One-pot synthesis of novel antiproliferative 9-aminoacridines

Article abstract of DOI:10.1002/ejoc.201100133

Highly efficient one-pot syntheses of antiproliferative 9-aminoacridine (9-AA) derivatives are described. Simple S_NAr and addition/elimination reactions, using readily accessible starting materials, give a fast entry to novel 9-(pyridylamino)ac

Full text of DOI:10.1002/ejoc.201100133

FULL PAPER
DOI: 10.1002/ejoc.201100133
One-Pot Synthesis of Novel Antiproliferative 9-Aminoacridines
[a]
[a,b]
[b]
[a]
Gary Gellerman,* Sagiv Waintraub,
Amnon Albeck, and Vladimir Gaisin
Keywords: 9-Aminoacridine / addition-elimination / Nucleophilic substitution / one-pot synthesis / anticancer / Quinones
Highly efficient one-pot syntheses of antiproliferative 9-ami-
noacridine (9-AA) derivatives are described. Simple S Ar
and addition/elimination reactions, using readily accessible
starting materials, give a fast entry to novel 9-(pyridylamino)-
acridines, 9-(pyrimidinylamino)acridines and potential
“dual-function” bioreductive 9-(acridinylamino)quinone in-
tercalators. The synthetic routes reported in this work are ge-
neral and readily applicable, significantly expanding the
range and scope of potential 9-AA anticancer candidates.
N
Introduction
cancer drugs. The advantage of 9-AA and similar small mo-
lecules as anticancer agents that do not induce DNA dam-
age was recently discussed. These compounds elicit fewer
A wide variety of DNA intercalators have found great
utility in anticancer therapy, from natural products such as
doxorubicin and actinomycin D to synthetic drugs such as
mitoxantrone and amsacrine.[1]
Synthetic intercalators based on the 9-aminoacridine (9-
AA) core, a structure that appears in many biologically
active compounds with antimalarial and anticancer applica-
tions, are of particular interest. Aromatic 9-AA derivatives
such as quinacrine[1c] intercalate into DNA, and conse-
quently inhibit transcription in parasites. In addition, N-
alkylated 9-AA analogs have proven to be potent agents
[5]
and much less pronounced adverse side effects and present
a low risk of secondary cancer development, but are still as
potent as DNA-damaging agents in the killing of tumor
cells.
In the last two decades a large number of reports regard-
ing synthesis, SAR and anticancer activity have been pub-
lished, providing a solid foundation for drug design and
optimization studies of novel 9-amino- and 9-anilinoacrid-
ine-based compounds. However, one of the main obstacles
in pursuing these goals is the laborious synthesis of desired
[
1h]
against prion diseases in cultured neuroblastoma cells.
9
-AA derivatives, which often involves several steps and dif-
In the field of antitumor DNA-intercalating agents, 9-
anilinylacridine (9-AnA) derivatives play an important role
due to their antiproliferative properties, mostly as potent
DNA topoisomerase II inhibitors.[2] A series of potential
topoisomerase II targeting anticancer 9-AnAs, which are
designed to avoid biooxidation and possess long durations
of drug action, have been reported.[ Among these
[6]
ficult conditions. This has prompted us to look for a short
and efficient method for the derivatization of the 9-AA
scaffold suitable for rapid generation of new compounds for
biological evaluation.
Previously, we reported a new and highly efficient one-
pot derivatization of 9-AA at the amino position by simple
3]
reductive amination (II, Scheme 1) and S Ar reactions (I,
N
substances,
3-(9-acridinylamino)-5-hydroxymethylaniline
[7]
Scheme 1) using easily accessible starting materials. Here
(AHMA) and its alkylcarbamate derivatives were developed
we report on the extension of the one-pot derivatization
strategy of 9-AA, which applies a simple addition/elimi-
[3a,3c]
for potential clinical applications.
It was recently reported that 9-AA is associated with an-
other mechanism of action, as it suppresses PI3K/AKT/
mTOR, p53 and NF-kB pathways that are frequently de-
regulated in tumor cells.[4] The ability to affect simulta-
neously several biological pathways makes this a candidate
for a previously uncharacterized class of bitargeting anti-
nation (AE) reaction and a new aspect of the S Ar reaction
N
to give a fast entry to novel (9-acridinylamino)quinone (V,
VI) and 9-(azaarylamino)acridine (III, IV) derivatives,
respectively.
