1,4,9,10-Anthradiquinone as precursor for antitumor compounds

Article abstract of DOI:10.1016/j.bmc.2006.01.026

1,4,9,10-Anthradiquinone 5 was reacted with enamines 6 in the Nenitzescu reaction to yield unexpected 3,3a,6,12-tetrahydro-3a,7-dihydroxy-2-methyl-6,12-dioxo-naphtho[2,3-d]in dol-1-carboxylates 8A. However, anthracycline-like naphtho-condensed 5-hydroxyin

Full text of DOI:10.1016/j.bmc.2006.01.026

Bioorganic & Medicinal Chemistry 14 (2006) 3599–3614
1,4,9,10-Anthradiquinone as precursor for antitumor compounds
Lothar Werner Schenck,a Krystina Kuna,a Walter Frank,b Antje Albert,b
Christian Aschea and Uwe Kucklaendera,*
aInstitute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universitaet Duesseldorf, 40225 Duesseldorf, Germany
bInstitute for Inorganic Chemistry and Structural Chemistry, Heinrich-Heine-Universitaet Duesseldorf, 40225 Duesseldorf, Germany
Received 25 October 2005; revised 6 January 2006; accepted 10 January 2006
Available online 3 February 2006
Abstract—1,4,9,10-Anthradiquinone 5 was reacted with enamines 6 in the Nenitzescu reaction to yield unexpected 3,3a,6,12-tetra-
hydro-3a,7-dihydroxy-2-methyl-6,12-dioxo-naphtho[2,3-d]indol-1-carboxylates 8A. However, anthracycline-like naphtho-con-
densed 5-hydroxyindoles were not obtained from this diquinone. It yielded similar reaction products of the Nenitzescu reaction
like other quinones activated by two electron-withdrawing groups. Furthermore, these new compounds 8A were found to constitute
precursors for the synthesis of azonines. The conversion to dibenzoazonines 13 occurred in an unusual and up to now unknown way
consisting of isomerization, ring opening, and re-closure. 2-Chloro-anthradiquinone 19 reacted with enamines 6 as vinylogeous acid
chloride to pyrroloanthraquinone 20. No substitution of chlorine was observed. Naphtho-condensed indoles 26 were obtained by
the reactions of unsubstituted 1,4-anthraquinone 25 with enamines 6 via the normal Nenitzescu route. Indoles 26 were converted to
Mannich bases, reacting further to dimers by the Diels–Alder reaction of intermediate o-quinone methides. Most of the synthesized
heterocycles were evaluated for their anticancer properties in the NCI’s human-disease oriented in vitro anticancer screen. Partic-
ularly, carbinolamines 8A exhibited inhibitory activity of tumor cell growth and thus they constitute a new class of lead structures
for anticancer drug design.
ꢀ 2006 Elsevier Ltd. All rights reserved.
OH
1. Introduction
4'
NH2
Anthracycline antibiotics (e.g., daunorubicin, doxorubi-
cin, idarubicin, and epirubicin) represent an important
class of antitumor drugs. They are among the most
O
R2
O
O
OH
widely used drugs for cancer chemotherapy, characteris-
tically consisting of a four-membered fused ring system
derived from naphthacen and a p-quinone moiety
(Fig. 1). Within our ongoing research a modified
Nenitzescu reaction was developed,1,5–7 with regard to
the synthesis of new heterocyclic and cytotoxic com-
pounds with similar structure and cytotoxic activity like
anthracyclines and presumed to act via intercalation
into DNA.1–4 Aminomethyleneindanones 2, completely
substituted at position 2, were employed instead of
utilizing conventional 3-aminocrotonates as enamine
components. Their reaction with unsubstituted 1,4-
benzoquinone 1 was accompanied by intramolecular
rearrangement of a spiro-intermediate 3 and yielded qui-
4
OH
9
OH
O
R1
R1 = H, R2 = OCH3
1 = OH, R2 = OCH3
R1 = H, R2 = H
daunorubicin
doxorubicin
idarubicin
R
4'-epi-doxorubicin
epirubicin
Figure 1. Anthracycline antibiotics.
nonoid 5H-benzo[b]carbazoles
4
(Scheme 1).2,5–7
Synthetic pathways, anticancer activities as well as
structure–activity relationships for this series of com-
pounds have recently been published.3 Continuing this
work, we now investigated the reaction of alkyl
b-aminocrotonates 6 and 1,4,9,10-anthradiquinone 5
Keywords: Ring enlargement; Nenitzescu reaction; Quinones; Enam-
ines, Azonine; Cytostatic activity.
*
Corresponding author. Tel./fax: +49 211 8114984; e-mail:
kucklaen@uni-duesseldorf.de
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.01.026

3600
L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
O
HO
O
HO
O
R
NH
O
N
R
O
N
O
2
1
R
4
3
Scheme 1. Modified Nenitzescu reaction with p-benzoquinone 1 and aminomethyleneindanones 2 leading to benzocarbazolediones 4.
with the aim to obtain indoles 7 via a ‘normal’ Nenitze-
scu route (Scheme 2). These compounds would consist
of a fused heterocyclic ring system with a p-quinone sub-
structure similar to that of anthracycline chromophores,
which should be able to intercalate into DNA and there-
fore exhibit cytotoxic activity.
philic attack of the b-carbon of the starting enamine
to an electrophilic carbon atom of the quinone. In the
case of the symmetric quinone 5, there are different con-
ceivable electrophilic positions for a nucleophilic addi-
tion: The attack at the activated carbon 2 should
finally lead to typical Nenitzescu products 7, containing
a 5-hydroxyindol substructure and would be in accor-
dance with the reaction mechanism proposed for ami-
nomethyleneindanones 2 with p-benzoquinones 1 in
Scheme 1. The addition at carbon 4a, activated by two
carbonyl groups, however should lead to the formation
of spirocyclic compounds 8A/B. Additionally, it is also
quite possible that the enamine b-carbon attacks the car-
bonyl C-4, which should lead to the formation of com-
2. Chemistry
All Nenitzescu reactions of 5 with 6 were carried out
either in glacial acetic acid (route A) or in dry methanol
(route B) at room temperature. Main products were ob-
tained in yields between 46% and 79%. They precipitat-
ed as solids after dissolving or suspending quinone 58 in
the appropriate solvent and subsequently adding an
equimolar amount of a solution or suspension of the
respective enamine 6 (Scheme 2). Product structures
8A could be determined by NMR spectroscopic meth-
ods and X-ray analysis. The first step in the course of
the Nenitzescu reaction normally consists of a nucleo-
1
pounds 9. Since the H NMR spectra of all products
still showed a coupling between the hydrogens in posi-
tions 2 and 3 of quinone 5 (AB-system), indoles 7 could
thus be excluded. Moreover, 13C NMR data for the ben-
zyl-substituted compound revealed two additional sp3-
carbon atoms (93.86 and 59.05 ppm for 8Aa), which is
compatible with spirocyclic compounds 8 and 9, respec-
R1
R2
a
b
c
d
e
f
g
h
i
Bzl
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COOCH3
COCH3
COCH3
COCH3
COCH3
CN
O
O
O
O
4-tolyl
4-OCH3-Ph
4-Cl-Ph
4-OCH3-Bzl
2,4-diCl-Bzl
Ph
Bzl
4-tolyl
CH3
1
4
R2
2
3
4a
NH
R1
6
5
k
l
H
HOAc (route A) or MeOH
(route B), rt (46 - 79 %)
OH
O
OH
O
O
OH
O
OH
7
5
4
12a
O
OH
R2
3a
OH
R1
OH
O
N
3
O
N
O
N
O
R1
N
R1
R2
1
R2
R1
7
9
8A
8B
Scheme 2. Synthesis of compounds 8A from quinone 5 and enamines 6.

L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
3601
tively. Though the highly deshielded sp3-carbon at
93.86 ppm would indicate carbinolamine structures 8,
their isomers 9 could not be excluded. Determination
of the constitution of 8A was made by X-ray analysis
(Fig. 2). All enamines 6a–l (aminocrotonates, aminopen-
tenones, and aminocrotonitrile) utilized followed the
same reaction pathway. Even cyclic enamines 10 within
the dimedon series reacted analogously to yield the
pentacyclic products 11 under the same conditions in
53% yield (Scheme 3).
which was up to that time unknown in the literature,
an additional X-ray crystal structure determination of
the acetone solvate of 13d was performed (Fig. 3). The
azonine ring nearly adopts a boat conformation stabi-
lized by an intramolecular hydrogen bond between its
carbonyl oxygen and the phenolic hydrogen.
Since the new heterocyclic quinones 15 were now easily
accessible and the antitumor activity of azonines 13, 14,
and 15 was not satisfactory, we tried to modify the
structure by reaction with enamines 6 a,b,d,e,g to indoles
16. However, not the desired indoles 16 were produced,
but benzofuranes 17 or 18 were isolated (Scheme 5).
In order to obtain the desired aromatic indoles, the acid-
labile carbinolamines 8A were then treated with metha-
nolic hydrochloric acid (3.5 N) at room temperature.
Complete disappearance of the starting material and
formation of a new main product was observed after
1 h. But surprisingly, though the sp3-signals for carbons
3a and 12a of 8A disappeared in the 13C NMR spec-
trum, indicating a complete rearrangement, indoles were
not obtained. Mass spectra as well as elemental analysis
provided evidence of an isomeric structure. Since ring
opening of carbinolamine 8A and re-closure to the iso-
meric carbinolamine 12 seemed to be possible under
these conditions, a reaction pathway from 8A via 12
leading to dibenzo[c,f]azonine derivatives 13 was devel-
oped (Scheme 4). Indeed, the hydroquinonoid substruc-
ture in 13a–c was proven by acetylation to 14a–c,
utilizing acetic anhydride and catalytic amounts of pyr-
idine (61–65% yield), and oxidation to the correspond-
ing p-quinones 15 with silver(I)oxide in diethyl ether
(64–74% yield). Due to the unusual and strange forma-
tion of an unsaturated nine-membered ring system,
1
Comparison of H NMR-spectra of benzofuranes with
those of the other azonines 13, 14, and 15 led to ben-
zofurane structure 17. This was in agreement with the
expected chemical properties of quinone 15. Due to con-
jugation of nitrogen with 12-C-carbonyl, the higher elec-
trophilic activity in position 11 favors the addition of
enamine 6 with subsequent ring closure to furane.
OH
O
O
HOAc, rt (53 %)
OH
R
5
N
O
O
HN
R
a
b
R = Ph
R = Bzl
11
10
Scheme 3. Synthesis of compounds 11a and 11b.
Figure 2. Diagram of 8Aa. Displacement ellipsoids are drawn at the 30% probability level, radii of hydrogen atoms are chosen arbitrarily, and the
0
˚
hydrogen atom labels are omitted for clarity. Selected geometric features [A; ꢁ]: C1–C2 1.366(2), C1–C12A 1.535(2), C2–C4 1.486(2), C2–N3
1.339(2), N3–C3A 1.483(2), N3–C50 1.458(2), C3A–C12A 1.564(2), C3A–C4 1.494(3), C4–C5 1.317(3), C5–C6 1.449(3), C6–C6A 1.418(3), C6–O2
1.260(2), C6A–C12A 1.516(2), C6A–C7 1.368(2), C7–C7A 1.439(3), C7–O3 1.325(2), C7A–C11A 1.396(2), C11A–C12 1.484(2), C12–C12A 1.526(2),
C12–O4 1.211(2), O1–H1 0.84(2), H1ꢀ ꢀ ꢀO4 2.33(2), O1ꢀ ꢀ ꢀO4 2.941(2), H1ꢀ ꢀ ꢀO6# 2.03(2); O1ꢀ ꢀ ꢀO6# 2.738(2), O3–H3 1.01(3), H3ꢀ ꢀ ꢀO2 1.56(3),
O3ꢀ ꢀ ꢀO2 2.480(2); C2–N3–C50–C60 85.6(2), C4–C3A–C12A–C6A 32.0(2), C4–C3A–C12A–C1 ꢁ89.67(17), C4–C3A–C12A–C12 159.41(15), C5–C4–
C3A–C12A ꢁ9.2(3), C12A–C1–C30–O6 ꢁ172.27(18); symmetry code #: ꢁx, ꢁy + 1.5, z ꢁ 0.5. Dashed lines are indicating intra- and intermolecular
hydrogen bonds.

