New polyacridine compounds: Synthesis of acridine dimers and tetramers

Article abstract of DOI:10.1055/s-2001-15137

A series of 7,9-disubstituted acridine dimers and tetramers have been synthesized from nucleophilic attack of 2-bromomethyl-9-chloro-7-methoxy acridine 5 by different alkyl diamines.

Full text of DOI:10.1055/s-2001-15137

LETTER
1137
New Polyacridine Compounds: Synthesis of Acridine Dimers and Tetramers
Nathalie Filloux,* Jean-Pierre Galy
UMR 6009, Université d’Aix-Marseille III, case 552, Av. Escadrille Normandie-Niemen, 13397 Marseille Cedex 20, France
Fax 33 (4) 91288323; E-mail: m9701745@educ-012.u-3mrs.fr
Received 10 April 2001
mo-5,5’-dimethylimidazolidine-2,4-dione (DBDMI) in
Abstract: A series of 7,9-disubstituted acridine dimers and tetra-
cyclohexane and under nitrogen atmosphere, led to 5.7 Al-
mers have been synthesized from nucleophilic attack of 2-bromo-
methyl-9-chloro-7-methoxy acridine 5 by different alkyl diamines.
ready used as bromination agent at benzylic position,8
DBDMI gave higher yield (73%, Scheme 1) than the
Key words: acridines, DNA polyintercalands, antitumor agents,
polycycles, nucleophilic substitution
commonly employed N-bromosuccinimide.9 Note that
DBDMI must be added at two times to avoid the forma-
tion of the dibromomethyl compound. Moreover because
of its lower toxicity, cyclohexane was chosen rather than
Acridine derivatives have a wide range of biological ap-
the usual carbon tetrachloride.
plications, especially as antitumor agents.1 Because of its
The main step of the synthesis of both dimers 6a-c and tet-
ramers 9a-d was the nucleophilic attack of 5 by an alkyl
planar structure, the acridine chromophore has excellent
DNA binding properties.2 Since bis-intercalation would
theoretically increase DNA binding, the synthesis of poly-
acridinic compounds as potential bis-intercalating agents
has been extensively studied.3 Some mono- and bi-
bridged acridine dimers have recently been prepared in
our laboratory.4
diamine containing
a variable number of (CH2)
groups.10,11 The reaction was performed in CH2Cl2 under
reflux (Schemes 2 and 3) and yielded compounds 6 and 9.
Hence we synthesized new polyintercalands containing
two or four acridine moieties linked at position 2. The key
intermediate for these preparations was 2-bromomethyl-
9-chloro-7-methoxyacridine 5. Nucleophilic attack of 5
by different alkyl diamines gave two series of new
7,9-disubstituted polyacridinic compounds: dimers 6-8
and tetramers 9-11.
2-Bromomethyl-9-chloro-7-methoxyacridine 5 was pre-
pared in three steps (Scheme 1): an Ullmann condensation
between 2-bromo-5-methoxy benzoic acid 1 and p-tolui-
dine 2 yielded 5-methoxy-4’-methyl-N-phenylanthranilic
acid 3,5 which was then cyclized with phosphorus oxide
chloride to give 9-chloro-7-methoxy-2-methylacridine 4.6
Finally, benzylic photobromination of 4, using 1,3-dibro-
Scheme 2 a) 2HN-(CH2)n-NH2 (1.2 equiv. mol.), CH2Cl2, 5 h,
reflux; b) (NH4)2CO3, phenol, 5 h, 60 °C; c) HBr 48%, 3 days.
Scheme 1 a) K2CO3, Cu, DME, 3 h, reflux; b) POCl3, 15 min,
80 °C and 30 min, 120 °C; c) DBDMI, C6H12, h , 12 h.
Synlett 2001, No. 7, 1137–1139 ISSN 0936-5214 © Thieme Stuttgart · New York

1138
N. Filloux, J.-P. Galy
LETTER
Scheme 4
Scheme 5
as previously reported,14 these results suggested that the
amino-imino equilibrium is completely shifted towards
the imino tautomer B.
Scheme 3 a) 2HN-(CH2)n-NH2 (0.5 equiv. mol.), CH2Cl2, 12 h,
reflux; b) (NH4)2CO3, phenol, 5 h, 60 °C; c) HBr 48%, 3 days.