Results and Discussion
[
a] Department of Biological Chemistry, Ariel University Center
of Samaria,
A few 9-AAs were previously synthesized from 9-azido-
[
8]
Ariel 40700, Israel
acridines or other “pseudo”-9-chloroacridines. However,
no direct one-pot synthesis of 9-AAs from commercially
available starting materials has been developed. We recently
found that the amino group in 9-AA is nucleophilic enough
to take part in efficient nucleophilic aromatic substitution
Fax: +972-3-906-6634
E-mail: garyg@ariel.ac.il
[b] The Julius Spokojny Bioorganic Chemistry Laboratory,
Department of Chemistry,
Bar-Ilan University, Ramat Gan 52900, Israel
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100133.
(S Ar) reactions, yielding 9-anilinylacridines with halo-
N
4176
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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One-Pot Synthesis of Novel Antiproliferative 9-Aminoacridines
Scheme 1. General approaches for the one-pot derivatization of 9-aminoacridines.
benzenes bearing electron-withdrawing (EW) groups at in DMF at 90 °C to afford substituted 9-(pyridylamino)-
various positions on the reacting aryl ring.[ The starting acridines 1a–c and 9-(pyrimidinylamino)acridines 1d,e in
7]
electrophilic halobenzenes with one or two strong electron- reasonable to good yields (47–83%, Scheme 2).[
11]
This
withdrawing groups reacted smoothly with 9-AA to give method, namely Cs CO in DMF at 90 °C [Route (b)], is an
2
3
substituted 9-anilinylacridines in good yields. Recently, we efficient means of preparing substituted 9-AA derivatives. It
[
12]
decided to examine the influence of other types of substitu- significantly simplifies the formation of aryl-
and aza-
tion and structural factors on the one-pot formation of 9- aryl-substituted 9-AAs with EW groups, which are not ac-
AnAs. First, aza substitution in the electrophilic aryl rea- cessible by using the standard “reverse” approach, which
[
9]
gents, as in chloropyridines and chloropyrimidines, was calls for nucleophilic substitution of the deactivated amino-
employed, leading to novel N-pyridyl- and N-pyrimidinyl- pyridines or aminopyrimidines with 9-chloroacridines.[
12,13]
9
-AA derivatives (III and IV, Scheme 1). Secondly, halo-
quinone electrophiles were used in an AE reaction with with 9-AAs is the commercial availability of appropriately
-AA, affording novel 9-(acridinylamino)quinones (V and substituted 2-pyridyl and 2-pyrimidinyl halide reagents. We
VI Scheme 1), the structural chimeras bearing both re- also attempted the preparation of dicarboxyl compounds
An additional advantage of the one-pot S Ar reaction
N
9
[
10]
ductive (quinone) and intercalating (9-AA) moieties. Two 1f–h by treating 9-AA with 3-fluorophthalic, 4-bromo-
general one-pot reaction conditions were established. isophthalic and 2-bromoterephthalic acids 3f–h, respec-
Route (a) involves refluxing in EtOH overnight, whereas tively (Scheme 2). Unfortunately, only starting materials
Route (b) calls for the use of Cs CO in DMF at 90 °C for were isolated, probably due to insufficient electrophilicity
2
3
a period of 12 h. These conditions are optimized for the of the halobenzoic acids used. This suggested the necessity
preparation of the desired products in moderate to good of harsher Ullmann conditions.[14]
yields. Moreover, simple workup procedures further con-
tribute to the synthetic accessibility enabled by both routes.
Synthesis of 9-(Arylamino)acridine Derivatives 2a,b by
Using S Ar Reactions
N
Synthesis of 9-(Azaarylamino)acridine Derivatives 1a–e by
The above successful results encouraged us to examine
the influence of the unfavorable electron-donating (ED)
Using S Ar Reactions
N
We treated representative chloropyridines and pyrimid- methoxy group on the haloaryl reagent for the preparation
ines 3a–e with 9-AA in the presence of 1 equiv. of Cs CO3 of 9-AnAs. Electron-donating groups frequently appear on
2
Eur. J. Org. Chem. 2011, 4176–4182
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G. Gellerman, S. Waintraub, A. Albeck, V. Gaisin
FULL PAPER
N 2 3
Scheme 2. Synthesis of 9-AA derivatives 1 by S Ar reactions. Reagents and conditions: Cs CO , DMF, 90 °C, 12 h.
N 2 3
Scheme 3. Synthesis of 9-aminoacridine derivatives 2 by S Ar reactions. Reagents and conditions: Cs CO , DMF, 90 °C, 12 h.