3602
L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
HO
OH
O
O
OH
O
MeOH/HCL (3.5 N)
rt, 1 h (77 - 88 %)
OH
O
OH
R1
HO
N
N
O
N
O
O
R1
O
O
O
R1
O
O
13a-d
12
8A
acetic anhydride,
cat. pyridine,
reflux, 1.5 h
Ag2O, Na2SO4,
diethyl ether,
rt, 2 h (64 - 74 %)
R1
(61 - 65 %)
a
b
c
Bzl
4-tolyl
4-OCH3-Ph
4-Cl-Ph
O
d
O
O
O
O
O
O
O
O
O
N
N
O
O
O
O
R1
14a-c
R1
15a-d
Scheme 4. Synthesis of compounds 13–15.
Figure 3. Diagram of 13d in 13d · C3H6O. Displacement ellipsoids are drawn at the 30% probability level, radii of hydrogen atoms are chosen
0
˚
arbitrarily, and the hydrogen atom labels are omitted for clarity. Selected geometric features [A; ꢁ]: C5–O1 1.212(3), C5–N6 1.374(3), N6–C1
1.423(3), N6–C7 1.431(3), C7–C8 1.324(4), C8–C8A 1.507(3), C8A–C9 1.377(4), C12A–C13 1.448(4), C13–O2 1.241(3), C13–C13A 1.492(4), C13A–
C4A 1.376(4), C4A–C5 1.499(4), C9–O4 1.361(3), C12–O3 1.349(3), O3–H30 0.79(4), H30ꢀ ꢀ ꢀO2 1.84(4), O3ꢀ ꢀ ꢀO2 2.523(3), O4–H40 0.85(4),
H40ꢀ ꢀ ꢀO2# 1.93(4), O4ꢀ ꢀ ꢀ.O2# 2.756(3); C20–C10–N6–C7 ꢁ35.6(4), C5–N6–C7–C8 ꢁ60.9(3), N6–C7–C8–C8A ꢁ19.8(4), C7–C8–C8A–C12A
94.9(3), C8–C8A–C12A–C13 ꢁ0.9(4), C8A–C12A–C13–C13A ꢁ15.0(2), C12A–C13–C13A–C4A ꢁ53.2(4), C13–C13A–C4A–C5 6.8(4), C13A–C4A–
C5–N6 98.9(3), C4A–C5–N6–C7 ꢁ17.1(3); symmetry code #: x + 1, y, z. Dashed lines are indicating intra- and intermolecular hydrogen bonds.

L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
3603
HN
15a,c
6e
O
HOAc, rt, 8 h
(53 - 63 %)
O
O
O
O
O
O
O
HO
N
O
O
O
O
OH
O
OH
O
O
O
N
N
R1
N
O
O
O
O
O
O
R1
R1
16
18
17
R1
Bzl
4-OCH3-Bzl
a
b
Scheme 5. Synthesis of compounds 17.
O
O
O
O
O
3
2
NH
R
Cl
a
b
R = Ph
R = 4-tolyl
6h,i
19
HOAc
rt, 5 h
(7 - 8 %)
R
O
OH
O
O
OH
O
OH
O
O
N
Cl
O
Cl
O
O
R
Cl
N
HO
HO
O
N
N
O
OH
R
R
O
23
22
20
21
Scheme 6. Synthesis of compounds 20 from quinone 19 and enaminones 6h,i.
O
O
OH
Since the reactions of quinone 5 with enamines 6 did
not produce the desired and pharmacologically inter-
esting indoles 7, two other quinones 19 and 25 were
tested under the conditions of the modified Nenitzescu
reaction.
Cl
O
HO
N
The additional 2-chloro substituent of 2-chloro-
anthradiquinone 19, easily accessible from 5,9 should
lead to a more electrophilic carbon at position 3.
24
Figure 4.

3604
L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
However, under the same conditions as described in
Scheme 2, reactions with enamines 6h/k yielded carbi-
nolamines 20a/b (8% and 7% yield, respectively), which
were in this case the result of an addition to the enamine
b-carbon at position 2 of 19 (Scheme 6). Compound 19
reacted as vinylogeous acid chloride, though no substi-
tution of chlorine was observed. The target indol 21
and the chlorine-free indol 22 could be excluded, since
13C NMR spectra showed two singlets at 61.7 and
93.6 ppm for the two sp3-carbons 3a and 11b of 20a.
OH
O
O
O
5
HOAc
rt, 36 h
O
OC2H5
O
O
2
NH
R1
R2
(29 - 49 %)
1
OC2H5
N
O
OC2H5
1
N
R1
R2
6
26
25
R1
R2
27
Ag2O, Na2SO4,
acetone,
R1
R2
40 ˚C, 2 h
a
b
c
Bzl
4-tolyl
CH3
CH3
CH3
CH3
CH3
Ph
(48 %)
4-OCH3-Ph
4-OCH3-Bzl
isobutyl
4-OCH3-Ph
CH3
e
m
n
o
N
1'
C2H5O
CH3
3'
O
4'
H
O
O
H
4
O
28
3
OC2H5
N
1
Scheme 7. Synthesis of compounds 26 and 28.
R1
N
R2
OH
5
N
N
N
DCM, reflux, 2 h
(32 - 52 %)
C2H5O
4
O
O
26
O
O
cat. HOAc,
reflux, 2 h
OC2H5
N
29
(46 - 47 %)
O
1
R1
R2
OC2H5
N
31
R1
R2
R1
R2
a
b
c
isobutyl
4-OCH3-Ph
CH3
CH3
Ph
CH3
R2
R1
N
C2H5O
O
O
O
O
30
OC2H5
N
R1
R2
Scheme 8. Synthesis of the phenolic Mannich bases 29 and Diels–Alder dimerization of intermediate o-quinone methides 30 to 31.

L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
3605
We assume that the carbocyclus and the heterocyclus
3. In vitro anticancer activity
are cis-connected, that is, the 3a-chlorine and the 11b-
hydroxyl group positioned on the same side. No split
off of water is possible to yield indol 21. Quinone 19
reacted with enaminone 10b analogously to 24 (Fig. 4).
Most of the synthesized new heterocycles were evalu-
ated in the anticancer screen for human disease-orient-
ed tumor cell line developed at the NCI.15,16 This
in vitro screen is subdivided into a pre-test and a main
test. Within the one-dose pre-test consisting of three
tumor cell lines (MCF7 (breast), NCI-H460 (lung),
and SF-268 (CNS)) test agents are added at only
one concentration (10ꢁ4 M) to each cell line inoculat-
ed and preincubated on a microtiter plate, and the
culture is then incubated for 48 h. End-point determi-
nations are made with alamar blue.17 Results for each
test compound are reported as the percentage of
growth of the treated cells in comparison with that
of the untreated control cells. Negative numbers indi-
cate cell death. Compounds reducing the growth of
any one of the three cell lines by 32% or less are
called ‘active’ and subsequently passed on for evalua-
tion in the main test, this time consisting of approxi-
As a consequence of the fact that anthradiquinone re-
acts irregularly in the Nenitzescu reaction, we used a
procedure described by Lepage10 to synthesize unsubsti-
tuted 1,4-anthraquinone 25. When utilizing this qui-
none, the desired indol derivatives 26 were now
obtained as a result of a primary attack of the b-carbon
of enamines 6 at carbon 2 of quinone 25 with yields be-
tween 29% and 49% (Scheme 7). Because many of the
well-established antitumor agents (e.g., anthracyclines)
contain a quinone moiety, which at least partially con-
tributes to their activity, the o-quinonoid compounds
27 seemed to be an attractive target. Various conditions
and oxidizing agents were examined. But instead of the
monomeric target o-quinone 27 we were only able to iso-
late the dimeric indol 28 as the main product by reaction
of 26m with silver(I)oxide in acetone at 40 ꢁC (48%
yield). Accordingly, the 13C NMR-spectrum shows sig-
nals of two carbonyl groups at 199.5 ppm (s, CO) and
165.2 ppm (s, COOR) as well as a doublet for C-4 at
53.3 ppm (J = 110 Hz). Similar observations were made
by Diepenbrock11 and Teuber and Thaler who oxidized
5-hydroxyindoles with Fremy’s salt.12
Table 1. In vitro anticancer activity—NCI’s 3 cell line pre-testa
Compound
NCI-H460
MCF7
SF-268
Resultb
8Aa
8Ab
8Ac
8Ad
8Af
8Ag
8Ah
8Ai
8Al
11a
13a
13b
13c
14a
14b
15a
15b
17a
20a
20b
26a
26b
26c
26e
26f
0
0
0
22
ꢁ90
ꢁ61
0
0
6
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Active
Inactive
Active
Active
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
Inactive
ꢁ43
ꢁ32
0
ꢁ47
ꢁ81
1
0
0
0
Another interesting and promising idea to modify in-
doles 26 was to investigate the reaction with bisdimethyl-
aminomethane in order to obtain ortho-phenolic
Mannich bases 29. The incorporation of a dimethylam-
inomethyl substituent should not only lead to a more
water-soluble derivative under physiological conditions,
but it should also improve the anticancer activity, as it is
known from the drug topotecan used clinically. Heating
of 5-hydroxyindoles 26 for 2 h in bisdimethylaminome-
thane with catalytic amounts of acetic acid yielded the
ortho-phenolic Mannich bases 29 (46–47% yield)
(Scheme 8). Interestingly, further heating of compounds
29 under reflux in dichloromethane for 2 h led to the spi-
rocyclic dimers 31 as a result of a Diels–Alder dimeriza-
tion of intermediate o-quinone methides 30. These were
formed after thermal desamination of 29 (32–52% yield).
A similar reaction has been known for piperidinometh-
ylcycloheptanone for a long time.13 The 13C NMR-spec-
trum of 31c exhibited singlets at 199.50 ppm (CO
group), as well as at 167.05 and 166.10 ppm of the eth-
oxycarbonyl groups. The singlet for the spiro-carbon
was observed at 81.82 ppm and two triplets were regis-
tered at 28.82 and 21.49 ppm (J = 130 and 131 Hz) for
the ethylene bridge in the spiro-pyrane ring. Thus, the
structure of compounds 31 was proven.
1
1
1
0
0
1
1
1
1
6
33
12
11
76
1
9
0
0
61
24
0
66
65
0
50
0
27
0
64
0
3
0
5
100
0
83
0
83
0
59
92
98
86
97
91
95
67
79
59
92
77
79
30
72
83
98
88
122
65
64
118
112
92
122
99
17
76
89
122
97
145
59
104
145
111
84
139
82
26g
28
29a
29b
31a
31b
31c
a Data were obtained from the NCI’s in vitro anticancer 3 cell line pre-
test (for details see Refs. 15 and 16). Negative numbers indicate cell
kill. Each cell line was inoculated and preincubated on a microtiter
plate. Test agents (10ꢁ4 M) were added and the culture incubated for
48 h. End-point determinations were made with alamar blue. Results
for each test agent were reported as the percentage of growth of the
treated cells when compared to untreated control cells.
b Compounds which reduce the growth of any one of the cell lines to
32% or less are called ‘active’ and passed on for evaluation in the
main test.
In the case of the reaction of 26o with bisdimethylami-
nomethane, we were not able to isolate the Mannich
base 29c, but the dimer 31c. The easy dimerization of
29 via o-quinone methides stimulated the idea that the
ortho-phenolic Mannich bases 29 could show antitumor
activity, since some cytostatics such as mitomycin C or
even the anthracyclines are known to exhibit their activ-
ity partly via an intermediate quinone methide species.14

