H25N3O: C, 75.22; H, 7.46; N, 12.54. methanol as eluent to give 19 as a yellow oil: 45%. H-NMR (CDCl3) d:
Found: C, 75.34; H, 7.45; N, 12.48.
1.82 (2H, m, H5), 1.91 (2H, m), 2.13 (6H, s), 2.27 (6H, m), 3.72 (2H, t,
7-(N,N-Dimethylaminopropyl)-8,9,10,11-tetrahydroindolo[2,3- Jꢀ7.7 Hz), 5.36 (1H, s), 7.46 (2H, m), 7.59 (1H, d, Jꢀ2.3 Hz), 8.13 (2H, m),
c]quinolin-11-one 13 Compound 10 (0.23 g, 0.7 mmol) underwent irradia-
8.94 (1H, dd, Jꢀ4.2, 1.6 Hz); 13C-NMR (CDCl3) d: 22.8, 25.4, 29.0, 36.4,
tion for 2 h in a pyrex reactor using methanol as solvent. Then, the solvents 45.7, 51.4, 56.8, 101.2, 122.2, 126.6, 128.8, 129.9, 131.7, 136.2, 142.0,
were evaporated under reduced pressure. The crude product was chro- 147.2, 151.4, 164.8, 197.8. Anal. Calcd for C20H25N3O: C, 74.30; H, 7.74;
matographed on alumina gel using dichloromethane and a gradient of
methanol as eluent to give 13 as an orange oil: 35% (best yield). H-NMR
N, 13.0. Found: C, 74.41; H, 7.73; N, 13.06.
1
7-Methyl-5,6,8,9,10,11-hexahydropyrido[2,3-c]carbazol-11-one 20
Compound 16 (0.14 g, 0.6 mmol) underwent irradiation under different con-
ditions (see Tables 2, 3). Then, the solvents were evaporated under reduced
(CDCl3) d: 1.81 (2H, m), 2.06 (2H, m), 2.09 (6H, s), 2.15 (2H, t, Jꢀ6.4 Hz),
2.57 (2H, t, Jꢀ6.1 Hz), 2.76 (2H, t, Jꢀ6.2 Hz), 4.02 (2H, t, Jꢀ7 Hz), 7.58
(2H, m), 8.08 (1H, m), 8.86 (1H, s), 9.74 (1H, m); 13C-NMR (CDCl3) d: pressure. The crude product was chromatographed on alumina gel using
22.8, 23.1, 28.2, 39.4, 41.8, 45.6, 55.8, 115.3, 123.7, 126.4, 126.7, 127.5, dichloromethane and a gradient of methanol as eluent to give 20 as a white
128.4, 129.5, 130.1, 136.0, 144.7, 152.7, 193.5. Anal. Calcd for C20H23N3O:
C, 74.77; H, 7.17; N, 13.08. Found: C, 74.80; H, 7.20; N, 12.99.
powder: 22% (best yield), mp 196—198 °C. 1H-NMR (CDCl3) d: 2.17 (2H,
m), 2.45 (2H, t, Jꢀ6 Hz), 2.74 (2H, t, Jꢀ8.3 Hz), 2.85 (2H, t, Jꢀ6.2 Hz),
3-[(6ꢀ-Quinolinyl)methylamino]cyclohex-2-en-1-one 16 Compound 3.09 (2H, t, Jꢀ7.8 Hz), 3.63 (3H, s), 7.08 (1H, m), 8.13 (1H, dd, Jꢀ4.8,
15 (1 g, 4.2 mmol) was added to a suspension of sodium hydride (1 g,
1.6 Hz), 8.79 (1H, dd, Jꢀ4.2, 1.6 Hz); 13C-NMR (CDCl3) d: 20.2, 22.7, 23.4,
25 mmol, 60% in mineral oil) in anhydrous toluene (50 ml). The mixture was 30.5, 32.3, 39.4, 115.9, 117.3, 122.6, 128.4, 132.8, 133.5, 145.2, 145.7,
refluxed under nitrogen for 2 h and cooled to room temperature. Methyl 154.3, 194.1. Anal. Calcd for C16H16N2O: C, 76.19; H, 6.35; N, 11.11.
iodide (5 ml, 80 mmol) was then added and the mixture was stirred for 24 h
at 80 °C. After cooling, toluene was washed with water and the insoluble
Found: C, 76.29; H, 6.33; N, 11.15.