9
2
-AnA-based drugs.[1,2] Of particular interest was 1-fluoro- adjacent nitro group.[15] All attempts towards a reaction of
-methoxy-4-nitrobenzene (4a), since the resulting S Ar 2-fluoro-4-nitrophenol (4c), bearing a free hydroxy group,
N
product 2a could be considered an intermediate in the syn- with 9-AA under standard conditions [Route (b)] led to a
thesis of amsacrine (Scheme 3). The nitro group could be complex mixture of unidentified products. We reasoned that
reduced to the amine and the resulting amine then mesyl- the formation of a phenolate anion by Cs CO may inter-
2
3
ated to afford amsacrine. To our satisfaction, the reaction of fere with the formation of the desired products. Further-
-AA with 4a under standard conditions [Route (b)] yielded more, substitution of an F atom by the S Ar reaction re-
9
N
compound 2a in 64% yield, indicating a non-interruptive quires an activating NO substitution in para or ortho posi-
2
character of the ED methoxy group at the ortho position tion, whereas the corresponding substitution of 4c is in
with the powerful EW nitro group at the para position.
Next, we examined the impact of different substitutional
combinations of nitro and methoxy or hydroxy groups.
When 4b (methoxy group in meta position) was treated with
meta position.
Synthesis of 9-(Acridinylamino)quinone Derivatives 5a–f by
AE Reactions
9-AA under the same reaction conditions, 2a was obtained
in 58% yield. Production of 2b may be the result of an
In the context of exploring the rapid and simple derivati-
unexpected alkali demethylation, most likely assisted by the zation of the 9-AA scaffold, we applied AE reactions of 9-
4178
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One-Pot Synthesis of Novel Antiproliferative 9-Aminoacridines
AA with multisubstituted haloquinones (products V and moderate to good yields are presented in Schemes 4 and 5,
VI, Scheme 1). Halobenzoquinones and halonaphthoquin- respectively. To demonstrate the synthetic potential of this
ones are widely used as anticancer agents with bioreductive reaction with 9-AA, we employed two classes of representa-
[
10]
properties.
Members of this class of compounds can be tive quinones: halobenzoquinones 6a–c (Scheme 4) and
selectively activated to cytotoxic species by reduction. The halonaphthoquinones 6d–f (Scheme 5), yielding the respec-
selective bioactivation may be due to elevated levels of some tive bifunctional quinone-9AAs 5a–f under mild conditions.
reductases in certain tumors, or to hypoxia. Significant pre- Interestingly, during the course of our work, we noticed
cedence has shown that bioreductively activated drugs are that different reaction conditions lead to different products.
more toxic to acidic hypoxic cells than they are to well- When 9-AA was treated with equimolar amounts of tetra-
[
16]
oxygenated ones.
chlorobenzoquinone (6c) in refluxing EtOH overnight, the
Thus, we decided to combine a quinone anticancer moi- corresponding quinone-9-AA product 5c was obtained in
ety with a DNA intercalator, 9-AA, to obtain potential bi- 57% yield. This product possesses one ethoxy group as the
functional compounds with very interesting biological ac- result of an additional AE reaction with EtOH. The same
tivities. Although, a number of bifunctional bioreductive reaction, with analogous tetrabromobenzoquinone (6a), led
structures have been published,[ the use of DNA intercal- to the formation of a single product 5b in very low yield
ators as an active component of such compounds has not (3%). Mass spectrometry clearly showed the presence of
17]
1
yet been reported. The rationale driving the idea was to use only one bromine atom, and H NMR spectroscopy con-
the intercalator moiety to locate the bifunctional molecule firmed the presence of one quinone hydrogen atom [δ =
between the DNA strands followed by active species gener- 5.93 (s) ppm]. The chemical structures of 5b,c were fully
ation by reductive metabolism of the quinone under aerobic assigned on the basis of NOE, HMBC, HMQC experi-
conditions, which would then lead to damage to the cancer ments. The mechanism of the reduction remains unclear to
cells exceeding that possible using either the quinone or in- us. On the other hand, when using aprotic conditions
tercalator independent of each other. We based our work on (1 equiv. of Cs CO in DMF at 90 °C for 12 h) only 6a
2
3
several published syntheses calling for the straightforward underwent a classical AE reaction, leading to tribromoqui-
[
18]
amination of haloquinones under mild conditions.
Suc- none 5a in 79% yield after purification. The use of tetra-
cessful one-pot syntheses of “dual” agents 5a–c and 5d–f in chloroquinone 6c did not afford any recognizable products
Scheme 4. Synthesis of 9-aminoacridine derivatives 5a–c by using AE reactions. Reagents and conditions: (a) EtOH, reflux, overnight;
b) Cs CO , DMF, 90 °C, 12 h.
(
2
3
Scheme 5. Synthesis of 9-AA derivatives 5d–f by AE reactions. Reagents and conditions: EtOH, reflux, overnight.
