Regioselective synthesis of angular nitrogen polyheterocycles: Dipyrido[3,2-a:2′,3′-c]quinolino[2,3-h]phenazines

Article abstract of DOI:10.1016/S0040-4039(02)01900-7

Novel polyaza heterocycles, dipyrido[3,2-a:2′,3′-c]quinolino[2,3-h]phenazines, were synthesized via a regiocontrolled condensation between 5,6-phendione and 3,4-diaminoacridine derivatives.

Full text of DOI:10.1016/S0040-4039(02)01900-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7883–7885
Regioselective synthesis of angular nitrogen polyheterocycles:
dipyrido[3,2-a:2%,3%-c]quinolino[2,3-h]phenazines
Rodica Dinica, Franck Charmantray, Martine Demeunynck* and Pascal Dumy
LEDSS, UMR CNRS 5616, Universite´ Joseph Fourier, BP 53, 38041 Grenoble cedex 9, France
Received 29 August 2002; revised 2 September 2002; accepted 5 September 2002
Abstract—Novel polyaza heterocycles, dipyrido[3,2-a:2%,3%-c]quinolino[2,3-h]phenazines, were synthesized via a regiocontrolled
condensation between 5,6-phendione and 3,4-diaminoacridine derivatives. © 2002 Elsevier Science Ltd. All rights reserved.
DNA may adopt a variety of multistranded structures,
double-, triple- or quadruple-stranded. There is growing
interest in the design of ligands binding specifically to
one type of the multistranded structures, both as antitu-
mor agents or tools for molecular biology.1 Ligands
that bind strongly to quadruplexes (G-quadruplexes or
G-4 structures) may modulate telomerase activity in
cancer cells and induce cell death.2 Ligands with triplex
specificity are useful to promote and stabilize the for-
mation of triple helices in antigene strategy.3,4 A large
diversity of structures has been tested as triplex or
quadruplex specific binders. In this context linear and
angular extended fused polyaza heterocycles appeared
very promising. They interact by intercalation between
base triplets/quadruplexes or lay on the top of the
quadruplex region. To overcome the low solubility in
water of these polyheterocycles, polar substituents,
mainly amino side-chains, were added to the central
structure.
We therefore considered the synthesis of a novel hetero-
cycle: dipyrido[3,2-a:2%,3%-c]quinolino[2,3-h]phenazine
II, that only differs from I by the presence of five
heterocyclic nitrogens. Phenazine fused heterocycles,
which are prepared by condensation of an ortho-
diamino cycle with an ortho-diketo derivative, have
been studied as metal ligands,6–10 DNA nucleases11 or
anticancer agents.12
We report here the synthesis of angular extended metal
ligands,
dipyrido[3,2-a:2%,3%-c]quinolino[2,3-h]phena-
zines bearing various substituents.
It appeared interesting to combine the DNA intercalat-
ing properties of the acridine nucleus with the nuclease
activity of [1,10]phenanthroline ligands, to design a
novel family of angular DNA binders. We recently
reported the synthesis of novel tetraaza heptacycle ben-
zo[b]phenanthrolino[1,10][5,6-j ]phenanthroline I.5 The
key step was the reaction of 5-amino[1,10]phenan-
throline with 3-amino-4-hydroxymethyl acridine, pre-
cursor of quinone-imine-methide type reactive interme-
diate. The major drawback of the method is the
three-step synthesis of the acridine key-intermediate
that is not compatible with the presence of unprotected
or acid sensitive substituents.
* Corresponding author. Tel.: +33 (0)4 76514429; fax: +33 (0)4
76514946; e-mail: martine.demeunynck@ujf-grenoble.fr
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01900-7