To neutralize HBr formed during the reaction, the alkyl
diamine was used in excess. As shown in Scheme 4, 1.0
equiv. mol of diamine chain would theoretically be em-
ployed for the synthesis of dimers 6 and 0.75 equiv. mol
of diamine for tetramers 9. However, the best yields were
obtained with 1.2 equiv. mol of diamine for the prepara-
tion of dimers 6 (39-46%) and 0.5 equiv. mol of diamine
for tetramers 9 (47-50%). Some attempts with potassium
carbonate or pyridine as base were also performed but
they did not give better yields.
In conclusion, a series of new acridine dimers and tetram-
ers linked by different alkyl diamine were synthesized and
characterized. All these compounds are undergoing bio-
logical tests.
References and Notes
(1) Niedle, S.; Waring, M. Molecular Aspects of Anticancer
Drug-DNA Interactions Macmillan: Basingstoke 1994, Vol.
2; p 270. Baguley, B. C.; Zhuang, L.; Marshall, E. M. Cancer
Chemother. Pharmacol. 1995, 36, 244.
Next, dimers 6a-c and tetramers 9a-d were aminated at
position 9 with ammonium carbonate in phenol, with over
than 90% yield.12 In the last step, the demethylation of the
OCH3 groups by HBr under reflux during three days led
to the corresponding 9-amino-7-hydroxy dimers 8a-c and
tetramers 11a-d.13 Demethylation with aluminium chlo-
ride in toluene was also performed but all our attempts at
purification failed.
(2) Lerman, L. S. J. Mol. Biol. 1961, 3, 18.
(3) Le Pecq, J. B.; LeBret, M.; Barbet, J.; Roques, B. Proc. Natl.
Acad. Sci. 1975, 72, 2915. Gamage, S. A.; Spicer, J. A.;
Atwell, G. J.; Finlay, G. J.; Baguley, B. C.; Denny, W. A. J.
Med. Chem. 1999, 42, 2383. Wakelin L. P. G. Medicinal. Res.
Rev. 1986, 6, 295.
(4) Issmaili, S.; Boyer, G.; Galy, J. P. Synlett 1999, 641.
(5) Hannig, E.; Becke, E. Pharmazie 1975, 289.
(6) Patent I. G. Farbenind.; DE 632224; 1934; FTFVA6; Fortschr.
Teerfarbenfabr. Verw. Industriezweige; DE; GE; 23; 539.
Patent; Winthrop Chem. Co.; US 2121207; 1935.
(7) Compound 5: 9-Chloro-2-methoxy-7-methylacridine 4 (3.11
g, 12.08 mmol) was dissolved in freshly distilled cyclohexane
(150 mL) at 80 °C under a nitrogen atmosphere. 1,3-Bibromo-
5,5-dimethylimi-dazolidine-2,4-dione (DBDMI, 2.14 g, 7.51
mmol) was added and the mixture was irradiated for 5 h under
stirring with a 150 W halogen floodlamp. Next, one more drop
of DBDMI (0.93 g, 3.26 mmol) was added to the mixture and
the irradiation was performed another 7 h. Then the solvent
was removed in vacuo and the residue was washed with
CH3CN (250 mL) to yield 5 as an orange powder (2.96 g,
1
All these compounds were characterized by H and 13C
NMR spectroscopy. Moreover unambiguous differentia-
tion between dimer or tetramer compounds was easily
obtained from the area of significant protons (e.g. H-12
and H-3).
At least, 9-amino acridine derivatives (compounds 7, 8,
10 and 11) exist in two tautomeric forms A and B, as
shown in Scheme 5. For all these compounds the C-4,
C-4a, C-5 and C-5a resonances are shielded with respect
to the corresponding 9-chloro acridine derivatives. Thus
Synlett 2001, No. 7, 1137–1139 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
73%). mp 186 °C.
New Polyacridine Compounds: Synthesis of Acridine Dimers and Tetramers
1139
and C-13), 53.55 (C-12), 55.60 (OCH3), 58.64 (C-11), 99.92
(C-8), 122.84 (C-1), 123.99 (C-9a), 125.19 (C-8a), 125.50 (C-
6), 129.61 (C-4), 130.89 (C-3), 131.21 (C-5), 137.63 (C-2),
139.15 (C-9), 145.59 (C-5a), 146.65 (C-4a), 158.04 (C-7).