Eur. J. Org. Chem. 2011, 4176–4182
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G. Gellerman, S. Waintraub, A. Albeck, V. Gaisin
FULL PAPER
under the same conditions. Unfortunately, tetrafluoro- pounds. Attempts to facilitate the reactions by the use of
quinone 6b yielded only mixtures of unidentified products microwave-assisted chemistry are also in progress.
under both conditions [Routes (a) and (b)].
Moving forward, we decided to use chloronaphthoquin-
one reactants in AE reactions to attach the larger derivatized Conclusions
naphthoquinone moiety to the 9-AA scaffold. Naphtho-
We have developed new methods for the efficient one-pot
quinones can bear additional amino, hydroxy and methoxy
derivatization of the medicinally important 9-AA scaffold.
groups that, together with the quinonic ketone, are able
Surprisingly, the S Ar reaction between 9-AA and aryl ha-
lides does not require the strong electron-withdrawing NO2
possibly leading to the formation of more powerful DNA-
N
to enhance biologically important chelating properties,
damaging reactive species.[
19]
group on the aryl halide reagent. 2-Methoxy- and 3-meth-
oxy-4-nitroaryl halides, which bear the ED methoxy group,
also undergo this reaction to give products structurally re-
lated to amsacrine in good yields. Additionally, a simple AE
reaction between haloquinones and 9-AA represents a fast
entry to many potential “bitargeting” 9-(acridinylamino)-
quinone intercalators. The synthetic routes described in this
paper provide a rapid access to novel 9-AA derivatives,
which are being further evaluated for their biological prop-
erties.
First, we treated 9-AA with
commercially available naphthoquinones[
20]
6d,e using
Route (a) conditions, which led smoothly to monosubstitu-
tion by 9-AA (Scheme 5) and formation of the dark gray
crude chloronaphthoquinone products 5d,e. Simple workup
followed by flash-chromatography purification (silica gel;
EtOAc/petroleum ether, 1:2) gave the corresponding prod-
ucts in 82% and 88% yields, respectively. The existence of
one Cl atom in 5d,e was confirmed by mass spectrometry.
We then treated 2,3-dichloro-5,8-dihydroxy-1,4-naphtho-
[
21]
quinone (6f) with 9-AA in refluxing EtOH [Route (a)] to
afford reddish crude product 5f in 93% yield. This product
was of sufficient purity that no further purification was nec-
Experimental Section
essary. The spectral analysis of 5f revealed it to be a result General: Analytical HPLC was performed on a 250ϫ4.2 mm
of a double AE reaction. One AE reaction entailed 9-AA LiChroprep RP-18 column from Merck, with a 1 mL/min flow and
as the nucleophile, whereas the second AE reaction involved detection at 214 nm. The eluents were triply distilled water and
1
HPLC-grade CH CN containing 0.1% TFA or MeOH. The con-
centration of all the samples was 0.5%. Mass spectra were mea-
EtOH as the nucleophile (see H NMR and mass spectra
3
of 5f in the Supporting Information). This observation par-
allels those involving quinone derivatives 5b,c (Scheme 4)
but contrasts those involving naphthoquinone analogs 5d,e
Scheme 5), which underwent only one substitution reac-
tion. The assignment of a double AE reaction was sup-
sured in the positive and negative modes with a quadruple mass
spectrometer equipped with an electrospray ionization source and
1
13
cross-flow inlet. H and C NMR spectra were recorded at 700
or 300 and 75 MHz, respectively, in [D ]DMSO, unless otherwise
(
6
indicated. Assignments in the final products were supported by 2D
COSY, TOCSY, NOESY, ROESY, HMBC, and HMQC spec-
1
ported by the observed low-field shift in the H NMR spec-
trum for the signals of the nonsymmetrical phenolic pro- troscopy. All chemical shifts are reported with respect to TMS. SPE
tons at δ = 12.10 and 11.82 ppm, and the typical high-field (solid-phase extraction) was performed with LiChrospher 60 RP-
shift for the signal of the ethoxy methylene group attached 18 columns purchased from Agilent Technologies. Chromatography
was carried out by standard flash chromatography and TLC on
silica gel (Merck 7735).
to a double bond [δ = 4.58 (q, J = 6.5 Hz, 2 H) ppm; see
full assignment in Supporting Information].
Preliminary antiproliferative tests of the synthesized General Procedure for the Synthesis by Using AE Reactions
compounds revealed submicromolar leads against MDM- [Route (a)]: 9-AA (0.194 g, 1 mmol) and haloquinone (1 mmol)
were refluxed in EtOH (15 mL) overnight. While heating, the color
MD-A31 (renal cancer), OVCAR8 (ovarian cancer), NCI-
of the reaction mixture in most cases changed to dark red or gray.