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L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
mately 60 cell lines over a 5-log dose range (10ꢁ4
–
mitomycin C (MGM logGI50 = ꢁ6.09) for the same
10ꢁ8 M). Within the main test the antitumor activity
of a test compound is expressed by three different
dose–response parameters for each of the 60 cell lines
derived from nine different types of cancer: GI50 (mo-
lar concentration required for half-growth inhibition),
TGI (molar concentration leading to total growth
inhibition), and LC50 (molar concentration required
for 50% cell death). Moreover, a mean graph mid-
point (MGM) is calculated for each of the above-men-
tioned parameters, which displays an averaged activity
parameter over all cell lines.
subpanel.
4. Conclusion
Anthracycline-like naphtho-condensed indoles 7 were
not obtained from 1,4,9,10-anthradiquinone 5. This diq-
uinone reacted with enamines by addition to the doubly
activated C@C-bond in 4a-position and not by reaction
at the quinone in 2-position. Diquinone 5 therefore re-
acts comparably to other quinones activated by two
electron-withdrawing groups.21,22 The synthesized con-
densed spirocyclic carbinolamines 8A are absolutely
new lead structures for antitumor compounds. The reac-
tion of compounds 8A with methanolic hydrochloric
acid resulting in an isomerization and ring opening to
dibenzoazonine 13 is very surprising and interesting.
This is with no equivalent in the literature. Thus, a
new synthetic route to azonines 13 was found. 2-Chlo-
ro-anthradiquinone 19 reacted as vinylogeous carboxyl-
ic acid chloride, however, no substitution of the chlorine
atom was observed. Naphtho-condensed indoles 26 were
available from 1,4-anthraquinone 25 in a normal
Nenitzescu reaction. The phenolic Mannich bases 29
of 25 were unstable further reacting via a Diels–Alder
pathway.
The results of the pre-test for each tested compound are
presented in Table 1. The azonine derivative 17a, the 5-
hydroxyindoles 26, the ortho-phenolic Mannich bases
29, and the dimers 28 and 31 were found to be inactive,
whereas particularly the enamine–anthradiquinone ad-
ducts 8A and the hydroquinonoid and quinonoid azo-
nine derivatives 13–15 exhibited growth inhibitory
activity. Moreover, the 4-methoxyphenyl- and the 4-
chlorophenyl-substituted compounds 8Ac and 8Ad even
led to a cytotoxic effect. In Table 2, MGM logGI50,
logTGI, and logLC50 values over all cell lines for each
tested compound are given. Among this series of hetero-
cycles, the most active ones were at the nitrogen unsub-
stituted nitril derivative 8Al (MGM logGI50 = ꢁ5.55)
and the N-4-chlorophenyl-substituted derivative 8Ad
(MGM logGI50 = ꢁ5.39), however, the inhibition was
weaker than that obtained for mitomycin C (MGM
logGI50 = ꢁ6.13). Nitril 8Ak showed some selectivity
for the subpanel of leukemia cell lines (MGM
logGI50 = ꢁ6.32). This value was better than that of
5. Experimental
Melting points were determined with a Gallenkamp
apparatus and are uncorrected. IR spectra were record-
ed as frequency in cmꢁ1 on a Perkin Elmer 1600 series
FT-IR spectrometer in KBr. UV–vis spectra were ob-
tained on a Perkin Elmer Lamda 16 spectrometer.
NMR spectra were obtained on Bruker AC 200 in
DMSO-d6 or CDCl3 using tetramethylsilane (TMS) as
an internal standard. The chemical shifts are reported
in parts per million, in d units. Mass spectra were
recorded on Finnigan MAT 8200 or MAT 311A MAT
(EI, 70 eV). Elemental analyses were performed with
a Perkin Elmer PE 2400 CHN elemental analysator.
Commercially available solvents and reagents were used
without further purification unless otherwise mentioned.
Table 2. In vitro anticancer activity—NCI’s 60 cell line main testa
Compound MGM logGI50 MGM logTGIc MGM logLC50
b
d
8Aa
8Ab
8Ac
8Ad
8Ag
8Ai
8Al
11a
13a
13b
14a
14b
15a
15b
20a
20b
ꢁ4.98
ꢁ5.13
ꢁ4.87
ꢁ5.39
ꢁ4.93
ꢁ4.93
ꢁ5.55
ꢁ4.58
ꢁ4.17
ꢁ4.71
ꢁ4.31
ꢁ4.77
ꢁ4.27
ꢁ4.76
ꢁ5.27
ꢁ4.86
ꢁ4.50
ꢁ4.22
ꢁ4.64
ꢁ4.85
ꢁ4.32
ꢁ4.25
ꢁ4.68
ꢁ4.12
ꢁ4.04
ꢁ4.28
ꢁ4.03
ꢁ4.23
ꢁ4.06
ꢁ4.34
ꢁ4.43
ꢁ4.18
ꢁ4.14
ꢁ4.01
ꢁ4.19
ꢁ4.34
ꢁ4.06
ꢁ4.01
ꢁ4.17
>ꢁ4.00e
>ꢁ4.00e
ꢁ4.04
>ꢁ4.00e
ꢁ4.02
ꢁ4.01
ꢁ4.07
ꢁ4.03
ꢁ4.01
5.1. General procedure for the preparation of 3,3a,6,12-
tetrahydro-3a,7-dihydroxy-2-methyl-6,12-dioxonaph-
tho[2,3-d]indol-1-carboxylates (8A), 1,2,3,4,5,5a,8,14-
octahydro-5a,9-dihydroxy-3,3-dimethyl-naphtho[2,3-k]car-
bazole-1,8,14-triones (11) 9,14-dihydro-5-hydroxy-2,7-di-
methyl-9,14-dioxo-8-H-benzo[c][1]-benzofuro[6,7-f]azo-
nine-3,6-dicarboxylates (17), 3-acetyl-3a-chloro-3a,11b-
dihydro-5,11b-dihydroxy-2-methyl-naphtho[2,3-g]indol-
6,11-diones (20), 12-benzyl-7-chloro-7,8,9,10,11,12,12a,13-
octahydro-6,12a-dihydroxy-10,10-dimethyl-5H-naphtho[2,3-
a]carbazol-5,8,13-trione (24), and 5-hydroxy-2-methyl-1H-
naphtho[2,3-g]indol-3-carboxylates (26)
a Data were obtained from the NCI’s in vitro anticancer 60 cell line
main screen (for details see Refs. 15 and 16).
b Averaged log molar concentration for all tested cancer cell lines
which led to 50% growth inhibition.
c Averaged log molar concentration for all tested cancer cell lines
which led to total growth inhibition.
d Averaged log molar concentration for all tested cancer cell lines
which led to 50% cell death.
The amount of quinone was dissolved or suspended in
glacial acetic acid or dry methanol (1 ml corresponding
to 100 mg quinone) and mixed with a solution or sus-
pension of the appropriate enamine 6 in acetic acid or
e The highest tested concentration (10ꢁ4 M) of the drug did not lead to
50% cell death.

L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
3607
methanol (1 ml corresponding to 100 mg enamine) at
room temperature. The mixture was stirred for the time
indicated and the obtained solid was collected and treat-
ed as indicated followed by recrystallization from
isopropanol (compounds 8A), dichloromethane/hexanes
(40:60) (compounds 17), dichloromethane/hexanes
(20:80) (compounds 20 and compound 24) or dichloro-
methane (compounds 26).
where P ¼ ðF 2o þ 2F c2Þ=3, S = 1.109, and20 largest peak
2
and hole in the final difference map are 0.200 e/A and
˚
3
˚
ꢁ0.167 e/A , respectively. Anisotropic displacement
parameters were used for all non-hydrogen atoms. Indi-
vidual isotropic displacement parameters were refined
for all H atoms, individual coordinates for all but the
H atoms of methyl and methylen groups. The H atoms
of CH3 groups were allowed to ride on their parent car-
bon atom and to move collectively around the neighbor-
ing C–C axis. Furthermore, the C–H distances were
allowed to vary, the same shifts being applied along
the three C–H bonds of a group. Together with their
parent carbon atom the H atoms of the CH2 groups
were treated as rigid groups with idealized geometry, al-
lowed for rotational movement.
5.1.1.
Ethyl-3-benzyl-3,3a,6,12-tetrahydro-3a,7-dihy-
droxy-2-methyl-6,12-dioxo-naphtho[2,3-d]indol-1-carbox-
ylate (8Aa). Route A: 228 mg (1.2 mmol) ethyl-3-
benzylaminocrotonate 6a, 286 mg (1.2 mmol) 5, acetic
acid, 3 h, 365 mg (67%), route B: 228 mg (1.2 mmol) eth-
yl-3-benzylaminocrotonate 6a, 286 mg (1.2 mmol) 5,
methanol, 7 h, 402 mg (73%), mp 181 ꢁC (yellow crys-
tals), IR 3422, 1670, 1652, 1592, MS (EI) 457 (22;
M+), 440 (13), 385 (6), 368 (47), 277 (59), 250 (65), 225
(22), 165 (12), 138 (30), 91 (100), 64 (53), 1H NMR
(CDCl3) d 15.92 (s, 1H, 7-OH), 8.16 (mc, 1H) and 8.04
(mc, 1H, 8-H, 11-H), 7.75 (mc, 1H) and 7.59 (mc, 1H,
9-H, 10-H), 7.57 (mc, 5H, arom. H), 6.30 (d, 1H) and
6.25 (d, 1H, 4-H, 5-H, J = 10.2 Hz), 5.50 (s, 1H, 3a-
OH), 4.86 (d, 1H) and 4.56 (d, 1H, phe-CH2,
J = 16.8 Hz), 3.70 (mc, 2H, O–CH2), 2.16 (s, 3H, 2-
CH3), 0.78 (t, 3H, O–C–CH3, J = 7.2 Hz), 13C NMR
(CDCl3) d 198.25 (s, C@O (carbonyl)), 183.02 (s, C@O
(carbonyl)); 173.83 (s, C@O (ester)), 164.72 (s, C-2),
163.43 (br s, C-7, C–OH), 137.89, 135.73, 135.65,
134.75, 132.84, 131.95, 128.97, 127.49, 127.43, 127.01,
126.40, 125.09, 102.52 (s, C-1), 100.59 (s, C-6a), 93.86
(s, C-3a, C–OH), 59.05 (s, C-12a), 58.72 (t, O–CH2,
5.1.3. Ethyl-3,3a,6,12-tetrahydro-3a,7-dihydroxy-2-meth-
yl-6,12-dioxo-3-(4-tolyl)-naphtho[2,3-d]indol-1-carboxyl-
ate (8Ab). 228 mg (1.2 mmol) ethyl-3-(4-tolylamino)-
crotonate 6b, 286 mg (1.2 mmol) 5, acetic acid, 3 h,
450 mg (79%), mp 160 ꢁC (yellow crystals), IR 3262
m, 1678, 1591, 1568, MS (EI) 457 (8; M+), 368 (100),
338 (5), 280 (42), 251 (32), 223 (15), 168 (13), 131
(83), 91 (86), 64 (63), 1H NMR (CDCl3) d 15.87 (s,
1H, 7-OH), 8.17 (mc, 1H) and 8.02 (mc, 1H, 8-H, 11-
H), 7.80 (mc, 1H) and 7.62 (mc, 1H, 9-H, 10-H), 7.26
(mc, 4H, arom. H), 6.29 (d, 1H) and 6.22 (d, 1H, 4-H,
5-H, J = 10.2 Hz), 5.54 (s, 1H, 3a-OH), 3.74 (mc, 2H,
O–CH2), 2.43 (s, 3H, CH3), 2.08 (s, 3H, CH3), 0.81 (t,
3H, O–C–CH3, J = 7.1Hz), UV–vis (MeOH) 234
(4.54), 277 (4.24), 315 (4.40), 377 (3.85). Anal. Calcd
for C27H23NO6 (457.48): C, 70.89; H, 5.07 N: 3.06.
Found: C: 70.66 H: 5.03 N: 2.87.
1
1JC/H = 138.4 Hz), 44.53 (t, N–CH2, JC/H = 136.4 Hz),
1
14.35 (q, 2-CH3, JC/H = 130.0 Hz), 13.90 (q, CH3-ester,
1JC/H = 129.3 Hz), UV–vis (MeOH) 274 (4.22), 316
(4.06), 388 (3.76). Anal. Calcd for C27H23NO6 (457.46):
C, 70.89; H, 5.07; N, 3.06. Found: C, 70.67; H, 5.07; N,
2.92.
5.1.4. Ethyl-3-(4-methoxyphenyl)-3,3a,6,12-tetrahydro-
3a,7-dihydroxy-2-methyl-6,12-dioxo-naphtho[2,3-d]indol-
1-carboxylate (8Ac). 282 mg (1.2 mmol) ethyl-3-(4-meth-
oxyphenylamino)crotonate 6c, 286 mg (1.2 mmol) 5,
acetic acid, 8 h, 440 mg (78%), mp 180 ꢁC (yellow crys-
tals), IR 3439, 1676, 1591, 1568, MS (EI) 473 (9; M+),
418 (1), 384 (100), 356 (4), 280 (44), 223 (18), 147 (82),
5.1.2. Crystal structure determination of compound
8Aa18. Crystals of 8Aa, suitable for X-ray study, were
selected by means of a polarization microscope. One
was investigated on a Stoe Imaging Plate Diffraction
System, using graphite monochromatized Mo Ka
1
121 (70), 77 (39), 43 (11), H NMR(CDCl3) d 15.86 (s,
1H, 7-OH), 8.17 (mc, 1H) and 8.02 (mc, 1H, 8-H, 11-
H), 7.77 (mc, 1H) and 7.62 (mc, 1H, 9-H, 10-H), 7.15
(mc, 4H, arom. H), 6.29 (d, 1H) and 6.21 (d, 1H, 4-H,
5-H, J = 10.2 Hz), 5.55 (s, 1H, 3a-OH), 3.87 (s, 3H,
OCH3), 3.73 (mc, 2H, O–CH2), 2.08 (s, 3H, 2-CH3),
0.81 (t, 3H, O–C–CH3, J = 7.0 Hz), UV–vis (MeOH)
232 (4.30), 277 (3.99), 316 (4.15), 377 (3.70). Anal. Calcd
for C27H23NO7 (473.48): C, 68.49; H, 4.90; N, 2.96.
Found: C, 68.23; H, 5.04; N, 3.04.
˚
radiation (k = 0.71073 A). Unit cell parameters were
determined by a least-squares refinement on the
positions of 8000 strong reflections distributed equally
in reciprocal space. A monoclinic lattice was found,
and space group P21/c was uniquely determined.
Crystal data of 8Aa: Mr (C27H23NO6) = 457.46,
˚
˚
˚
˚
a = 14.4890(14) A, b = 10.4297(5) A, c = 14.4691(13) A,
3
b = 90.392(11)ꢁ,
V = 2186.5(3) A ,
Z = 4,
Dx =
1.390 g cmꢁ3, l = 0.099 mmꢁ1, T = 291 K, orange crystal
of dimensions 0.8 mm · 0.6 mm · 0.3 mm. 25470 inten-
sity data (Hmin = 2.41ꢁ, Hmax = 27.49ꢁ) were collected
and Lp corrections were applied. The structure was
solved by direct methods,19 and approximate positions
of all hydrogen atoms were found via difference Fourier
synthesis. Refinement (379 parameters, all of 5006
unique reflections used, 0 restraints) by full-matrix
least-squares calculations on F2,20 converged to the fol-
5.1.5. Ethyl-3-(4-chlorphenyl)-3,3a,6,12-tetrahydro-3a,7-
dihydroxy-2-methyl-6,12-dioxo-naphtho[2,3-d]indol-1-
carboxylate (8Ad). Route A: 287 mg (1.2 mmol)
ethyl-3-(4-chlorophenylamino)crotonate 6d, 286 mg
(1.2 mmol) 5, acetic acid, 3 h, 375 mg (65%), route
B: 287 mg (1.2 mmol) ethyl-3-(4-chlorophenylami-
no)crotonate 6d, 286 mg (1.2 mmol) 5, methanol,
6 h, 450 mg (79%), mp 172 ꢁC (yellow crystals from
isopropanol), IR 3266, 1678, 1592, 1568, MS (EI)
477 (3; M+), 431 (1), 388 (30), 351 (10), 280 (22),
250 (27), 224(9), 152 (100), 111 (36), 75 (48), 41
lowing final indicators: R1½F 2o > 2rðF o2Þꢂ ¼ 0:047,
2
wR2 = 0.098 (all data), w ¼ 1=½r2ðF o2Þ þ ð0:7PÞ þ 0:1Pꢂ