(12) General amination method for the preparation of compounds
7a-c and 10a-d: 9b (0.22 g, 0.37 mmol) was dissolved in
phenol (3 g) at 60 °C. Ammonium carbonate (0.60 g, 6.25
mmol) was added and the mixture was stirred for 6 h at 60 °C.
Then, cold acetone (50 mL) was added to the mixture to obtain
a green precipitate. This precipitate was filtered off and stirred
2 h in an alcaline solution (NaOH, 3N, 50 mL). The solution
was then filtered and the precipitate was washed with water to
obtain 10b (0.20 g, 0.36 mmol, 92%) as a green powder, mp
227 °C. Dimers 7a-c and tetramers 10a,c,d were obtained by
the same procedure.
1H NMR (300 MHz, CDCl3) 4.00 (s, 3H, OCH3), 4.70 (s,
2H, H-11), 7.43 (d, 1H, J = 2.5 Hz, H-8), 7.46 (dd, 1H, J = 2.7
and 9.3 Hz, H-6), 7.74 (dd, 1H, J = 2.0 and 9.0 Hz, H-3), 8.15
(d, 1H, J = 9.3 Hz, H-5), 8.19 (d, 1H, J = 8.9 Hz, H-4), 8.30
(d, 1H, J = 2.0 Hz, H-1). 13C NMR (300 MHz, CDCl3)
33.45 (C-11), 55.87 (OCH3), 99.98 (C-8), 123.83 (C-1),
124.06 (C-9a), 125.68 (C-8a), 126.70 (C-6), 130.26 (C-4),
130.88 (C-3), 130.99 (C-5), 136.72 (C-2), 138.95 (C-9),
145.76 (C-5a), 146.07 (C-4a), 158.63 (C-7).
(8) Orazi et al. Annales Asoc. Quim. Argentina 1952, 40, 91.
Pintado, O. A. Rev. Fac. Cienc. Quim. Univ. La Plata 1955,
29, 53.
(9) Acheson, R. M.; Bolton, R. G. J. Chem. Soc. Perkin Trans 1
1975, 650. Takashi, K.; Castle, N. R. J. Heterocycl. Chem.
1987, 24, 977.
Spectroscopy data of selected compound 10b: 1H NMR (300
MHz, DMSO-d6 / TFA) : 1.40 (s br, 2H, H-14), 1.99 (s br,
4H, H-13), 3.30 (s br, 4H, H-12), 3.89 (s, 6H, OCH3), 4.62 (s,
4H, H-11), 7.57 (dd, 2H, J = 2.4 and 8.8 Hz, H-6), 7.64 (d, 2H,
J = 9.0 Hz, H-5), 7.70 (d, 2H, J = 8.9 Hz, H-4), 7.77 (d, 2H,
J = 1.8 Hz, H-8), 7.95 (d br, 2H, J = 9.1 Hz, H-3), 8.53 (s br,
2H, H-1), 9.73 (s, 2H, NH). 13C NMR (300 MHz, DMSO-d6 /
TFA) 23.27 (C-14), 23.27 (C-13), 46.59 (C-12), 57.06 (C-
11), 56.29 (OCH3), 102.87 (C-8), 110.63 (C-9a), 112.48 (C-
8a), 119.31 (C-4), 120.72 (C-5), 126.08 (C-1), 127.86 (C-2),
128.41 (C-6), 134.75 (C-5a), 136.31 (C-3), 138.30 (C-4a),
156.72 (C-7), 157.08 (C-9).
General procedure for the synthesis of dimers 6a-c:
2-(Bromomethyl)-9-chloro-7-methoxyacridine 5 (1 g, 2.97
mmol) and 1,4-butanediamine (0.31 g, 3.51 mmol) were
refluxed under stirring for 5 h in CH2Cl2 (35 mL). The hot
mixture was filtered and the resulting precipitate was warmed
under stirring in CHCl3 (100 mL) for 1 h. The hot solution was
filtered and the organic layer was dried and evaporated to give
6a (0.38 g, 0.63 mmol, 43%) as a beige powder, mp 206 °C.
Dimers 6b-c were obtained by the same procedure.