7-Ethyl-5,6,8,9,10,11-hexahydropyrido[2,3-c]carbazol-11-one 21
residue in the balloon flask was dissolved in dichloromethane and also Compound 17 (0.16 g, 0.6 mmol) underwent irradiation under different con-
washed with water. The organic layers were dried over sodium sulfate and ditions (see Tables 2, 3). Then, the solvents were evaporated under reduced
evaporated in vacuo. The crude product was chromatographed on alumina
pressure. The crude product was chromatographed on alumina gel using
1
gel with ether and a gradient of methanol as eluent to give 16 as a yellow dichloromethane as eluent to give 21 as a yellow oil: 43% (best yield). H-
1
powder: 40%, mp 134—136 °C. H-NMR (CDCl3) d: 1.87 (2H, m), 2.27 NMR (CDCl3) d: 1.22 (3H, t, Jꢀ7.2 Hz), 2.08 (2H, m), 2.46 (2H, t,
(4H, m), 3.30 (3H, s), 5.35 (1H, s), 7.49 (3H, m), 8.12 (2H, m), 8.92 (1H, d, Jꢀ6 Hz), 2.73 (4H, m), 3.09 (2H, t, Jꢀ7.6 Hz), 3.79 (2H, q, Jꢀ7.2 Hz), 7.07
Jꢀ3.6 Hz); 13C-NMR (CDCl3) d: 22.3, 28.4, 35.9, 40.6, 101.2, 121.7, 125.0,
(1H, m), 8.13 (1H, dd, Jꢀ4.9, 1.5 Hz), 8.85 (1H, dd, Jꢀ7.8, 1.5 Hz); 13C-
128.3, 128.6, 131.1, 135.6, 143.0, 146.7, 150.8, 164.4, 197.3. Anal. Calcd NMR (CDCl3) d: 16.2, 20.2, 22.5, 23.6, 32.6, 39.1, 39.5, 116.2, 121.0,
for C16H16N2O: C, 76.19; H, 6.35; N, 11.11. Found: C, 76.27; H, 6.37; N, 122.6, 128.4, 132.1, 133.5, 145.0, 145.3, 154.4, 194.1. Anal. Calcd for
11.09.
3-[(6ꢀ-Quinolinyl)ethylamino]cyclohex-2-en-1-one 17 Compound 15
(1 g, 4.2 mmol) was added to a suspension of sodium hydride (1 g, 25 mmol,
C17H18N2O: C, 76.69; H, 6.77; N, 10.53. Found: C, 76.75; H, 6.78; N, 10.58.
7-(N,N-Diethylaminoethyl)-5,6,8,9,10,11-hexahydropyrido[2,3-c]car-
bazol-11-one 22 Compound 18 (0.4 g, 1.2 mmol) underwent irradiation
60% in mineral oil) in anhydrous toluene (50 ml). The mixture was refluxed under different conditions (see Tables 2, 3). Then, the solvents were evapo-
under nitrogen for 2 h and cooled to room temperature. Ethyl iodide (3 ml, rated under reduced pressure. The crude product was chromatographed on
38 mmol) was then added and the mixture was stirred for 24 h at 80 °C.