3608
L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
1
(16), H NMR (CDCl3) d 15.85 (s, 1H, 7-OH), 8.18
(mc, 1H) and 8.03 (mc, 1H, 8-H, 11-H), 7.78 (mc,
1H) and 7.62 (mc, 1H, 9-H, 10-H), 7.35 (m, 4H,
arom. H), 6.28 (d, 1H) and 6.17 (d, 1H, 4-H, 5-
H), 5.55 (s, 1H, 3a-OH), 3.75 (mc, 2H, O–CH2),
2.09 (s, 3H, 2-CH3), 0.83 (t, 3H, O–C–CH3), UV–
vis (MeOH) 234 (4.54), 314 (4.40), 377 (3.97). Anal.
Calcd for C26H20ClNO6 (477.90): C, 65.35; H, 4.22;
N, 2.93. Found: C, 65.23; H, 4.06; N, 2.93.
5.1.9. 1-(3-Benzyl-3,3a,6,12a-tetrahydro-3a,7-dihydroxy-
2-methyl-6,12-dioxo-naphtho[2,3-d]indol-1-yl)-ethanone
(8Ah). 227 mg (1.2 mmol) 4-benzylaminopent-3-en-2-
one 6h, 286 mg (1.2 mmol) 5, acetic acid, 8 h, 350 mg
(68%), mp 170 ꢁC (yellow crystals), IR 3429, 1685,
1647, 1593, 1568, MS (EI) 427 (5; M+), 385 (25), 368
(11), 278 (38), 251 (29), 225 (16), 149 (12), 91 (100), 65
1
(21), 43 (40), H NMR (CDCl3) d 15.79 (s, 1H, 7-OH),
8.23 (m, 1H) and 7.99 (m, 1H, 8-H, 11-H), 7.77 (mc,
1H) and 7.60 (mc, 1H, 9-H, 10-H), 7.44 (mc, 5H, arom.
H), 6.21 (d, 1H) and 6.30 (d, 1H, 4-H, 5-H, J = 10.2 Hz),
5.40 (s, 1H, 3a-OH), 4.91 (d, 1H) and 4.64 (d, 1H, CH2–
phe, J = 16.9 Hz), 2.11 (s, 3H, CH3), 2.04 (s, 3H, CH3),
UV–vis (MeOH) 215 (4.34), 309 (4.29). Anal. Calcd for
C26H21NO5 (427.45): C, 73.06; H, 4.95; N, 3.28. Found:
C, 72.81; H, 5.16; N, 3.13.
5.1.6.
Ethyl-3,3a,6,12-tetrahydro-3a,7-dihydroxy-3-(4-
methoxybenzyl)-2-methyl-6,12-dioxo-naphtho[2,3-d]indol-1-
carboxylate (8Ae). 298 mg (1.2 mmol) ethyl-3-(4-meth-
oxybenzylamino)crotonate 6e, 286 mg (1.2 mmol) 5,
acetic acid, 3 h, 430 mg (74%), mp 170 ꢁC (yellow crys-
tals), IR 3444, 1654, 1632, 1592, 1558. MS (EI) 487 (4;
M+), 398 (4), 339 (1), 280 (8), 240 (18), 180 (4), 136
(6), 121 (100), 77 (9), 51 (4), 1H NMR (CDCl3) d
15.92 (s, 1H, 7-OH), 8.15 and 8.02 (mc, 2H, 8-H, 11-
H), 7.76 and 7.63 (mc, 1H, 9-H, 10-H), 7.2 (mc, 4H,
arom. H), 6.29 (d, 1H) and 6.22 (d, 1H, 4-H, 5-H,
J = 10.2 Hz), 5.50 (s, 1H, 3a-OH), 4.78 (d, 1H) and
4.56 (d, 1H, phe-CH2, J = 16.4 Hz), 3.84 (s, 3H,
OCH3), 3.70 (mc, 2H, O–CH2), 2.17 (s, 3H, 2-CH3),
0.78 (t, 3H, CH3–C–O), UV–vis (MeOH) 215 (4.53),
261 (4.17), 303 (4.29), 364 (3.88). Anal. Calcd for
C28H25NO7 (487.50): C, 68.98; H, 5.17; N, 2.87. Found:
C, 68.70; H, 5.03; N, 2.78.
5.1.10. 1-(3,3a,6,12a-Tetrahydro-3a,7-dihydroxy-2-meth-
yl-6,12-dioxo-1-(4-tolyl)-naphtho[2,3-d]indol-1-yl)-etha-
none (8Ai). 227 mg (1.2 mmol) 4-(4-tolylamino)pent-3-
en-2-one 6i, 286 mg (1.2 mmol) 5, acetic acid, 8 h,
350 mg (68%), mp 181 ꢁC (yellow crystals), IR 429,
1641, 1593, 1569, MS (EI) 427 (3; M+), 384 (25), 356
(100), 338 (9), 278 (47), 240 (54), 190 (15), 175 (31),
1
133 (84), 108 (75), H NMR (CDCl3) d 15.75 (s, 1H,
7-OH), 8.23 (mc, 1H) and 7.97 (mc, 1H, 8-H, 11-H),
7.77 (mc, 1H) and 7.59 (mc, 1H, 9-H, 10-H), 7.28 (mc,
4H, arom.H), 6.29 (d, 1H) and 6.20 (d, 1H, 4-H, 5-H),
5.39 (s, 1H, 3a-OH), 2.44 (s, 3H, CH3), 2.09 (s, 3H,
CH3), 2.04 (s, 3H, CH3), UV–vis (MeOH), 216 (4.47),
310 (4.45). Anal. Calcd for C26H21NO5 (427.45): C,
73.06; H, 4.95; N, 3.28. Found C, 73.01; H, 4.75; N,
3.06.
5.1.7.
Ethyl-3-(2,4-chlorbenzyl)-3,3a,6,12-tetrahydro-
3a,7-dihydroxy-2-methyl-6,12-dioxo-naphtho[2,3-d]indol-
1-carboxylate (8Af). 343 mg (1.2 mmol) ethyl-3-(2,4-dic-
hlorbenzylamino)crotonate 6f, 286 mg (1.2 mmol) 5,
acetic acid, 5 h, 490 mg (78%), mp 186 ꢁC (yellow crys-
tals), IR 3424, 1713, 1666, 1592, 1562, MS (EI) 526
(17; M+), 508 (35), 452 (27), 436 (10), 379 (3), 320
(12), 279 (14), 251 (30), 200 (4), 159 (100), 139 (5), 89
(4), 1H NMR (CDCl3) d 15.91 (s, 1H, 7-OH), 8.17
(mc, 1H) and 8.04 (mc, 1H, 8-H, 11-H), 7.78 (mc, 1H)
and 7.62 (mc, 1H, 9-H, 10-H), 7.42 (mc, 3H. arom.
H), 6.33 (d, 1H) and 6.32 (d, 1H, 4-H, 5-H,
J = 10.2 Hz), 5.36 (s, 1H, 3a-OH), 4.66 (s, 2H, CH2–
phe), 3.73 (mc, 2H, O–CH2), 2.13 (s, 3H, 2-CH3), 0.79
(t, 3H, O–C–CH3), UV–vis (MeOH) 227 (4.48), 314
(4.26), 376 (3.87). Anal. Calcd for C27H21Cl2NO6
(477.90): C, 61.61; H, 4.02; N, 2.66. Found: C, 61.12;
H, 3.80; N, 2.59.
5.1.11. 1-(3,3a,6,12a-Tetrahydro-3a,7-dihydroxy-2,3-di-
methyl-6,12-dioxo-naphtho[2,3-d]indol-1-yl)-ethanone
(8Ak). 136 mg (1.2 mmol) 4-methylaminopent-3-en-2-
one 6k, 286 mg (1.2 mmol) 5, acetic acid, 9 h, 195 mg
(46%), mp 167 ꢁC (yellow crystals), IR 3430, 1681,
1640, 1594, 1570, MS (EI) 351 (14; M+), 309 (90), 278
(25), 251 (71), 221 (48), 195 (5), 165 (46), 139 (27), 76
(35), 1H NMR (CDCl3) d 15.75 (s, 1H, 7-OH), 8.22
(mc, 1H) and 7.91 (mc, 1H, 8-H, 11-H), 7.76 (mc, 1H)
and 7.58 (mc, 1H, 9-H, 10-H), 6.26 (d, 1H) and 6.21
(d, 1H, 4-H, 5-H, J = 10.2 Hz), 5.25 (s, 1H, 3a-OH),
3.11 (s, 3H, N–CH3), 2.25 (s, 3H, CH3), 2.05 (s, 3H,
CH3), UV–vis (MeOH) 217 (4.33), 264 (4.05), 309
(4.30), 364 (3.79). Anal. Calcd for C20H17NO5
(351.35): C, 68.37; H, 4.88; N, 3.99. Found: C, 68.22;
H, 4.88; N, 3.79.
5.1.8. 1-(3,3a,6,12a-Tetrahydro-3a,7-dihydroxy-2-methyl-
6,12-dioxo-1-phenyl-naphtho[2,3-d]indol-1-yl)-ethanone (8Ag).
210 mg (1.2 mmol) 4-phenylamino-pent-3-en-2-one 6g,
286 mg (1.2 mmol) 5, acetic acid, 8 h, 330 mg (67%), mp
172 ꢁC (yellow crystals), IR 3440, 1683, 1640, 1593, 1569,
MS (EI) 413 (3; M+), 371 (15), 353 (100), 278 (47), 240 (27),
5.1.12. 1-Cyano-3,3a,6,12-tetrahydro-3a,7-dihydroxy-2-
methyl-6,12-dioxo-naphtho[2,3-d]indol (8Al). 97.5 mg
(1.2 mmol) 3-aminocrotonitrile 6l, 286 mg (1.2 mmol)
5, acetic acid, 5 h, 190 mg (49%), mp 196 ꢁC (yellow
crystals), IR 3430, 2188, 1678, 1650, 1592, 1565, MS
(EI) 320 (21; M+), 302 (100), 273 (52), 240 (55), 190
1
193 (12), 140 (32), 119 (70), 107 (16), 93 (82), H NMR
(CDCl3) d 15.82 (s, 1H, 7-OH), 8.32 (mc, 1H) and 8.06
(mc, 1H, 8-H, 11-H), 7.85 (mc, 1H) and 7.68 (mc, 1H,
9-H, 10-H), 7.53 (mc, 5H, arom. H), 6.37 (d, 1H) and
6.28 (d, 1H, 4-H, 5-H, J = 10.2 Hz), 5.50 (s, 1H, 3a-OH),
2.17 (s, 3H, CH3), 2.13 (s, 1H, CH3), UV–vis (MeOH)
228 (4.53), 309 (4.46). Anal. Calcd for C25H19NO5
(423.42): C, 72.63; H, 4.63; N, 3.39. Found: C, 72.41; H,
4.58; N, 3.24.
1
(44), 174 (16), 136 (41), 95 (44), 76 (53), 53 (70), H
NMR (CDCl3) d 15.83 (s, 1H, 7-OH), 8.15 (mc, 1H)
and 8.02 (mc, 1H, 8-H, 11-H), 7.82 (mc, 1H) and 7.68
(mc, 1h, 9-H, 10-H), 6.45 (s, 1H, NH), 6.28 (d, 1h)
and 6.21 (d, 1H, 4-H, 5-H, J = 10.2 Hz), 4.79 (s, 1H,
3a-OH), 2.02 (s, 3H, 2-CH3), UV–vis (MeOH) 231