(10) Spectroscopy data of selected compound 6a: 1H NMR (300
MHz, CDCl3) 1.66 (t, 4H, J = 6.0 Hz, H-13), 2.75 (t, 4H,
J = 6.0 Hz, H-12), 4.00 (s, 6H, OCH3), 4.02 (s, 4H, H-11),
7.42 (dd, 2H, J = 2.7 and 9.2 Hz, H-6), 7.45 (d, 2H, J = 2.7 Hz,
H-8), 7.70 (dd, 2H, J = 1.5 and 8.9 Hz, H-3), 8.04 (d, 2H,
J = 9.2 Hz, H-5), 8.09 (d, 2H, J = 8.9 Hz, H-4), 8.21 (s, 2H, H-
1).13C NMR (300 MHz, CDCl3) 27.95 (C-13), 49.42 (C-
12), 54.00 (C-11), 55.77 (OCH3), 99.92 (C-8), 122.04 (C-1),
124.28 (C9a), 125.41 (C-8a), 125.69 (C-6), 130.07 (C-4),
130.36 (C-3), 131.54 (C-5), 137.79 (C-2), 139.15 (C-9),
145.91 (C-5a), 146.85 (C-4a), 158.27 (C-7).
(11) General procedure for the synthesis of tetramers 9a-d: A
mixture of 2-(bromomethyl)-9-chloro-7-methoxyacridine 5
(1.24 g, 3.68 mmol) and 1,5-pentanediamine (0.20 g, 1.93
mmol) in CH2Cl2 (80 mL) was refluxed under stirring for 24
h. The hot mixture was filtered. The organic phase was dried
and evaporated, and the resulting solid was chromatographed
on silica gel (CHCl3/EtOH : 99/1) to yield 9a (0.49 g, 0.43
mmol, 47%) as a yellow powder, mp 212 °C. Tetramers 9b-d
were obtained by the same procedure.
(13) General demethylation method for the synthesis of
compounds 8a-c and 11a-d: 0.20 g (0.36 mmol) of 7a was
refluxed 3 days in 10 mL of HBr (48%). Then the mixture was
poured into cold water (50 mL). The solution was basified
with NH3 (10%) until pH = 9 and the red precipitate was
filtered to give 8a (0.074 g, 0.14 mmol, 39%) as a red solid,
mp 316 °C. Dimers 8b-c and tetramers 11b-d were obtained
by the same procedure.
Spectroscopy data of selected compound 8a: 1H NMR (300
MHz, DMSO-d6 / TFA) : 1.77 (s br, 4H, H-13), 3.04 (s br,
4H, H-12), 4.28 (s, 4H, H-11), 7.62 (dd, 2H, J = 1.9 and 9.0
Hz, H-6), 7.79 (d, 2H, J = 9.1 Hz, H-5), 7.84 (s br, 2H, H-8),
7.86 (d, 2H, J = 8.7 Hz, H-4), 8.02 (d br, 2H, J = 8.8 Hz, H-3),
8.80 (s br, 2H, H-1). 13C NMR (300 MHz, DMSO-d6 / TFA)
23.73 (C-13), 46.97 (C-12), 51.00 (C-11), 106.72 (C-8),
111.35 (C-9a), 120.20 (C-8a), 121.02 (C-4), 121.23 (C-5),
127.47 (C-1), 128.73 (C-6), 128.98 (C-2), 134.78 (C-5a),
136.64 (C-3), 139.35 (C-4a), 155.32 (C-7), 157.32 (C-9).
(14) Galy J. P.; Faure R.; Barbe J.; Elguero J. Spectrosc. Lett. 1988,
21, 809.
Spectroscopy data of selected compound 9a: 1H NMR (300
MHz, CDCl3) : 1.53 (m, 2H, C-14), 1.81 (m, 4H, H-13), 2.55
(t, 4H, J = 6.7 Hz, H-12), 3.67 (s, 8H, H-11), 3.92 (s, 12H,
OCH3), 7.32 (d, 4H, J = 1.2 Hz, H-8), 7.32 (dd, 4H, J = 2.8
and 10.3 Hz, H-6), 7.72 (dd, 4H, J = 1.8 and 8.9 Hz, H-3), 7.97
(d, 4H, J = 10.1 Hz, H-5), 8.03 (d, 4H, J = 8.8 Hz, H-4), 8.16
(s br, 4H, H-1). 13C NMR (300 MHz, CDCl3) : 26.60 (C-14
Article Identifier:
1437-2096,E;2001,0,07,1137,1139,ftx,en;D04701ST.pdf
Synlett 2001, No. 7, 1137–1139 ISSN 0936-5214 © Thieme Stuttgart · New York