alumina gel using ether and a gradient of methanol as eluent to give 22 as a
1
After cooling, toluene was washed with water and the insoluble residue in yellow oil: 38% (best yield). H-NMR (CDCl3) d: 0.90 (6H, t, Jꢀ7.2 Hz),
the balloon flask was dissolved in dichloromethane and also washed with 2.08 (2H, m, H9), 2.47 (6H, m), 2.54 (2H, t, Jꢀ7.1 Hz), 2.77 (4H, m), 3.09
water. The organic layers were dried over sodium sulfate and evaporated in (2H, t, Jꢀ7.5 Hz), 3.80 (2H, t, Jꢀ6.9 Hz), 7.07 (1H, m), 8.13 (1H, d,
vacuo. The crude product was chromatographed on alumina gel with
dichloromethane and a gradient of methanol as eluent to give 17 as a yellow 20.5, 22.8, 23.6, 31.3, 39.3, 43.8, 48.1 (2C), 53.5, 116.2, 117.4, 122.6,
Jꢀ4.1 Hz), 8.84 (1H, dd, Jꢀ7.9, 1.6 Hz); 13C-NMR (CDCl3) d: 12.4 (2C),
1
oil: 37%. H-NMR (CDCl3) d: 1.14 (3H, t, Jꢀ7.1 Hz), 1.82 (2H, m), 2.17
(2H, t, Jꢀ6.1 Hz), 2.23 (2H, t, Jꢀ6.2 Hz), 3.66 (2H, q, Jꢀ7.1 Hz), 5.29 (s,
1H), 7.38 (m, 2H), 7.52 (1H, d, Jꢀ2.3 Hz), 8.1 (2H, m), 8.87 (1H, dd,
128.4, 132.6, 133.4, 145.4, 145.5, 154.5, 194.2. Anal. Calcd for C21H27N3O:
C, 74.78; H, 8.01; N, 12.46. Found: C, 74.90; H, 7.99; N, 12.49.
7-(N,N-Dimethylaminopropyl)-5,6,8,9,10,11-hexahydropyrido[2,3-
Jꢀ4.2, 1.6 Hz); 13C-NMR (CDCl3) d: 12.5, 22.8, 29.0, 36.4, 48.0, 101.0, c]carbazol-11-one 23 Compound 19 (0.3 g, 0.9 mmol) underwent irradia-
122.3, 126.7, 128.8, 130.1, 130.7, 136.3, 141.8, 147.3, 151.4, 164.5, 198.0.
Anal. Calcd for C17H18N2O: C, 76.70; H, 6.77; N, 10.53. Found: C, 76.58; H, evaporated under reduced pressure. The residue couldn’t be purified by usual
6.77; N, 10.57. column chromatography techniques, so the proportions of compounds 27
tion under different conditions (see Tables 2, 3). Then, the solvents were
3-[(6ꢀ-Quinolinyl)diethylaminoethylamino]cyclohex-2-en-1-one 18 and 23 in the mixture (orange oil) were deduced from proton integrations in
Compound 15 (0.75 g, 3.2 mmol) was added to a suspension of sodium hy-
dride (2 g, 50 mmol, 60% in mineral oil) in anhydrous toluene (50 ml). The
1H-NMR spectrum. Best yield: 32%. 1H-NMR (CDCl3) d: 1.71 (2H, m),
2.06 (2H, m), 2.13 (6H, s), 2.17 (2H, t, Jꢀ6.7 Hz), 2.45 (2H, t, Jꢀ6 Hz),
mixture was refluxed under nitrogen for 2 h and cooled to room temperature. 2.74 (4H, m), 3.06 (2H, t, Jꢀ7.5 Hz), 3.80 (2H, t, Jꢀ7.5 Hz), 7.06 (1H, m),
Diethylaminoethylchloride hydrochloride (0.5 g, 2.9 mmol) was then added 8.11 (1H, dd, Jꢀ4.9, 1.7 Hz), 8.84 (1H, dd, Jꢀ7.8, 1.7 Hz); 13C-NMR
and the mixture was refluxed for 2 h. After cooling, toluene was washed with (CDCl3) d: 20.4, 22.7, 23.7, 28.7, 32.7, 39.4, 42.1, 45.7 (2C), 56.3, 116.1,
water and the insoluble residue in the balloon flask was dissolved in 117.4, 122.5, 128.4, 132.6, 133.5, 145.4, 145.6, 154.5, 194.2.