L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
3609
(4.47), 286 (4.25), 377 (3.88). Anal. Calcd for
C18H12N2O4 (320.30): C, 67.50; H, 3.78; N, 8.75. Found:
C, 67.09; H, 4.11; N, 8.43.
165.91 (s, COOC2H5), 157.89 (s, C-12), 150.56 (s, C-9),
145.02 (s, C-7), 137.16, 136.90, 136.33, 131.97, 129.32,
129.25, 128.75, 128.72, 128.44, 127.83, 125.65, 125.13
(s), 121.88 (d), 119.98 (s), 119.07 (s, C-8), 61.44 (t,
COOCH2), 48.24 (t, N–CH2), 19.73 (q, 7-CH3), 13.83
(q, O–C–CH3), UV–vis (MeOH) 385 (3.39). Anal. Calcd
for C27H23NO6 (457.48): C, 70.89; H, 5.07; N, 3.06.
Found: C, 70.74; H, 4.96; N, 2.87.
5.1.13. 1,2,3,4,5,5a,8,14-Octahydro-5a,9-dihydroxy-3,3-
dimethyl-5-phenyl-naphtho[2,3-k]carbazole-1,8,14-trione
(11a). 258 mg (1.2 mmol) 5,5-dimethyl-3-phenylamino-
cyclohex-2-enone 10a, 286 mg (1.2 mmol) 5, acetic acid,
24 h, 290 mg (53%), mp 220 ꢁC (yellow crystals from iso-
propanole), IR 3416, 1684, 1629, 1592, 1561, MS (EI)
453 (27; M+), 408 (24), 379 (30), 290 (8), 249 (18), 176
(13), 147 (15), 116 (17), 83 (100), 53 (56), 1H NMR
(CDCl3) d 15.88 (s, 1H, 9-OH), 8.25 (mc, 1H) and 7.96
(mc, 1H, 10-H, 13-H), 7.80 (mc, 1H) and 7.60 (mc,
1H, 11-H, 12-H), 7.42 (mc, 5H, arom. H), 5.45 (s, 1H,
5a-OH), 6.27 (d, 1H) and 6.17 (d, 1H, 6-, 7-H,
J = 10.3 Hz), 2.20 (mc, 2H, 2-CH2), 1.89 (mc, 2H, 4-
CH2), 0.97 (s, 3H, 3-CH3), 0.83 (s, 3H, 3-CH3), UV–
vis (MeOH) 242 (4.39), 317 (4.36), 381 (3.73). Anal.
Calcd for C28H23NO5 (453.49): C, 74.16; H, 5.11; N,
3.09. Found: C, 74.07; H, 5.08; N, 2.86.
5.2.2. Ethyl-6,13-dihydro-9,12-dihydroxy-7-methyl-5,13-
dioxo-6-(4-tolyl)-5H-dibenzo[c,f]azonine-8-carboxylate
(13b). 457 mg (1 mmol) 8Ab), 350 mg (77%), mp
193 ꢁC (yellow crystals), IR 3305, 1724, 1681, 1644,
1588, 1512, MS (EI) 457 (9; M+), 411 (6), 366 (8),
350 (6), 286 (22), 245 (14), 213 (14), 149 (48), 132
1
(100), 91 (42), 44 (68), H NMR (CDCl3) d 11.74 (s,
1H, 12-OH), 7.76 (mc, 1H, arom. H), 7.54 (mc, 2H,
arom. H), 7.11–7.60 (m, 6H, arom. H), 6.96 (d, 1H,
10-H, or 11-H, J = 9.0 Hz), 5.76 (s, 1H, 9-OH), 4.03
(mc, 2H, O–CH2), 2.32 (s, 3H, CH3–tol), 1.92 (s,
3H, 7-CH3), 1.00 (t, 3H, O–C–CH3). Anal. Calcd
for C27H23NO6 (457.48): C, 70.89; H, 5.07; N, 3.06.
Found: C, 70.70; H, 4.74; N, 3.03.
5.1.14. 5-Benzyl-1,2,3,4,5,5a,8,14-octahydro-5a,9-dihy-
droxy-3,3-dimethyl-naphtho[2,3-k]carbazole-1,8,14-trione
(11b). 275 mg (1.2 mmol) 3-benzylamino-5,5-dimethyl-
cyclohex-2-enone 10b, 286 mg (1.2 mmol) 5, acetic acid,
24 h, 295 mg (53%), mp 189 ꢁC (yellow crystals), IR
3420, 1682, 1623, 1592, 1568, MS (EI) 467 (28; M+),
393 (30), 376 (31), 320 (8), 274 (8), 251 (10), 165 (6),
5.2.3. Ethyl-6,13-dihydro-9,12-dihydroxy-6-(4-methoxyb-
enzyl)-7-methyl-5,13-dioxo-5H-dibenzo[c,f]azonine-8-car-
boxylate (13c). 488 mg (1 mmol) 8Ae, 410 mg (84%), mp
184 ꢁC (yellow crystals), IR 3166, 1716, 1632, 1590,
1514, MS (EI) 487 (4; M+), 441 (1), 353 (1), 303 (4),
279 (2), 251 (1), 136 (7), 121 (100), 91 (3), 77 (3), 44
(1), 1H NMR (CDCl3) d 11.57 (s, 1H, 12-OH), 7.72
(mc, 1H, arom. H), 7.48 (mc, 2H, arom. H), 7.12 (mc,
6H, arom. H), 6.82 (d, 1H, J = 8.5 Hz), 4.84 (d, 1H)
and 4.12 (d, 1H, CH2–phe, J = 14.6 Hz), 4.81 (s, 1H,
9-OH), 3.99 (mc, 2H, O–CH2), 3.81 (s, 3H, OCH3),
1.76 (s, 3H, 7-CH3), 1.05 (t, 3H, O–C–CH3), UV–vis
(MeOH) 397 (3.47). Anal. Calcd for C28H25NO7
(487.50): C, 68.98; H, 5.17; N, 2.87. Found: C, 68.72;
H, 4.92; N, 2.74.
1
139 (6), 83 (100), 44 (7), H NMR (CDCl3) d 15.90 (s,
1H, 9-OH), 8.23 (mc, 1H) and 7.98 (mc, 1H, 10-H, 13-
H), 7.78 (mc, 1H) and 7.59 (mc, 1H, 11-H, 12-H), 7.41
(mc, 5H, arom. H), 6.28 (d, 1H) and 6.23 (d, 1H, 6-H,
7-H, J = 10.5 Hz), 6.25 (s, 1H, 5a-OH), 4.84 (d, 1H)
and 4.58 (d, 1H, CH2–phe, J = 16.7 Hz), 2.00 (mc, 4H,
2-CH2, 4-CH2), 0.92 (s, 3H, 3-CH3), 0.80 (s, 3H, 3-
CH3), UV–vis (MeOH) 231 (4.34), 304 (4.25), 366
(3.71). Anal. Calcd for C29H25NO5 (467.52): C, 74.50;
H, 5.39; N, 3.00. Found: C, 74.26; H, 5.68; N, 2.82.
5.2. General procedure for the preparation of 6,13-
dihydro-9,12-dihydroxy-7-methyl-5,13-dioxo-5H-di-
benzo[c,f]azonine-8-carboxylates (13)
5.2.4.
Ethyl-6-(4-chlorphenyl)-6,13-dihydro-9,12-dihy-
droxy-7-methyl-5,13-dioxo-5H-dibenzo[c,f]azonine-8-car-
boxylate (13d). 478 mg (1 mmol) 8Ad, 400 mg (84%), mp
215 ꢁC (yellow crystals), IR 3384, 1719, 1684, 1646,
1589, 1492, MS (EI) 477 (6; M+), 387 (14), 358 (9),
305 (38), 249 (16), 152 (100), 111 (32), 75 (34), 44 (15),
1H NMR (CDCl3) d 11.71 (s, 1H, 12-OH), 7.77 (mc,
1H, arom. H), 7.57 (mc, 2H, arom. H), 7.23–7.41 (m,
5H, arom. H), 7.10 (d, 1H) and 6.96 (d, 1H, 10-H, 11-
H, J = 9.1 Hz), 5.88 (s, 1H, 9-OH), 4.04 (mc 2H, O–
CH2), 1.93 (s, 3H, 7-CH3), 1.10 (t, 3H, O–C–CH3).
Anal. Calcd for C26H20ClNO6 (477.90): C, 65.35; H,
4.22; N, 2.93. Found: C, 65.16; H, 4.32; N, 2.85.
Ethyl
3,3a,6,12-tetrahydro-3a,7-dihydroxy-2-methyl-
6,12-dioxo-naphtho[2,3-d]indol-1-carboxylates 8A were
dissolved in 250 ml of 3.5 N methanolic HCl at room
temperature for 1 h and then diluted with 250 ml of
water. The precipitate was collected, dried, and recrys-
tallized from dichloromethane/hexanes (35:65).
5.2.1.
Ethyl-6-benzyl-6,13-dihydro-9,12-dihydroxy-7-
methyl-5,13-dioxo-5H-dibenzo[c,f]azonine-8-carboxylate
(13a). 457 mg (1 mmol) 8Aa, 400 mg (88%), mp 188 ꢁC
(yellow crystals), IR 3208, 1716, 1624, 1590, MS (EI)
457 (19; M+), 411 (20), 356 (12), 320 (9), 279 (14), 251
5.2.5. Crystal structure determination of compound 13d ·.
C3H6O.18 Only relatively weak diffracting crystals of
limited quality were available. Some were selected by
means of a polarization microscope and investigated
on a Stoe Imaging Plate Diffraction System using graph-
1
(22), 223 (1), 132 (2), 106 (21), 91 (100), 45 (25), H
NMR (CDCl3) d 10.87 (s, 1H, 12-OH), 8.23 (s, 1H, 9-
OH), 7.26–7.84 (m, 9H, arom. H), 7.17 (d, 1H) and
6.92 (d, 1H, 10-H, 11-H, J = 9.0 Hz), 4.92 (d, 1H) and
4.18 (d, 1H, CH2–phe, J = 15 Hz), 3.95 (mc, 2H, O–
CH2), 1.93 (s, 3H, 7-CH3), 1.02 (t, 3H, O–C–CH3),
13C NMR (CDCl3) d 198.33 (s, C-13), 169.03 (s, C-5),
˚
ite monochromatized Mo Ka radiation (k = 0.71073 A).
Unit cell parameters were determined by a least-squares
refinement on the positions of 8000 reflections, distribut-
ed equally in reciprocal space. An anorthic lattice was