After completion of the reaction (determined by TLC monitoring),
the mixture was cooled and concentrated to give a crude red or
gray solid. The products were purified by flash column chromatog-
raphy on silica gel 60 to yield the corresponding products.
ADR (associated with MDR ovarian cancer), MCF-7mito
(mitoxantrone selected and associated with MDR breast
cancer), HT29 (colon carcinoma) and H1299, and almost
completely insensitive to chemotherapy lung carcinoma.
Some of the tested compounds showed greatly enhanced
cytoxicity relative to amsacrine. Interestingly, large differ-
ences in the sensitivity to the tested compounds were ob-
served among these cell lines, and more detailed biological
results will be published in due course.
General Procedure for the Synthesis by Using S
Route (b)]: 9-AA (0.194 g, 1 mmol), aryl halide or haloquinone
1 mmol), and Cs CO (0.161 g, 0.5 mmol) were heated in dry
N
Ar Reactions
[
(
2
3
DMF (5 mL) at 90 °C for 12 h. While heating, the color of the
reaction mixture in most cases changed to dark red. After comple-
tion of the reaction (determined by TLC monitoring), the mixture
was cooled and poured into water. The resulting precipitate was
In summary, the one-pot synthetic methodologies de-
scribed in this paper can efficiently yield novel medicinally
important 9-(arylamino)acridines by S Ar reactions and collected by filtration, washed several times with water, and dried
N
potential “dual-function” bioreductive intercalators, 9-(ac- to give a crude red or orange solid. The products were purified by
ridinylamino)quinones, by AE reactions using easily access- flash column chromatography on silica gel 60 to yield the corre-
sponding products.
ible starting materials. The synthetic methodology reported
in this work is general and readily applicable, significantly 9-(2-Pyridylamino)acridine (1a): Synthesized according to Route (b)
expanding the scope of potential 9-AA anticancer com- from 3a (0.113 g). Orange solid after chromatography (CHCl
3
);
4
180 Eur. J. Org. Chem. 2011, 4176–4182
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

One-Pot Synthesis of Novel Antiproliferative 9-Aminoacridines
1
+
0
.13 g, 47% yield; R
f
= 0.65 (EtOAc). H NMR (300 MHz, [D
6
]-
118.2 ppm. HRMS (CI): calcd. for C19
found 332.106.
14 3 3
H N O [M + H] 332.103;
DMSO): δ = 9.12 (br. s, 1 H, NH), 8.23 (d, J = 6.8 Hz, 2 H), 8.04–
.89 (m, 3 H), 7.76–7.51 (m, 3 H), 7.38–7.27 (m, 2 H), 6.74–6.68
m, 2 H) ppm. 13C NMR (75 MHz, [D
]DMSO): δ = 157.1, 150.6,
48.2, 141.5, 130.3, 129.0, 125.2, 122.6, 121.0, 119.6, 113.2,
7
(
1
1
2
-(Acridin-9-ylamino)-3,5,6-tribromo-1,4-benzoquinone (5a): Syn-
thesized according to Route (b) from 6a (0.424 g). Dark green solid
after chromatography (CHCl ); 0.32 g, 79% yield; R = 0.80
). H NMR (300 MHz, [D ]DMSO): δ = 8.07 (d, J =
.8 Hz, 2 H), 7.81 (t, J = 6.8 Hz, 2 H), 7.54 (t, J = 6.8 Hz, 2 H),
6
3
f
+
09.5 ppm. HRMS (CI): calcd. for C18
H
14
N
3
[M + H] 272.118;
1
(CHCl
3
6
found 272.086.
-(5-Cyano-2-pyridylamino)acridine (1b): Synthesized according to
Route (b) from 3b (0.137 g). Orange solid after chromatography
6
6
1
3
6
.92 (d, J = 6.8 Hz, 2 H) ppm. C NMR (75 MHz, [D ]DMSO):
δ = 188.3, 181.9, 173.1, 168.4, 144.0, 140.8, 133.2, 131.7, 129.2,
126.5, 122.3, 121.6, 118.9 ppm. HRMS (EI): calcd. for
9
1
(CHCl
3
); 0.18 g, 68% yield; R
f
= 0.60 (EtOAc). H NMR
]DMSO): δ = 9.85 (br. s, 1 H, NH), 8.34–8.11 (m, 3
+
C
19
H10Br
3
N
2
O
2
[M] 534.829; found 533.802 (35%), 535.807
(300 MHz, [D
6
(
100%), 537.811 (98%), 539.798 (28%).