dichloromethane and also washed with water. The organic layers were dried
7-Methyl-8,9,10,11-tetrahydropyrido[2,3-c]carbazol-11-one 24

1354
Vol. 55, No. 9
Method 1: Compound 20 (70 mg, 0.3 mmol) was added to a supension of
nate diphenylether and dichloromethane and a gradient of methanol to give
1
Pd/carbon 10% (100 mg) in diphenylether (20 ml) and the reaction mixture 38 as a white powder: 30%, mp 223—225 °C. H-NMR (CDCl3) d: 2.24
was refluxed under nitrogen for 2 h. Still hot, the reaction mixture was fil- (2H, m), 2.69 (2H, t, Jꢀ7.1 Hz), 3.03 (2H, t, Jꢀ6.3 Hz), 7.53 (1H, m), 7.69
tered in order to eliminate Pd/Carbon, which was washed with a hot mixture (1H, d, Jꢀ8.9 Hz), 7.87 (1H, d, Jꢀ9 Hz), 8.79 (1H, dd, Jꢀ4.2, 1.6 Hz),
of dichloromethane and methanol (50/50). Dichloromethane and methanol
were evaporated in vacuo and the diphenylether containing the final product 116.3, 118.9, 119.9, 123.2, 128.2, 132.8, 137.4, 145.2, 147.1, 151.4, 194.1.
was chromatographed on silica gel using dichloromethane as eluent to elimi- Anal. Calcd for C15H12N2O: C, 76.27; H, 5.08; N, 11.86. Found: C, 76.32; H,
nate diphenylether and dichloromethane and a gradient of methanol to give 5.07; N, 11.91.
10.33 (1H, d, Jꢀ8.5 Hz); 13C-NMR (CDCl3) d: 23.4, 23.8, 39.2, 116.0,
24 as a yellow powder: 30%, mp 214—216 °C.
Method 2: Compound 16 (0.14 g, 0.6 mmol) underwent irradiation under
Biological Assay Doxorubicin hydrochloride (Pharmacia, St-Quentin en
Yvelines, France), RPMI 1640 medium and fetal calf serum (Polylabo,
different conditions (see Tables 2, 3). Then, the solvents were evaporated Paris, France) were used in this study. 3-(4,5-dimethylthiazol-2-yl)-2,5-
under reduced pressure. The crude product was chromatographed on alu-
mina gel using dichloromethane and a gradient of methanol as eluent to give
diphenyltetrazolium bromide (MTT) was provided by Sigma (St-Quentin
Fallavier, France). All other reagents were of analytical grade and were ob-
24 as a yellow powder: 30% (best yield), mp 214—216 °C. 1H-NMR tained from commercial sources.
(CDCl3) d: 2.10 (2H, m), 2.54 (2H, t, Jꢀ6.0 Hz), 2.67 (2H, t, Jꢀ6.0 Hz),
3.41 (3H, s), 7.22 (1H, m), 7.39 (1H, d, Jꢀ9 Hz), 7.80 (1H, d, Jꢀ9 Hz), 8.78
Cells and Culture: The human leukemic cell line K 562 was obtained
from the American type culture collection (Rockville, MD, U.S.A.). The
(1H, dd, Jꢀ4.3, 1.6 Hz), 10.22 (dd, 1H, Jꢀ8.5, 1.6 Hz): 13C-NMR (CDCl3) human ovarian carcinoma cell line A 2780 was generously given by Dr. P.
d: 22.9, 23.1, 30.3, 39.3, 113.7, 115.9, 119.2, 120.9, 123.6, 125.8, 133.9, Canal (Centre Claudius Régaud, Toulouse). The doxorubicin resistant cell
137.1, 146.2, 148.4, 151.2, 193.5. Anal. Calcd for C16H14N2O: C, 76.80; H, line A 2780 R was established by the continuous exposure of cells to gradu-
5.60; N, 11.20. Found: C, 76.84; H, 5.61; N, 11.24.