7884
R. Dinica et al. / Tetrahedron Letters 43 (2002) 7883–7885
Scheme 1. Preparation of the ortho-diaminoacridine synthons. (i) p-nitrophenyl diazonium, NaBF4, MeOH, 0°C; (ii) Na2S2O4, pH
7 phosphate buffer, rt; (iii) AlCl3, xylene, 90°C.
As shown in Fig. 1, the synthesis of II involves conden-
sation of 3,4-diaminoacridine derivatives with the phen-
5,6-dione. We designed
a regioselective two-step
synthesis (Scheme 1) to prepare the ortho-diamino-
acridine key intermediates from commercially available
3,6-diaminoacridine 1 (proflavine) and 6,9-diamino-2-
ethoxyacridine 4 (ethacridine). As reported previ-
ously,13 proflavine or ethacridine react with p-nitro-
benzenediazonium salt to give the corresponding 3-
amino-4-p-nitrophenylazo compounds 2 and 6 in 70
and 80% yields, respectively. The reaction is fully
regioselective and does not require protection of the
other amino substituents. In the case of proflavine, the
reaction allows the dessymmetrization of the molecule
as the electrophilic substitution only proceeds in one
side of the molecule because of the strong electron
withdrawing effect of the diazo group that prevents a
second substitution to occur. We extended this elec-
trophilic reaction to the 9-hydroxy analogue of
ethacridine 5 to prepare the diazo compound 7 in 93%
yield. Reduction of the diazo group with sodium
dithionite afforded the ortho-diamines 3, 8 and 9 in
moderate to good yields (45–70%). Cleavage of the
Scheme 2.
various side-chains on the intercalating heterocycles in
order to improve their solubility in water and modulate
their interaction with DNA. In preliminary experiments
(data not shown), compounds 12 and 13 were shown to
exhibit DNA cleavage properties similarly to those
known for phenanthroline in the presence of Cu(I).
Acknowledgements
2-ethoxy group of
8 to give 2-hydroxy-5,6,9-tri-
aminoacridine 10 was achieved in 88% yield by reflux-
ing 8 in xylene in the presence of AlCl3.
This work was supported by the Centre National pour
la Recherche Scientifique (CNRS), in the framework of
Laboratoire Europe´en Associe´ (LEA) and COST D14
action, as well as by the Institut Universitaire de France
(IUF). We also acknowledge the MENRT for a grant
for F.C.
The final condensation of the ortho-diamine (3, 8–10)
with phen-5,6-dione 1114 was achieved by refluxing
stoichiometric amounts of the two compounds in etha-
nol (Scheme 2). Pentaaza heptacycles 12–15 were thus
obtained in good yields (64–89%). The structures of all
1
new compounds were assessed by H and 13C NMR,
and mass spectrometry.15
References
As a conclusion, we have devised a general and very
efficient route to variously substituted angular pentaaza
heptacyclic compounds derived from the corresponding
phenanthroline and acridine. The presence of amino
and/or hydroxy groups will now allow introduction of
1. Belmont, P.; Constant, J. F.; Demeunynck, M. Chem.
Soc. Rev. 2001, 30, 70–80.
2. Kerwin, S. M. Curr. Pharmaceut. Des. 2000, 6, 441–471.
3. Fox, K. R. Curr. Med. Chem. 2000, 7, 17–37.