2-(Acridin-9-ylamino)-3-bromo-5-ethoxy-1,4-benzoquinone
43.5, 141.7, 130.0, 127.1, 125.2, 121.0, 118.2, 116.1, 114.5, Synthesized according to Route (a) from 6a (0.424 g). Greenish so-
H), 8.10–7.97 (m, 2 H), 7.82–7.57 (m, 2 H), 7.39–7.18 (m, 4 H)
ppm. 13C NMR (75 MHz, [D
1
1
]DMSO): δ = 160.2, 151.3, 149.4,
6
(5b):
–1
03.9 ppm. IR (KBr): ν˜ = 2250, 1570, 1430, 1105 cm . HRMS
3 f
lid after chromatography (CHCl ); 0.01 g, 3% yield; R = 0.60
(CHCl ). H NMR (300 MHz, [D ]DMSO): δ = 12.28 (br. s, 1 H,
3 6
+
1
(CI): calcd. for C19
H
13
N
4
[M + H] 297.1134; found 297.1114.
NH), 7.96 (d, J = 7.2 Hz, 2H-4,5), 7.75 (t, J = 7.2 Hz, 2H-2,7),
.60 (d, J = 7.2 Hz, 2H-1,8), 7.29 (t, J = 7.2 Hz, 2H-3,6), 5.92 (s,
1 6Ј-H), 4.06 (q, J = 6.2 Hz, OCH ), 1.36 (t, J = 6.2 Hz, CH ) ppm.
]DMSO): δ = 178.05 (s, C-1Ј, C=O), 172.77
s, C-4Ј, C=O), 160.16 (s, C-5Ј), 157.27 (s, C-9), 152.79 (s, C-2Ј),
139.59 (s, 2 C-4a,8b), 133.40 (d, 2 C-2,7), 126.43 (d, 2 C-4,5),
22.51 (d, 2 C-3,6), 117.42 (d, 2 C-1,8), 116.45 (s, 2 C-4b,8a), 104.91
(s, C-3Ј), 103.90 (s, C-6Ј), 65.56 (t, OCH ), 13.74 (q, CH ) ppm.
HRMS (ES): calcd. for C21 14BrN [M – H] 421.018, 423.016;
found 421.284 (89%), 423.281 (100%).
-(Acridin-9-ylamino)-3,6-dichloro-5-ethoxy-1,4-benzoquinone (5c):
Synthesized according to Route (a) from 6c (0.246 g). Greenish so-
lid after chromatography (CHCl ); 0.27 g, 57% yield; R = 0.70
). H NMR (300 MHz, [D ]DMSO): δ = 12.40 (br. s, 1 H,
NH), 8.01 (d, J = 6.8 Hz, 2 H-4,5), 7.78 (t, J = 6.8 Hz, 2 H-2,7),
9
-(3-Nitro-2-pyridylamino)acridine (1c): Synthesized according to
7
Route (b) from 3c (0.158 g). Reddish solid after chromatography
1
2
3
(
(
2
CHCl
300 MHz, [D
H), 8.22–8.03 (m, 2 H), 7.87–7.41 (m, 5 H), 7.19–7.04 (m, 2 H)
3
); 0.25 g, 81% yield; R
f
= 0.50 (EtOAc). H NMR
1
3
C NMR (75 MHz, [D
6
6
]DMSO): δ = 11.52 (br. s, 1 H, NH), 8.60–8.41 (m,
(
13
ppm. C NMR (75 MHz, [D
6
]DMSO): δ = 154.3, 152.0, 150.4,
1
143.2, 136.6, 134.3, 130.2, 128.9, 127.7, 120.8, 115.3, 113.5 ppm.
+
2
3
13 4 2
HRMS (CI): calcd. for C18H N O [M + H] 317.103; found
3
–
H
2 3
O
17.120.
9
-(2-Pyrimidinylamino)acridine (1d): Synthesized according to
2
Route (b) from 3d (0.114 g). Orange solid after chromatography
1
(
(
6
7
CHCl
300 MHz, [D
3
); 0.19 g, 75% yield; R
]DMSO): δ = 9.80 (br. s, 1 H, NH), 8.52 (d, J =
.7 Hz, 2 H), 8.28 (d, J = 6.8 Hz, 2 H), 8.12–7.98 (m, 4 H), 7.64–
f
= 0.40 (EtOAc). H NMR
3
f
6
1
(CHCl
3
6
.38 (m, 2 H), 7.08 (t, J = 6.7 Hz, 1 H) ppm. 1 C NMR (75 MHz,
]DMSO): δ = 171.3, 156.1, 150.0, 148.3, 144.4, 135.7, 130.3,
29.8, 124.2, 121.7, 117.1 ppm. HRMS (CI): calcd. for C17
3
7
.63 (d, J = 7.2 Hz, 2 H-1,8), 7.30 (t, J = 7.2 Hz, 2 H-3,6), 4.63 (q,
[D
6
1
3
2 3
J = 5.8 Hz, OCH ), 1.36 (t, J = 6.2 Hz, CH ) ppm. C NMR
1
[
13 4
H N
(
75 MHz, [D
6
]DMSO): δ = 172.91 [s, C-1Ј(4Ј), C=O], 172.69 [s, C-
M + H]+ 273.113; found 273.122.