3610
L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
found compatible with space groups P1 and P1. The lat-
ter was confirmed in the course of the structure refine-
ment. Crystal data: Mr (C29H26ClNO7) = 535.96,
MS (EI) 541 (23; M+), 499 (16), 457 (16), 411 (2), 350
(3), 305 (2), 251 (2), 132 (100), 91 (20), 43 (15), 1H
NMR (CDCl3) d 8.18 (mc, 1H, arom. H), 7.57 (mc,
2H, arom. H), 7.13–7.36 (m, 7H, arom. H), 4.00 (mc,
2H, O–CH2), 2.33 (s, 3H, CH3–tol), 2.24 (s, 3H,
CH3CO), 2.24 (s, 3H, CH3CO), 2.00 (s, 3H, 7-CH3),
1.07 (t, 3H, O–C–CH3). Anal. Calcd for C31H27NO8
(541.55): C, 68.75; H, 5.03; N, 2.59. Found: C, 68.63;
H, 4.71; N, 2.57.
˚
˚
˚
a = 8.3481(7) A, b = 11.3715(11) A, c = 13.6753(13) A,
a = 87.145(11)ꢁ, b = 88.903(11)ꢁ, c = 89.437(11),
V = 1296.3(2) A , Z = 2, Dx = 1.373 g cmꢁ3
l =
3
˚
,
0.197 mmꢁ1, T = 291 K, yellow crystal of dimensions
0.7 mm · 0.25 mm · 0.15 mm. 18866 intensity data
(Hmin = 2.39ꢁ, Hmax = 26.11ꢁ) were collected and Lp
corrections were applied. The structure was solved by di-
rect methods,19 and approximate positions of all but the
hydrogen atoms of the solvent acetone molecule were
found via difference Fourier syntheses. Refinement
(401 parameters, all of 4799 unique reflections used, five
restraints idealizing acetone geometry) by full-matrix
least-squares calculations on F,2,20 converged to the
5.3.3. Ethyl-9,12-diacetoxy-6,13-dihydro-6-(4-methoxy-
benzyl)-7-methyl-5,13-dioxo-5H-dibenzo[c,f]azonine-8-
carboxylate (14c). 488 mg (1 mmol) 13c, 350 mg (61%),
mp 208 ꢁC (white powder), IR 3070, 1774, 1719, 1661,
1592, 1514, MS (EI) 571 (1; M+), 512 (1), 455 (2), 395
(18), 352 (27), 321 (12), 279 (18), 178 (3), 121 (100), 43
1
following final indicators: R1½F 2o > 2rðF o2Þꢂ ¼ 0:050,
(23), H NMR (CDCl3) d 8.15 (m, 1H, arom. H), 7.52
2
wR2 = 0.100 (all data), w ¼ 1=½r2ðF o2Þ þ ð0:007PÞ þ
(mc, 2H, arom. H), 7.25 (m, 5H, arom. H), 6.87 (mc,
2H, 10-H, 11-H), 5.06 (d, 1H) and 3.67 (d, 1H, CH2–
phe, J = 14.5 Hz), 4.00 (mc, 2H, O–CH2), 3.81 (s, 3H,
O–CH3), 2.28 (s, 3H, CH3CO), 2.20 (s, 3H, CH3CO),
1.72 (s, 3H, 7-CH3), 1.08 (t, 3H, O–C–CH3). Anal.
Calcd for C32H29NO9 (571.58): C, 67.24; H, 5.11; N,
2.45. Found: C, 67.09; H, 4.98; N, 2.31.
1:0Pꢂ where P ¼ ðF o2 þ 2F 2cÞ=3, S = 1.033,20 and largest
peak and hole in the final difference map are 0.400 e/
2
3
˚
˚
A and ꢁ0.313 e/A , respectively. Anisotropic displace-
ment parameters were used for all non-hydrogen atoms.
Individual isotropic displacement parameters were re-
fined for all H atoms with the exception of methyl group
hydrogen atoms of the acetone molecule, The isotropic
displacement parameters of these H atoms were kept
equal to 150% of the equivalent isotropic displacement
parameters of the parent primary carbon atom. Individ-
ual coordinates were refined for all but the H atoms of
methyl groups that were allowed ride on their parent
carbon atom and to move collectively around the neigh-
boring C–C axis. For the methyl groups of 13d itself also
the C–H distances were allowed to vary, the same shifts
being applied along the three C–H bonds of a group.
5.4. General procedure for the preparation of ethyl-
6,9,12,13-tetrahydro-7-methyl-5,9,12,13-tetraoxo-5H-
dibenzo[c,f]azonine-8-carboxylates (15)
Ethyl-6,13-dihydro-9,12-dihydroxy-7-methyl-5,13-dioxo-
5H-dibenzo[c,f]azonine-8-carboxylates (13) were dis-
solved in 250 ml of diethyl ether. Anhydrous sodium sul-
fate and silver(I)oxide were then added and the reaction
mixture was stirred for 2 h at room temperature. After
filtration and concentration in vacuo, quinones 15 were
obtained and recrystallized from diethyl ether.
5.3. General procedure for the synthesis of ethyl-9,12-
diacetoxy-7-methyl-5,13-dioxo-6,13-tetrahydro-5H-
dibenzo[c,f]azonine-8-carboxylates (14)
5.4.1.
Ethyl-6-benzyl-6,9,12,13-tetrahydro-7-methyl-
5,9,12,13-tetraoxo-5H-dibenzo[c,f]azonine-8-carboxylate
(15a). 457 mg (1 mmol) 13a, 1.4 g sodium sulfate, 4.1 g
silver(I)oxide, 320 mg (70%), mp 144 ꢁC (yellow pow-
der), IR 1724, 1678, 1666, 1592, MS (EI) 455 (1; M+),
411 (4), 382 (2), 364 (3), 322 (31), 250 (30), 204 (1),
Ethyl-6,13-dihydro-9,12-dihydroxy-7-methyl-5,13-dioxo-
5H-dibenzo[c,f]azonine-8-carboxylates (13) were heated
for 90 min in acetic anhydride (10 ml) with catalytic
amounts of pyridine under reflux followed by evapora-
tion and recrystallization from water/methanol (60:40).
1
133 (6), 106 (4), 91 (100), 43 (2), H NMR (CDCl3) d
8.20 (mc, 1H, 1-H), 7.60 (mc, 2H, arom. H), 7.30 (mc,
6H, arom. H), 6.75 (d, 1H) and 6.86 (d, 1H, 10-H and
11-H, J = 10.2 Hz), 4.10 (d, 1H) and 5.00 (d, 1H,
CH2–Phe, J = 14.8 Hz), 4.05 (q, 2H, O–CH2), 1.11 (t,
3H, O–C–CH3), UV–vis (MeOH) 231 (4.35). Anal.
Calcd for C27H21NO6 (455.46): C, 71.20; H, 4.65; N,
3.08. Found: C, 71.04; H, 4.90; N, 2.92.
5.3.1.
Ethyl-9,12-diacetoxy-6-benzyl-7-methyl-5,13-
dioxo-6,13-tetrahydro-5H-dibenzo[c,f]azonine-8-carbox-
ylate (14a). 457 mg (1 mmol) 13a, 350 mg (65%), mp
142 ꢁC (white powder), IR 3064, 1770, 1719, 1661,
1593, MS (EI) 542 (21; M++H), 500 (11), 434 (4), 392
(6), 352 (10), 304 (6), 279 (6), 253 (6), 136 (16), 91
1
(100), 77 (21), H NMR (CDCl3) d 8.24 (mc, 1H, arom.
H), 7.61 (mc, 2H, arom. H), 7.38 (mc, 8H, arom. H),
5.19 (d, 1H) and 3.84 (d, 1H, CH2–phe, J = 15.0 Hz),
4.05 (mc, 2H, O–CH2), 2.36 (s, 3H, CH3CO), 2.35 (s,
3H, CH3CO), 1.82 (s, 3H, 7-CH3), 1.16 (t, 3H, O–C–
CH3). Anal. Calcd for C31H27NO8 (541.55): C, 68.75;
H, 5.03; N, 2.59. Found: C, 68.58; H, 5.04; N, 2.52.
5.4.2. Ethyl-6,9,12,13-tetrahydro-7-methyl-5,9,12,13-tet-
raoxo-6-(4-tolyl)-5H-dibenzo[c,f]azonine-8-carboxylate
(15b). 457 mg (1 mmol) 13b, 1.4 g sodium sulfate, 4.1 g
silver(I)oxide, 315 mg (69%), mp 131 ꢁC (yellow pow-
der), IR 1724, 1682, 1590, MS (EI) 455 (47; M+), 411
(8), 382 (12), 322 (9), 249 (56), 165 (9), 132 (100), 91
1
(43), 65 (9), 44 (6) H NMR (CDCl3) d 8.25 (mc, 1H,
5.3.2. Ethyl-9,12-diacetoxy-6,13-dihydro-7-methyl-5,13-
dioxo-6-(4-tolyl)-5H-dibenzo[c,f]azonine-8-carboxylate
(14b). 45 mg (1 mmol) 13b, 340 mg (63%), mp 208 ꢁC
(white powder), IR 3060, 1775, 1718, 1676, 1590, 1510,
1-H), 7.64 (mc. 2H, arom. H), 7.27 (mc, 5H, arom.
H), 6.81 (‘s,’ 2H, 10-H and 11-H), 4.09 (m, 2H, O–
CH2), 2.34 (s, 3H, CH3), 2.11 (s, 3H, CH3), 1.15 (t,
3H, O–C–CH3). Anal. Calcd for C27H21NO6 (455.46):

L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
3611
C, 71.20; H, 4.65; N, 3.08. Found: C, 71.03; H, 4.56; N,
3.01.
(mc, 2H, O–CH2), 3.80 (s, 3H, OCH3), 2.71 (s, 3H, 2-
CH3), 1.72 (s, 3H, 7-CH3), 1.44 (t, 3H, O–C–CH3),
1.07 (t, 3H, O–C–CH3). Anal. Calcd for C34H31NO9
(597.62): C, 68.33; H, 5.23; N, 2.34. Found: C, 68.54;
H, 4.98; N, 2.37.
5.4.3.
Ethyl-6,9,12,13-tetrahydro-7-methyl-6-(4-meth-
oxybenzyl)-5,9,12,13-tetraoxo-5H-dibenzo[c,f]azonine-8-
carboxylate (15c). 488 mg (1 mmol) 13c, 1.4 g sodium
sulfate, 4.4 g silver(I)oxide, 310 mg (64%), mp 128 ꢁC
(yellow powder), IR 1722, 1677, 1666, 1591, MS (EI)
485 (2; M+), 398 (1), 353 (1), 277 (1), 249 (4), 191 (2),
5.4.7.
3-Acetyl-3a-chloro-3a,11b-dihydro-5,11b-dihy-
droxy-2-methyl-1-phenyl-naphtho[2,3-g]indol-6,11-dione
(20a). 210 mg (1.2 mmol) 4-phenylaminopent-3-en-2-
one 6g, 286 mg (1.2 mmol) 2-chloro-1,4,9,10-anthradiq-
uinone 19, acetic acid, 5 h, 41.0 mg (8%), mp 139 ꢁC
(yellow crystals), IR 3420, 1663, 1684,1592, 1564, MS
447 (28; M+), 405 (19), 371 (10), 314 (7), 274 (14), 240
1
121 (100), 77 (6), 44 (3). H NMR (CDCl3) d 8.19 (m,
1H, 1-H), 7.57 (mc, 2H, arom. H), 7.26 (mc, 3H, arom.
H), 6.86 (mc, 2H, arom. H), 6.73 (d, 1H) and 6.88 (d,
1H, 10-H, 11-H, J = 10.2 Hz), 4.94 (d, 1H) and 4.08 (d,
1H, –CH2–phe, J = 14.5 Hz), 4.05 (mc, 2H, O–CH2),
3.82 (s, 3H, OCH3), 2.03 (s, 3H, 7-CH3), 1.10 (t, 3H,
O–C–CH3). Anal. Calcd from C28H23NO7 (485.49):
C, 69.27; H, 4.78; N, 2.89. Found: C, 69.01; H, 4.99; N,
2.88.
1
(11), 175 (5), 133 (9), 118 (100), 77 (60), 44 (21), H
NMR (CDCl3) d 15.49 (s, 1H, 5-OH), 8.23 (mc, 1H)
and 7.97 (mc, 1H, 7-H, 10-H), 7.80 (mc, 1H, arom.
H), 7.66–7.36 (m, 6H, arom. H), 6.45 (s, 1H, 4-H),
5.29 (s, 1H, 11b-OH), 2.11 (s, 3H, CH3), 2.06 (s, 3H,
CH3), 13C NMR (CDCl3) d 198.60 (s, C@O (carbonyl)),
190.04 (s, C@O (carbonyl)), 178.51 (s, C@O (carbonyl)),
172.30 (s, C-2), 158.61 (s, br, C-5, C–OH), 135.09,
134.80, 133.14, 132.87, 132.79, 132.42, 132.16, 131.47,
131.12, 126.68, 126.54, 125.66, 125.39, 124.26, 116.37,
102.53 (s, C-3), 93.62 (s, C-11b, C–OH), 61.69 (s, C-
5.4.4.
Ethyl-6-(4-chlorphenyl)-6,9,12,13-tetrahydro-7-
methyl-5,9,12,13-tetraoxo-5H-dibenzo[c,f]azonine-8-car-
boxylate (15d). 478 mg (1 mmol) 13d, 1.4 g sodium sul-
fate, 4.3 g silver(I)oxide, 350 mg (74%), mp 160 ꢁC, IR
1724, 1683, 1669, 1590, MS (EI) 475 (5; M+), 402 (12),
348 (13), 322 (14), 249 (98), 165 (18), 152 (100), 104
1
3a), 30.08 (q, CH3, JC/H = 127.5 Hz), 16.37 (q, CH3,
1
(21), 75 (18), 44 (16), H NMR (CDCl3) d 8.26 (mc.,
1JC/H = 130.1 Hz). Anal. Calcd for C25H18ClNO5
(447.87): C, 67.04; H, 4.05; N, 3.13. Found: C, 66.77;
H, 3.78; N, 3.05.
1H, 1-H), 7.66 (mc, 2H, arom. H), 7.31 (mc, 5H, arom.
H), 6.82 (d, 1H) and 6.84 (d, 1H, 10-H, 11-H,
J = 10.2 Hz), 4.10 (m, 2H, O–CH2), 2.11 (s, 3H, 7-
CH3), 1.15 (t, 3H, O–C–CH3). Anal. Calcd for
C26H18ClNO6 (475.88): C, 65.62; H, 3.81; N, 2.94.
Found: C, 65.52; H, 3.78; N, 2.86.
5.4.8.
3-Acetyl-3a-chloro-3a,11b-dihydro-5,11b-dihy-
droxy-2-methyl-1-(4-tolyl)-naphtho[2,3-g]indol-6,11-dione
(20b). 210 mg (1.2 mmol) 4-(4-tolylamino)pent-3-en-2-
one 6i, 286 mg (1.2 mmol) 2-chloro-1,4,9,10-anthradiq-
uinone 19, acetic acid, 5 h, 38 mg (7%), mp 223 ꢁC (yel-
low crystals), IR 3269, 1693, 1644, 1585, 1511, MS (EI)
462 (9; M+), 418 (2), 374 (1), 307 (14), 289 (11), 242 (2),
5.4.5.
Diethyl-8-benzyl-9,14-dihydro-5-hydroxy-2,7-di-
methyl-9,14-dioxo-8-H-benzo[c]benzo[b]furo[6,7-f]azonine-
3,6-dicarboxylate (17a). 455mg (1 mmol) 15a, 250 mg
1
(1 mmol)
ethyl-3-(4-methoxy-benzylamino)crotonate
176 (15), 154 (100), 77 (54), H NMR (CDCl3) d 10.14
6e, acetic acid, 8 h, 356 mg (63%), mp 211 ꢁC (white
powder from dichloromethane/hexane), IR 3403, 1716,
1674, 1662, 1592, MS (EI) 567 (12; M+), 521 (16), 476
(9), 414 (14), 389 (8), 307 (7), 176 (12), 154 (71), 136
(s, 1H, 5-OH), 9.64 (s, 1H, 11b-OH), 8.06 (mc, 1H)
and 7.77 (mc, 1H, 7-H, 10-H), 7.60 (mc, 2H, 8-H, 9-
H), 7.38–7.17 (m, 4H, arom. H), 7.06 (s, 1H, 4-H),
2.31 (s, 3H, CH3–tol), 1.92 (s, 3H, CH3), 1.78 (s, 3H,
CH3). Anal. Calcd for C26H20ClNO5 (461.90): C,
67.61; H, 4.36; N, 3.03. Found: C, 67.42; H, 3.67; N,
2.91.
1
(58), 91 (100), 65 (13), H NMR (CDCl3) d 8.23 (mc,
1H, 13-H), 7.69 (s, 1H, 4-H), 7.58 (mc, 2H, arom. H),
7.30 (mc, 6H, arom. H), 6.09 (s, 1H, OH), 5.01 (d,
1H) and 3.84 (d, 1H, CH2–phe, J = 14.7 Hz), 4. 42 (q,
2H, O–CH2), 4.08 (mc, 2H, O–CH2), 2.74 (s, 3H, 2-
CH3), 1.71 (s, 3H, 7-CH3), 1.46 (t, 3H, O–C–CH3),
1.11 (t, 3H, O–C–CH3). Anal. Calcd for C33H29NO8
(567.59): C, 69.83; H, 5.15; N, 2.47. Found: C, 69.76;
H, 5.25; N, 2.36.
5.4.9. 12-Benzyl-7-chloro-7,8,9,10,11,12,12a,13-octahy-
dro-6,12a-dihydroxy-10,10-dimethyl-5H-naphtho[2,3-a]car-
bazol-5,8,13-trione (24). 210 mg (1.2 mmol) 3-benzyl-
amino-5,5-dimethylcyclohex-2-enone
10b,
286 mg
(1.2 mmol) 2-chloro-1,4,9,10-anthradiquinone 19, acetic
acid, 5 h, 180 mg (30%), mp 209 ꢁC (yellow crystals), IR
3416, 1682, 1625, 1590, 1566, MS (EI) 501 (25; M+), 467
(13), 410 (17), 374 (7), 336 (2), 290 (2), 249 (5), 83 (100),
5.4.6. Diethyl-9,14-dihydro-5-hydroxy-8-(4-methoxyben-
zyl)-2,7-dimethyl-9,14-dioxo-8-H-benzo[c][1]-benzofuro[6,7-
f]azonine-3,6-dicarboxylate (17b). 485mg (1 mmol) 15c,
250 mg (1 mmol) ethyl-3-(4-methoxy-benzylamino)crot-
onate 6e, acetic acid, 8 h, 315 mg (53%), mp 156 ꢁC,
IR 3297, 1715, 1660, 1642, 1592, MS (EI) 597 (1; M+),
551 (1), 462 (6), 414 (43), 389 (81), 361 (12), 149 (4),
121 (100), 91 (5), 45 (9), 1H NMR (CDCl3) d 8.22
(mc, 1H, 13-H), 7.70 (s, 1H, 4-H), 7.55 (mc, 2H, arom.
H), 7.24 (mc, 3H, arom. H), 6.84 (mc, 2H, arom. H),
6.50 (s, 1H, 5-OH), 3. 78 (d, 1H) and 4.96 (d, 1H,
CH2–phe, J = 14.5 Hz), 4.40 (q, 2H, O–CH2), 4.11
1
55 (9), H NMR (CDCl3) d 15.71 (s, 1H, 5-OH), 8.22
(mc, 1H) and 7.97 (mc, 1H, 7-H, 10-H), 7.82 (mc, 1H)
and 7.62 (mc, 1H, 8-H, 9-H), 7.57–7.32 (m, 5H, arom.
H), 6.50 (s, 1H, 4-H), 6.19 (s, 1H, 12b-OH), 4.83 (d,
1H) and 4.60 (d, 1H, CH2–phe, J = 16.6 Hz), 2.18 (mc,
4H, 2· CH2), 0.94 (s, 3H, CH3), 0.79 (s, 3H, CH3),
UV–vis (MeOH) 232 (3.99), 258 (3.94), 323 (3.86), 387
(3.45). Anal. Calcd for C29H24ClNO5 (501.96): C,
69.39; H, 4.82; N, 2.79. Found: C, 69.27; H, 4.79; N,
2.79.