R. Dinica et al. / Tetrahedron Letters 43 (2002) 7883–7885
7885
4. Praseuth, D.; Guieysse, A. L.; Helene, C. Biochim. Bio-
phys. Acta 1999, 1489, 181–206.
5. Charmantray, F.; Demeunynck, M.; Lhomme, J.; Duflos,
A. J. Org. Chem. 2001, 66, 8222–8226.
6. Bolger, J.; Gourdon, A.; Ishow, E.; Launay, J.-P. Inorg.
Chem. 1996, 35, 2937–2944.
7. Gourdon, A. Synth. Commun. 1997, 27, 2893–2897.
8. Holmlin, R. E.; Yao, J. A.; Barton, J. K. Inorg. Chem.
1999, 38, 174–189.
d) 10.50 (1H, d, J=8.2 Hz), 9.83 (1H, d, J=7.9 Hz),
9.44–9.37 (3H, m), 8.55–8.45 (2H, m), 8.38–8.31 (1H, m),
8.25 (1H, d, J=9.3 Hz), 8.16 (1H, d, J=9.3 Hz), 7.38
(2H, m); 13C NMR (75 MHz, TFA-d) 157.5, 149.5 (CH),
149.4 (CH), 146.9, 145.6 (CH), 143.3, 142.7, 141.5 (CH),
141.0 (CH), 140.6, 140.3, 138.9, 137.3, 134.4, 133.3 (CH),
132.7 (CH), 130.3, 130.0, 128.5 (CH), 128.3 (CH), 127.7
(CH), 126.6, 124.4 (CH), 123.7; MS (positive FAB, glyc-
erol) m/z 399 (M+1)+.
13. (81% yield). Mp>350°C; 1H NMR (300 MHz,
DMSO-d6) 9.92 (1H, d, J=7.5 Hz), 9.67 (1H, d, J=7.7
Hz), 9.34 (2H, m), 8.78 (1H, d, J=9.2 Hz), 8.25 (1H, d,
J=9.2 Hz), 8.09 (2H, s, NH2), 7.98–7.80 (4H, m), 7.58
(1H, d, J=8.8 Hz), 4.35 (2H, q, CH2), 1.56 (3H, t, CH3;
13C NMR (75 MHz, TFA-d) 162.87, 150.44 (CH), 150.13
(CH) 147.70, 143.62, 142.39, 141.32 (CH), 141.03, 139.72,
138.64, 137.43,135.92, 133.96 (CH), 130.83, 129.15 (CH),
129.00 (CH), 128.48 (CH), 127.46 (CH), 122.94 (CH),
121.40, 121.17, 115.81, 114.02, 110.26, 102.47 (CH), 66.93
(CH2), 14.03 (CH3); MS (positive FAB, glycerol) m/z
443.2 (M+1)+.
9. Ruminski, R. R.; Deere, P. T.; Olive, M.; Serveiss, D.
Inorg. Chim. Acta 1998, 281, 1–9.
10. Zou, X.-H.; Ye, B.-H.; Liu, J.-G.; Xiong, Y.; Ji, L.-N. J.
Chem. Soc., Dalton Trans. 1999, 1423–1428.
11. Ambroise, A.; Maiya, B. G. Inorg. Chem. 2000, 39,
4256–4263.
12. Vicker, N.; Burgess, L.; Chuckowree, I. S.; Dodd, R.;
Folkes, A. J.; Hardick, D. J.; Hancox, T. C.; Miller, W.;
Milton, J.; Sohal, S.; Wang, S.; Wren, S. P.; Charlton, P.
A.; Dangerfield, W.; Liddle, C.; Mistry, P.; Stewart, A. J.;
Denny, W. A. J. Med. Chem. 2002, 45, 721–739.
13. Mo¨hrle, H.; Von der Lieck-Waldheim, U.; Martin, H. D.;
Possberg, N.; Beutner, S. Pharmazie 1997, 52, 603–611.
14. Paw, W.; Eisenberg, R. Inorg. Chem. 1997, 36, 2287–
2293.
1
14. (64% yield). Mp>350°C; H NMR (300 MHz, TFA-
d) 11.20 (1H, d, J=8.3 Hz), 11.13 (1H, d, J=8.7 Hz),
10.19 (2H, m), 9.81 (1H, d, J=9.8 Hz), 9.33–9.22 (4H,
m), 8.88–8.82 (2H, m), 5.21 (2H, q, CH2), 2.40 (3H, t,
CH3); 13C NMR (75 MHz, TFA-d) 167.81, 150.45 (CH),
149.96 (CH), 147.59, 143.49, 142.32 (CH), 141.28, 141.02
(CH), 139.65, 138.58, 137.28, 135.77, 133.65 (CH),
130.66, 130.36, 129.01 (CH), 128.86 (CH), 128.31 (CH),
127.39 (CH), 122.86 (CH), 121.32, 117.82, 115.73, 114.03,
102.56 (CH), 66.71 (CH2), 14.03 (CH3); MS (positive
FAB, glycerol) m/z 444.2 (M+1)+.
15. Typical procedures. Synthesis of 12.
Synthesis of 3,4-diaminoacridine synthon 3. To a solution
of azo compound 213 (0.5 g, 1.4 mmol) in DMF (15 mL)
was slowly added a solution of Na2S2O4 (0.3 M in pH 7
phosphate buffer, 250 mM, 40 mL). After 5 h of stirring
at rt; the solution was poured into water (400 mL) and
the pH was adjusted to pH 8 by adding NH4OH. Extrac-
tion with AcOEt afforded 3 in 70% yield.
Formation of 15-amino-dipyrido[3,2-a:2%,3%-c]quinolino-
15. (74% yield). Mp>350°C; 1H NMR (300 MHz,
DMSO-d6, five drops TFA) 10.47 (1H, d, J=8.3 Hz),
9.83 (1H, d, J=7.6 Hz), 9.44 (2H, m), 8.73 (1H, d, J=9.6
Hz), 8.44 (2H, m), 8.22 (1H, d, J=7.5 Hz), 8.01 (1H, d,
J=9.6 Hz), 7.53 (1H, s), 7.38 (1H, d, J=7.5 Hz); MS
(positive FAB, glycerol) m/z 415.2 (M+1)+.
[2,3-h]phenazine 12.
A stoichiometric mixture (0.67
mmol) of 3 and 5,6-phendione 11 in absolute EtOH (30
mL) was refluxed for 1 h. After cooling, the solid that
formed was filtered and washed with absolute EtOH.
Compound 12 was thus obtained in 89% yield. Mp>
1
350°C; H NMR (200 MHz, DMSO-d6, five drops TFA-