4Ј(1Ј), C=O], 158.16 (s, C-9), 156.51 (s, C-5Ј), 149.43 (s, C-2Ј),
9-(5-Bromo-2-pyrimidinylamino)acridine (1e): Synthesized accord-
139.55 (s, 2 C-4a,8b), 133.59 (d, 2 C-2,7), 126.57 (d, 2 C-4,5),
ing to Route (b) from 3e (0.194 g). Orange solid after chromatog-
raphy (CHCl ); 0.24 g, 83% yield; R = 0.70 (MeOH/CHCl
H NMR (300 MHz, [D ]DMSO): δ = 9.64 (br. s, 1 H, NH), 8.58 HRMS (ES): calcd. for C H Cl N O [M] 413.045; found
s, 2 H), 8.24 (d, J = 6.8 Hz, 2 H), 8.10–7.92 (m, 4 H), 7.60–7.33
m, 2 H) ppm. 13C NMR (75 MHz, [D
]DMSO): δ = 154.7, 151.2,
43.4, 142.9, 133.7, 131.1, 127.2, 120.0, 119.8, 116.1, 114.4 ppm.
122.65 (d, 2 C-3,6), 119.67 (s, C-3Ј), 117.54 (d, 2 C-1,8), 116.39 (s,
3
f
3
2 3
, 2:98). 2 C-4b,8a), 112.12 (s, C-6Ј), 70.70 (t, OCH ), 15.88 (q, CH ) ppm.
1
–
6
2
1
15
2
2
3
(
(
1
413.270 (48%), 415.276 (31%), 417.273 (7%).
-(Acridin-9-ylamino)-3-chloro-1,4-naphthoquinone (5d): Synthe-
sized according to Route (a) from 6d (0.226 g). Dark gray solid
after chromatography (CHCl ); 0.34 g, 82% yield; R = 0.75
). H NMR (300 MHz, [D ]DMSO): δ = 8.20–8.03 (m, 3
H), 7.90–780 (m, 3 H), 7.72–7.65 (m, 2 H), 7.60–7.57 (m, 2 H),
6
2
+
4
HRMS (EI): calcd. for C17H11BrN [M + H] 350.016, 352.014;
3
f
found 350.020 (46%), 352.021 (43%).
-(2-Methoxy-4-nitrophenylamino)acridine (2a): Synthesized ac-
cording to Route (b) from 4a (0.171 g). Orange solid after
1
(CHCl
3
6
9
1
3
6
7.23 (t, J = 6.9 Hz, 2 H) ppm. C NMR (75 MHz, [D ]DMSO): δ
chromatography (5% MeOH/CHCl ); 0.21 g, 64% yield; R
= 0.60 = 181.3, 181.0, 164.1, 157.2, 148.4, 146.2, 138.9, 135.5, 132.8, 133.0,
, 5:95). H NMR (300 MHz, CDCl ): δ = 8.37 (d,
132.5, 130.1, 129.3, 127.3, 125.7, 120.8, 118.2 ppm. HRMS (ES):
J = 6.8 Hz, 2 H), 8.08 (d, J = 6.8 Hz, 2 H), 7.90–7.76 (m, 2 H), calcd. for C23 14ClN
[M + H]+ 385.074, 387.072; found
.70–7.65 (m, 1 H), 7.53–7.49 (m, 2 H), 7.30–7.20 (m, 2 H), 6.25
385.136 (100%), 387.1410 (36%).
d, J = 6.5 Hz, 1 H, NH), 4.18 (s, 3 H, OMe) ppm. 13C NMR
3
f
1
(MeOH/CHCl
3
3
H
2 2
O
7
(
(
1
2
-(Acridin-9-ylamino)-3-chloro-6,7-dimethyl-1,4-naphthoquinone
75 MHz, CDCl ): δ = 153.3, 145.7, 143.1, 134.4, 131.0, 128.3,
3
(
5e): Synthesized according to Route (a) from 6e (0.254 g). Dark
27.2, 126.0, 124.8, 124.0, 122.4, 121.7, 120.2, 56.5 ppm. HRMS
3
f
gray solid after chromatography (CHCl ); 0.38 g, 88% yield; R =
+
(CI): calcd. for C20
H
16
N
3
O
3
[M + H] 346.119; found 346.177.