7-Ethyl-8,9,10,11-tetrahydropyrido[2,3-c]carbazol-11-one 25 Method
1: Compound 21 (80 mg, 0.3 mmol) was added to a suspension of Pd/carbon
ally increasing concentrations of doxorubicin and was maintained in a
medium supplemented with doxorubicin at 0.1 mg/ml. The MDR phenotype
expression of A 2780 R cell lines was assessed by an immunohistochemistry
10% (100 mg) in diphenylether (20 ml) and the reaction mixture was re- method, using the two P-glycoprotein specific murine monoclonal antibody
fluxed under nitrogen for 2 h. Still hot, the reaction mixture was filtered in C219 (Cantocor, Malvern, PA, U.S.A.) and JSB1 (Tebu, Le Perray en Yve-
order to eliminate Pd/Carbon, which was washed with a hot mixture of lines, France). Cultures were grown in RPMI 1460 medium supplemented
dichloromethane and methanol (50/50). Dichloromethane and methanol
with 10% fetal calf serum, antibiotics and glutamine at 37 °C in a humidified
were evaporated in vacuo and the diphenylether containing the final product atmosphere containing 5% CO2.
was chromatographed on silica gel using dichloromethane as eluent to elimi-
Cytotoxicity Assay: In all the experiments, K 562 and A 2780 cells were
nate diphenylether and dichloromethane and a gradient of methanol to give seeded at a final density of 5000 cells/well in 96 well microtiter plates and
25 as an orange oil: 30%.
Method 2: Compound 17 (0.16 g, 0.6 mmol) underwent irradiation under
were treated with drugs (doxorubicin and compounds 11, 12, 13, 20, 21, 22,
37, 38 and 39). Seven dilutions were used for each drug. After 96 h of incu-
different conditions (see Tables 2, 3). Then, the solvents were evaporated bation, 10 ml of MTT solution in PBS (5 mg/ml, phosphate-buffer saline pH
under reduced pressure. The crude product was chromatographed on alu-
7.3) were added to each well and the wells were exposed to 37 °C for 4 h.
This colorimetric assay is based on the ability of live and metabolically
unimpaired tumor-cell targets to reduce MTT to a blue formazan product.
Then, 100 ml of a mixture of isopropanol and 1 M hydrochloric acid (96/4,
v/v) were added to each well. After 10 min of vigourous shaking so as to sol-
mina gel using dichloromethane as eluent to give 25 as an orange oil: 38%
1
(best yield). H-NMR d: 1.37 (3H, t, Jꢀ7.4 Hz), 2.22 (2H, m), 2.63 (2H, t,
Jꢀ6.4 Hz), 2.93 (2H, t, Jꢀ6.2 Hz), 4.17 (2H, q, Jꢀ7.4 Hz), 7.45 (1H, m),
7.63 (d1H,, Jꢀ9.1 Hz), 7.93 (1H, d, Jꢀ9 Hz), 8.79 (1H, dd, Jꢀ4.4, 1.8 Hz),
10.31 (1H, dd, Jꢀ8.5, 1.8 Hz); 13C-NMR (CDCl3) d: 15.6, 23.0, 23.4, 39.1, ubilize formazan crystals, the absorbance was measured on a microculture
39.5, 113.9, 116.3, 120.7, 121.0, 124.6, 126.0, 133.2, 137.4, 146.1, 148.2, plate reader (Dynatech MR 5000, France) at 570 nm. For each assay, at least
150.5, 193.6. Anal. Calcd for C17H16N2O: C, 77.27; H, 6.06; N, 10.61. three experiments were performed in triplicate. The resistance factor was
Found: C, 77.36; H, 6.09; N, 10.58.
7-(N,N-Diethylaminoethyl)-8,9,10,11-tetrahydropyrido[2,3-c]carbazol-
11-one 26 Compound 18 (0.4 g, 1.2 mmol) underwent irradiation under
calculated from the ratio between the IC50% growth-inhibitory concentra-
tions (IC50 values) recorded from A 2780 R and A 2780 S cells, respectively,
for the following tested drugs: doxorubicin, compounds 11, 12, 13, 20, 21,
different conditions (see Tables 2, 3). Then, the solvents were evaporated 22, 37, 38 and 39.