3612
L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
5.4.10.
Ethyl-1-benzyl-5-hydroxy-2-methyl-1H-naph-
1,4-anthraquinone 25, acetic acid, 20 h, 210 mg (46%),
mp 282 ꢁC, IR 3254, 1658, 1584, 1519, MS (EI) 375
(100; M+), 346 (8), 290 (16), 259 (13), 216 (10), 189
(5), 149 (4), 119 (2), 57 (6), 41 (9), 1H NMR
(DMSO-d6) d 10.01 (s, 1H, OH), 8.87 (s, 1H) and
8.74 (s, 1H, 6-H, 11-H), 8.12 (mc, 2H, 7-H, 10-H),
7.67 (s, 1H, 4-H), 7.50 (mc, 2H, 8-H, 9-H), 4.52 (br,
2H, CH2–isobu), 4.31 (q, 2H, O–CH2), 2.77 (s, 3H,
2-CH3), 2.28 (m, 1H, CH–isobu), 1.40 (t, 3H, O–C–
CH3), 0.94 (‘s,’ 6H, (CH3)2–isobu), UV–vis (MeOH)
291 (4.22). Anal. Calcd for C24H25NO3 (375.46): C,
76.77; H, 6.71; N, 3.73. Found: C, 76.54; H, 6.71; N,
3.72.
tho[2,3-g]indol-3-carboxylate (26a). 263 mg (1.2 mmol)
ethyl-3-benzylaminocrotonate 6a, 250 mg (1.2 mmol)
1,4-anthraquinone 25, acetic acid, 36 h, 180 mg (37%),
mp 263 ꢁC, IR 3272, 1654, 1584, 1521, MS (EI) 409
(100; M+), 364 (11), 318 (19), 290 (32), 272 (17), 216
(16), 152 (12), 91 (14), 49 (11), 44 (11) 1H NMR
(DMSO-d6) d 10.03 (s, 1H, OH), 8.81 (s, 1H, 6-H),
8.06 (m, 1H) and 7.80 (m, 1H, 7-H, 10-H), 7.71 (s, 1H,
4-H), 7.43 (mc, 2H, 8-H, 9-H), 7.26 (m, 5H, arom. H),
6.04 (s, 2H, CH2–phe), 4.36, (q, 2H, O–CH2), 2.80 (s,
3H, 2-CH3), 1.43 (t, 3H, O–C–CH3). Anal. Calcd for
C27H23NO3 (409.48): C, 79.20; H, 5.66; N, 3.42. Found:
C, 78.97; H, 5.81; N, 3.27.
5.4.15. Ethyl-5-hydroxy-1-(4-methoxyphenyl)-2-phenyl-
1H-naphtho[2,3-g]indol-3-carboxylate (26n). 356 mg
(1.2 mmol) ethyl-3-(4-methoxyphenylamino)cinnamate
6n, 250 mg (1.2 mmol) 1,4-anthraquinone 25, acetic
acid, 36 h, 270 mg (46%), mp 282 ꢁC, IR 3244, 1650,
1584, 151, MS (EI) 487 (100; M+), 459 (10), 414
(3), 341 (6), 221 (5), 170 (22), 149 (36), 91(16), 57
(40), 43 (80), 1H NMR (DMSO-d6): d 10.18 (s, 1H,
OH), 8.86 (s, 1H, 6-H), 8.09 (m, 1H, arom. H), 7.76
(s, 1H, 4-H), 7.25 (mc, 13H, arom. H), 4.07 (q, 2H,
O–CH2), 3.85 (s, 3H, O–CH3), 1.03 (t, 3H, O–C–
CH3). Anal. Calcd for C32H25NO4 (487.55): C,
78.83; H, 5.17; N, 2.87. Found: C, 78.75; H, 5.12;
N, 2.65.
5.4.11. Ethyl-5-hydroxy-2-methyl-1-(4-tolyl)-1H-naph-
tho[2,3-g]indol-3-carboxylate (26b). 263 mg (1.2 mmol)
ethyl-3-(4-tolylamino)crotonate 6b, 250 mg (1.2 mmol)
1,4-anthraquinone 25, acetic acid, 36 h, 185 mg (38%),
mp 251 ꢁC, IR 3304, 1662, 1621, 1514, MS (EI) 409
(100; M+), 381 (34), 320 (16), 291 (16), 245 (14), 182
(21), 149 (10), 91 (10), 57 (10), 43 (10), 1H NMR
(DMSO-d6) d 10.06 (s, 1H, OH), 8.81 (s, 1H, 6-H), 8.06
(m, 1H, 7-H), 7.69 (s, 1H, 4-H), 7.42 (mc, 8H, arom.
H), 4.36 (q, 2H, O–CH2), 2.59 (s, 3H, 2-CH3), 2.46 (s,
3H, CH3), 1.41 (t, 3H, O–C–CH3). Anal. Calcd for
C27H23NO3 (409.48): C, 79.20; H, 5.66; N, 3.42. Found:
C, 79.07; H, 5.37; N, 3.21.
5.4.12. Ethyl-5-hydroxy-1-(4-methoxyphenyl)-2-methyl-
1H-naphtho[2,3-g]indol-3-carboxylate (26c). 282 mg
(1.2 mmol) ethyl-3-(4-methoxyphenylamino)crotonate
6c, 250 mg (1.2 mmol) 1,4-anthraquinone 25, acetic acid,
36 h, 150 mg (29%), mp 263 ꢁC, IR 3236, 1664, 1619,
1512, MS (EI) 425 (100; M+), 397 (26), 380 (7), 352
(7), 320 (8), 308 (7), 190 (9), 140 (6), 126 (4), 43 (12),
1H NMR (DMSO-d6) d 10.06 (s, 1H, OH), 8.82 (s,
1H, 6-H), 8.06 (m, 1H, arom. H), 7.70 (s, 1H, 4-H),
7.45 (mc, 8H, arom. H), 4.35 (q, 2H, O–CH2), 3.98 (s,
3H, OCH3), 2.46 (s, 3H, 2-CH3), 1.41 (t, 3H, O–C–
CH3), UV–vis (MeOH) 289 (4.36). Anal. Calcd for
C27H23NO4 (425.48): C, 76.22; H, 5.45; N, 3.29. Found:
C, 75.97; H, 5.72; N, 3.12.
5.4.16.
Ethyl-5-hydroxy-1,2-dimethyl-1H-naphtho[2,3-
g]indol-3-carboxylate (26o). 172 mg (1.2 mmol) ethyl-3-
methylaminocrotonate 6o, 250 mg (1.2 mmol) 1,4-an-
thraquinone 25, acetic acid, 36 h, 180 mg (45%), mp
286 ꢁC, IR 3257, 1643, 1582, 1518, MS (EI) 333 (100;
M+), 304 (54), 259 (12), 231 (8), 216 (7), 152 (5), 144
1
(7), 95(3), 44 (4) H NMR (DMSO-d6) d 9.96 (s, 1H,
OH), 9.06 (s, 1H) and 8.86 (s, 1H, 6-H, 11-H), 8.15
(mc, 2H, 7-H, 10-H), 7.65 (s, 1H, 4-H), 7.50 (mc, 2H,
8-H, 9-H), 4.28 (m, 5H, O–CH2, N–CH3), 2.77 (s, 3H,
2-CH3), 1.41 (t, 3H, O–C–CH3). Anal. Calcd for
C21H19NO3 (333.38): C, 75.66; H, 5.74; N, 4.20. Found:
C, 75.40; H, 5.79; N, 4.23.
5.4.17. Diethyl-4,40,5,50-tetrahydro-1,10-diisobutyl-2,20-
dimethyl-5,50-dioxo-1H,10H-4,40binaphtho[2,3-g]indol-
3,30-dicarboxylate (28). 250 mg (0.67 mmol) of 26m was
dissolved in 15 ml of acetone and treated with 9 g of sil-
ver(I)oxide and 3 g of anhydrous sodium sulfate for 2 h
at 40 ꢁC. Recrystallization after evaporation in vacuo
afforded 28. 120 mg (48%), mp 276 ꢁC (from dichlorme-
thane/hexane (70:30)), IR 1694, 1598, 1515, MS (EI)
748 (7; M+), 703 (2), 629 (3), 570(1), 397 (15), 374
(100), 330 (9), 307 (13), 290 (12), 272 (11), 230 (6),
1H NMR (CDCl3) d 8.00 (s, 2H, 6-H, 60-H), 7.77
(mc, 4H, 7-H, 70-H, 10-H, 100-H), 7.53 (m, 4H, 8-H,
80-H, 9-H, 90-H), 7.43 (s, 2H, 11-H, 110-H), 4.84 (s,
2H, 4-H, 40-H), 4.10 (m, 2H, O–CH2), 4.30 (m, 2H,
OCH2), 3.70 and 3.40 (m, 4H, 2· CH2–isobut), 2.36
(s, 6H, 2· 2-CH3), 1.83 (m, 2H, 2· CH–isobu), 1.42
(t, 6H, 2· O–C–CH3), 0.80 and 0.65 (d, 6H, (CH3)2–
isobu, J = 6.6 Hz). Anal. Calcd for C48H48N2O6
(748.91): C, 76.98; H, 6.46; N, 3.74. Found: C, 76.75;
H, 6.60; N, 3.70.
5.4.13. Ethyl-5-hydroxy-1-(4-methoxybenzyl)-2-methyl-
1H-naphtho[2,3-g]indol-3-carboxylate (26e). 248 mg
(1.2 mmol) ethyl-3-(4-methoxybenzylamino)crotonate
6e, 250 mg (1.2 mmol) 1,4-anthraquinone 25, acetic acid,
36 h, 260 mg (49%), mp 199 ꢁC, IR 3272, 1666, 1584,
1513, MS (EI) 439 (36; M+), 394 (1), 318 (2), 290 (4),
272 (6), 216 (5), 189 (4), 152 (5), 121 (100), 91 (5), 44
1
(10), H NMR (DMSO-d6): d 10.04 (s, 1H, OH), 8.83
(s, 1H) and 8.69 (s, 1H, 6-H, 11-H), 8.07 (mc, 1H) and
7.84 (mc, 1H, 7-H, 10-H), 7.72 (s, 1H, 4-H), 7. 46 (mc,
2H, 8-H, 9-H), 6.98 (mc, 4H, arom. H), 5.94 (s, 2H,
CH2–phe), 4.36 (q, 2H, O–CH2), 3.64 (s, 3H, OCH3),
2.79 (s, 3H, 2-CH3), 1.44 (t, 3H, O–C–CH3). Anal.
Calcd for C28H25NO4 (439.51) C, 76.52; H, 5.73; N,
3.19. Found: C, 76.46; H, 5.49; N, 3.10.
5.4.14. Ethyl-5-hydroxy-1-isobutyl-2-methyl-1-H-naph-
tho[2,3-g]indol-3-carboxylate (26m). 221 mg (1.2 mmol)
ethyl-3-isobutylaminocrotonate 6m, 250 mg (1.2 mmol)