1
0
3
2
.80 (CHCl
3
). H NMR (300 MHz, [D
6
]DMSO): δ = 8.17–8.00 (m,
H), 7.86–7.80 (m, 2 H), 7.77–7.60 (m, 3 H), 7.26 (t, J = 6.9 Hz,
9
-(3-Hydroxy-4-nitrophenylamino)acridine (2b): Synthesized ac-
1
3
H), 2.46 (s, 3 H, Me), 2.53 (s, 3 H, Me) ppm. C NMR (75 MHz,
]DMSO): δ = 181.1, 180.6, 164.0, 157.2, 148.5, 147.3, 137.8,
134.3, 133.7, 133.4, 131.9, 131.1, 129.0, 128.2, 126.7, 121.8, 117.5,
cording to Route (b) from 4b (0.187 g). Orange solid after
chromatography (10% MeOH/CHCl ); 0.19 g, 58% yield; R = 0.50
, 1:9). H NMR (300 MHz, CDCl ): δ = 10.08 (br.
[D
6
3
f
1
(MeOH/CHCl
3
3
+
19.2, 18.7 ppm. HRMS (ES): calcd. for C25
2 2
H18ClN O [M + H]
s, 1 H, OH), 8.38–8.27 (m, 3 H), 8.02 (d, J = 6.8 Hz, 2 H), 7.88 (t,
J = 6.8 Hz, 2 H), 7.61 (t, J = 6.8 Hz, 2 H), 6.83 (d, J = 6.8 Hz, 2
413.105, 415.103; found 413.110 (98%), 415.111 (34%).
H), 6.24 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl
): δ =
2-(Acridin-9-ylamino)-3-ethoxy-5,8-dihydroxy-1,4-naphthoquinone
3
137.6, 135.2, 130.3, 127.7, 125.2, 124.6, 123.2, 121.8, 119.5, (5f): Synthesized according to Route (a) from 6f (0.256 g). Dark
Eur. J. Org. Chem. 2011, 4176–4182
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4181

G. Gellerman, S. Waintraub, A. Albeck, V. Gaisin
FULL PAPER
red solid; 0.41 g, 93% yield; R
1
f
= 0.30 (MeOH/CHCl
3
, 1:99). H
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NMR (300 MHz, [D
H, OH), 10.16 (br. s, 2 H, NH
.02–7.95 (m, 4H-3,4,5,6), 7.59 (t, J = 7.0 Hz, 2H-2,7), 7.40–7.38
m, 2H-6Ј,7Ј), 4.58 (q, J = 6.2 Hz, OCH ), 1.37 (t, J = 6.2 Hz, CH
]DMSO): δ = 181.56 (s, 2-C=O),
57.72 (s, C-9), 157.20 (s, C-3Ј), 156.88 (s, C-5Ј), 156.16 (s, C-8Ј),
39.25 (s, 2C-4a,8b), 135.48 (d, 2C-3,6), 129.52 (d, C-7Ј), 129.10
6
]DMSO): δ = 12.10 (s, 1 H, OH), 11.82 (s, 1
+
2
), 8.72 (d, J = 7.0 Hz, 2H-1,8)
[
[
[
[
8
(
2
3
)
13
ppm. C NMR (75 MHz, [D
6
8
36–839.
1
1
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1
972, 161–165.
(
1
(
d, C-6Ј), 127.38 (s, C-2Ј), 124.72 (d, 2 C-1,8), 123.73 (d, 2 C-2,7),
18.67 (d, 2 C-4,5), 111.44 (s, 2 C-4b,8a), 127.38 (s, C-2Ј), 111.24
s, C-8bЈ), 110.46 (s, C-8aЈ), 70.67 (t, OCH ), 15.83 (q, CH
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3
) ppm. [10] a) P. Workman, I. J. Stratford, Oncol. Res. 1994, 6, 493–500; b)
+
HRMS (ES): calcd. for C25
H
19
–
N
2
O
5
[M + H] 427.129; found
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427.134 (38%), 425.131 [M – H] (100%).
522.
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11] Compound 1a and similar agents were previously synthesized
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Supporting Information (see footnote on the first page of this arti-
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1
[
[
Acknowledgments
2
We wish to thank Dr. Hugo Gotlib from Bar Ilan University for
analytical assistance and fruitful advice.
3
[
[
[
[
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Received: January 28, 2011
Published Online: May 27, 2011
4182
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4176–4182