under reduced pressure. The crude product was chromatographed on alu-
mina gel using ether and a gradient of methanol as eluent to give 26 as a yel- References
low oil: 23% (best yield). 1H-NMR (CDCl3) d: 0.85 (6H, t, Jꢀ7.2 Hz), 2.19
(2H, m), 2.46 (4H, q, Jꢀ7.2 Hz), 2.63 (2H, t, Jꢀ6.3 Hz), 2.69 (2H, t,
Jꢀ6.1 Hz), 2.98 (2H, t, Jꢀ6.3 Hz), 4.14 (2H, t, Jꢀ6.1 Hz), 7.43 (1H, m),
7.60 (1H, d, Jꢀ9.1 Hz), 7.89 (1H, d, Jꢀ9.1 Hz), 8.79 (1H, dd, Jꢀ4.1,
1.6 Hz), 10.30 (1H, dd, Jꢀ8.5, 1.6 Hz); 13C-NMR (CDCl3) d: 11.3, 23.4
(2C), 39.4, 43.8, 48.2 (2C), 53.0, 113.9, 116.2, 120.7, 121.0, 124.5, 126.2,
133.5, 137.1, 146.4, 148.5, 151.6, 193.7. Anal. Calcd for C21H25N3O: C,
75.22; H, 7.46; N, 12.54. Found: C, 75.28; H, 7.47; N, 12.49.
1) Delvaux E., J. Pharm. Belg., 13, 955—959 (1931).
2) Wright C., Addae-Kyereme J., Breen A. G., Brown J. E., Cox M. F.,
Croft S. L., Gokçek Y., Kendrick H., Philips R. M., Pollet P. L., J.
Med. Chem., 44, 3187—3194 (2001).
3) Paulo A., Pimentel M., Viegas S., Pires I., Duarte A., Cabrita J.,
Gomes E., J. Ethnopharmacol., 44, 73—77 (1994).
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Gaspard C., Marsais F., Godard A., Quéguiner G., J. Med. Chem., 44,
949—960 (2001).
5) Bonjean K., De Pauw-Gillet M. C., Defresne M. P., Colson P.,
Houssier C., Dassonneville L., Bailly C., Greimers R., Wright C.,
Quetin-Leclercq J., Tits M., Angenot L., Biochemistry, 37, 5136—
5146 (1998).
7-(N,N-Dimethylaminopropyl)-8,9,10,11-tetrahydropyrido[2,3-c]car-
bazol-11-one 27 Compound 19 (0.3 g, 0.9 mmol) underwent irradiation
under different conditions (see Tables 2, 3). Then, the solvents were evapo-
rated under reduced pressure. The residue couldn’t be purified by usual col-
umn chromatography techniques, so the proportions of compounds 27 and
23 in the mixture (orange oil) were deduced from proton integrations in 1H-
6) Goodwin S., Smith A. F., Horning E. C., J. Am. Chem. Soc., 81,
1903—1908 (1959).
1
NMR spectrum. Best yield: 45%. H-NMR (CDCl3) d: 1.99 (2H, m), 2.30
(10H, m), 2.72 (2H, t, Jꢀ5.7 Hz), 3.07 (2H, t, Jꢀ6.2 Hz), 4.31 (2H, t,
Jꢀ7.0 Hz), 7.52 (1H, m), 7.80 (1H, d, Jꢀ9.1 Hz), 7.99 (1H, d, Jꢀ9 Hz), 8.88
(1H, dd, Jꢀ4.1, 1.6 Hz), 10.38 (1H, dd, Jꢀ8.5, 1.6 Hz); 13C-NMR (CDCl3)
d: 23.2, 23.5, 28.2, 39.6, 41.9, 45.8 (2C), 56.1, 114.2, 116.3, 120.6, 121.0,
124.5, 126.3, 133.8, 137.1, 146.5, 148.6, 151.2, 194.2.
7) Chu Y., Hsu M. T., Nucleic Acids Res., 20, 4033—4038 (1992).
8) Monnot M., Mauffret O., Simon V., Lescot E., Psaume B., Saucier J.
M., Charra M., Belehradek J., Fermandjian S., J. Biol. Chem., 25,
1820—1829 (1991).
9) Stiborova M., Bieler C. A., Wiessler M., Frei E., Biochem.
Pharmacol., 62, 1675—1684 (2001).
7H-8,9,10,11-Tetrahydropyrido[2,3-c]carbazol-11-one 38 Compound
37 (50 mg, 0.21 mmol) was added to a suspension of Pd/carbon 10%
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