L. W. Schenck et al. / Bioorg. Med. Chem. 14 (2006) 3599–3614
3613
5.5. General procedure for the preparation of ethyl-4-
[(dimethylamino)methyl]-5-hydroxy-2-methyl-1H-naph-
tho[2,3-g]indol-3-carboxylates (29)
5.6.2.
Spiro[ethyl-4,5-dihydro-1-(4-methoxyphenyl)-5-
oxo-2-phenyl-1H-naphtho[2,3-g]indol-3-carboxylat-4,20-ethyl-
20,30,40,70-tetrahydro-70-(40-methoxyphenyl)-60-phenyl-naph-
tho[20,30-g]pyrano[30,20-e]indol-50-carboxylate (31b). 544 mg
(1.0 mmol) 29b, 160 mg (32%), mp 300 ꢁC, IR 3051, 1703,
1622, 1519, MS (EI) 499 (100), 455 (8), 426 (8), 383 (4), 354
(6), 306 (2), 252 (2), 235 (7), 177 (2), 109 (1), 77 (1), 44 (4).
Anal. Calcd for C66H50N2O8 (999.13): C, 79.18; H, 5.04;
N, 2.80. Found: C, 78.73; H, 4.98; N, 2.81.
Ethyl-5-hydroxy-2-phenyl-1H-naphtho[2,3-g]indol-3-
carboxylates 26 were heated in bisdimethylaminome-
thane (2 ml) with catalytic amounts of acetic acid
(2 ml) under reflux for 2 h. After evaporation in vacuo,
the obtained residue was recrystallized from dichloro-
methane/hexanes (40:60).
5.6.3.
Spiro[ethyl-4,5-dihydro-1,2-dimethyl-5-oxo-1H-
5.5.1. Ethyl-4-[(dimethylamino)methyl]-5-hydroxy-1-iso-
butyl-2-methyl-1H-naphtho[2,3-g]indol-3-carboxylate (29a).
450 mg (1.2 mmol) 26m, 200 mg (46%), mp 149 ꢁC, IR
1690, 1617, 1533, MS (EI) 432 (11; M+), 387 (100), 375
(23), 342 (16), 286 (19), 230 (10), 154 (47), 77(36), 50
naphtho[2,3-g]indol-3-carboxylat-4,20-ethyl-20,30,40,70-tet-
rahydro-60,70-dimethyl-naphtho[20,30-g]pyrano[30,20-e]indol-
50-carboxylate (31c). 26o was brought to reaction like 26m
and 26n. Mannich-base 29c was not isolable and directly
reacted to spiro-compound 31c, 180 mg (52%), mp
287 ꢁC, IR 1698, 1621, 1522, MS (EI) 690 (7; M+), 490
(5), 460 (10), 345 (22), 329 (31), 307 (100), 289 (53), 272
1
(38), H NMR (CDCl3) d 11.0 (br, 1H, OH), 8.98 (s,
1H) and 8.61 (s, 1H, 6-H, 11-H), 8.00 (m, 2H, 7-H, 10-
H), 7.48 (m, 2H, 8-H, 9-H), 4.41 (m, 4H, O–CH2, N–
CH2–C), 4.05 (s, 2H, (CH3)2N–CH2), 2.65 (s, 3H, 2-
CH3), 2.53 (m, 1H, CH–isobu), 2.41 (s, 6H, N(CH3)2),
1.45 (t, 3H, O–C–CH3), 1.05 (d, 6H, (CH3)2–C), UV–vis
(MeOH) 299 (4.29). Anal. Calcd for C27H32N2O3
(432.56): C, 74.97; H, 7.46; N, 6.48. Found: C, 74.86; H,
7.58; N, 6.38.
1
(11), 202 (6), 159 (6), 109 (4), 44 (5), H NMR (CDCl3)
d 8.84 (s, 1H, arom. H), 8.77 (s, 1H, arom. H), 8. 46 (s,
1H, arom. H), 7.90 (mc, 5H, arom. H), 7.47 (mc, 4H,
arom. H), 4.25 (mc, 2H, O–CH2), 4.16 (s, 3H, N–CH3),
3.95 (s, 3H, N–CH3), 3.63 (mc, 1H) and 2.93 (mc, 4H,
pyran-H, O–CH2me), 2.56 (s, 3H, CH3), 2.42 (s, 3H,
CH3), 2.24 (mc, 1H, pyran-H), 1.30 (t, 3H, O–C–CH3),
0.35 (t, 3H, O–C–CH3). Anal. Calcd for C44H38N2O6
(690.79): C, 76.50; H, 5.54; N, 4.06. Found: C, 76.43; H,
5.48; N, 4.32.
5.5.2. Ethyl-4-[(dimethyl-amino)-methyl]-5-hydroxy-1-(4-
methoxy-phenyl)-2-phenyl-1H-naphtho[2,3-g]indol-3-car-
boxylate (29b). 406 mg (1.2 mmol) 26n, 310 mg (47%),
mp 285 ꢁC, IR 1700, 1617, 1512, MS 544 (5; M+), 499
(42), 454 (16), 352 (4), 329 (24), 176 (100), 136 (33),
Acknowledgment
1
77(41), 50 (40), H NMR (CDCl3) 10.5 (br, 1H, OH),
We wish to thank Dr. Narayanan from the NCI (Bethes-
da, MD, USA) for the in vitro testing of our
compounds.
8.91 (s, 1H, 6-H), 8.00 (m, 1H, 7-H), 7.43–6.92 m,
13H, arom. H), 4.20 (s, 2H, (CH3)2N–CH2), 4.11 (q,
2H, O–CH2), 3.88 (s, 3H, OCH3), 2.50 (s, 6H,
N(CH3)2), 0.98 (s, 3H, O–C–CH3). Anal. Calcd for
C35H32N2O4 (544.65): C, 77.18; H, 5.92; N, 5.14. Found:
C, 76.91; H, 5.96; N, 5.37.
References and notes
1. Kucklaender, U.; Pitzler, H.; Kuna, K. Arch. Pharm.
(Weinheim) 1994, 327, 137.
2. Asche, C. Ph.D. Dissertation, Heinrich-Heine-Universi-
taet Duesseldorf, Germany, 2002.
3. Asche, C.; Frank, W.; Albert, A.; Kucklaender, U. Bioorg.
Med. Chem. 2005, 13, 819.
5.6. General procedure for the preparation of spiro[ethyl-
4,5-dihydro-2-methyl-5-oxo-1H-naphtho[2,3-g]indol-3-
carboxylat-4,20-ethyl-20,30,40,70-tetrahydro-60-methyl-
naphtho[20,30-g]pyrano[30,20-e]indol-50-carboxylates
(31)
4. Kreul, J.D. Ph.D. Dissertation, Heinrich-Heine-Universi-
taet Duesseldorf, Germany, 1997.
5. Kucklaender, U.; Toeberich, H. Chem. Ber. 1981, 114,
2238.
6. Kucklaender, U.; Toeberich, H. Arch. Pharm. (Weinheim)
1981, 314, 379.
. Kucklaender, U.; Toeberich, H. Chem. Ber. 1983, 116, 152.
8. Dimroth, O.; Friedemann, O.; Kuemmerer, H. Ber. Dtsch.
Chem. Ges. 1920, 53, 481.
Ethyl-4-[(dimethylamino)methyl]-5-hydroxy-2-methyl-
1H-naphtho[2,3-g]indol-3-carboxylates 29 were heated
in dichlormethane under reflux for 2 h. Evaporation of
the reaction mixture and recrystallization of the ob-
tained residue from dichloromethane/hexanes (30:70)
yielded compounds 31.
5.6.1. Spiro[ethyl-4,5-dihydro-1-isobutyl-2-methyl-5-oxo-
1H-naphtho[2,3-g]indol-3-carboxylat-4,20-ethyl-20,30,40,
70-tetrahydro-70-isobutyl-60-methyl-naphtho[20,30-g]pyrano[30,
20-e] indol-50-carboxylate (31a). 432 mg (1.0 mmol) 29a,
150 mg (39%), mp 272 ꢁC, IR 1700, 1622, 1520, MS
(EI) 775 (14; M+), 682 (4), 410 (4), 387 (100), 358
(4), 342 (12), 302 (6), 285 (15), 270 (5), 244 (6), 228
(4), 202 (4), UV–vis (MeOH) 258 (3.66), 315 (3.37),
346 (3.85). Anal. Calcd for C50H50N2O6 (774.95): C,
77.49; H, 6.50; N, 3.61. Found: C, 77.50; H, 6.58; N,
3.46.
9. Cano, P.; Farina, F.; Parelladaa, C.; Pascual, C.; Prados,
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Centre as supplementary publication no. CCDC 287332
and CCDC 287333. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44 (0)1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
15. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.;
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18. Scattering factors, dispersion corrections, and absorption
coefficients were taken from International Tables for
Crystallography (1992, Vol. C, Tables 6.114, 4.268 and
4.2.4.2). Crystallographic data (excluding structure fac-
tors) for the structures reported in this paper have been
deposited with the Cambridge Crystallographic Data
19. Sheldrick, G. M. SHELXS86. Program for the Solution of
Crystal Structures, University of Go¨ttingen, 1985.
20. Sheldrick, G. M. SHELXL97. Program for the Refine-
ment of Crystal Structures, University of Go¨ttingen, 1997.
21. Schenck, L. W.; Sippel, A.; Kuna, K.; Frank, W.; Albert,
A.; Kucklaender, U. Tetrahedron 2005, 61, 9129.
22. Sippel, A. Ph.D. Dissertation, Heinrich-Heine-Universi-
taet Duesseldorf, Germany, 2002.