N,N′-Bis-((dimethylamino)ethylamino)-2,6-bis(2-(3-(dimethyl-
amino)methyl-4-hydroxyphenyl)ethylamino)-1,4-5,8-naphthale-
netetracarboxylic bisimide tetrahydrochloride (6·4HCl). Violet
role in key biological processes as well as offering the exciting
perspective of novel cancer-related target identification.
Although the therapeutic approaches based on G4 targeting
are still in their infancy, accumulating evidence indicates that
telomeric G4 stabilizing agents are able to selectively impair the
growth of cancer cells without affecting the viability of normal
cells.2,35 This observation, along with the recently completed
phase I–II clinical trials with the G4 binder quarfloxin (www.
ClinicalTrial.gov), points to G4 ligands as possible drug candi-
dates for future clinical applications.
1
solid. M.p. dec. >350 °C. H NMR (CD3OD, 300 MHz): δ =
8.50 (s, 2H); 7.17 (m, 4H); 6.82 (d, 2H, J = 10.3 Hz); 4.57 (m,
4H); 4.26 (s, 4H); 3.60 (t, 4H, J = 7.7 Hz); 3.31 (m, 4H); 3.04
(s, 12H); 2.84 (s, 12H); 2.72 (s, 4H). 13C NMR (CD3OD): δ =
173.5; 165.4; 156.5; 152.5; 133.8; 133.6; 132.4; 126.4; 125.5;
125.0; 117.8; 116.7; 108.4; 58.7; 57.8; 44.8; 44.4; 43.5; 42.3;
37.4; 35.8; 28.3; 22.8. Elemental analysis (%) calcd for
C44H60Cl4N8O6: C, 56.29; H, 6.44; Cl, 15.11; N, 11.94; O,
10.23. Found C, 56.32; H, 6.41; Cl, 15.18; N, 12.00.
Experimental
Nucleophilic aromatic substitution reaction at r.t.
Microwave assisted synthesis of the NDIs
The NDI 914 (250 mg, 0.4 mmol) and the corresponding amine
(11 and 12,11 0.6 mmol) were heated in DMF in a microwave
reactor (closed vessel) at 180 °C, 200 psi and 200 W for
3–10 min. The violet solution was cooled at r.t. and water
(50 ml) was added to induce precipitation. The filtered crude
was purified by HPLC, using a C-18 reverse phase column
(CH3CN : H2O 0.1% TFA, as eluent). Addition of 0.5 ml HCl
1 M solution to each chromatographic portion and solvent
evaporation under vacuum afforded adducts 1, 1Br, 2, 2Br, and
6 as hydrochlorides.
The NDI 9 (250 mg, 0.4 mmol) was dissolved into 20 ml of
DMF in a round bottom flask together with the corresponding
amine (11, 13 and 14; 0.6 mmol). The mixture was stirred at r.t.
for 8–48 h under argon. The resulting red solution was poured in
water (100 ml) and filtered. The solid collected was washed with
water and purified by preparative HPLC chromatography
(CH3CN : H2O, 0.1% TFA). HCl 1 M solution was added to
each chromatographic portion. Solvent evaporation under
vacuum afforded the adducts 1, 1Br, 3, 3Br and 4 as
hydrochlorides.
Acknowledgements
N,N′-Bis-((dimethylamino)ethylamino)-2-(2-(3-(dimethylamino)
methyl-4-hydroxy phenyl)ethylamino)-1,4-5,8-
naphthalenetetracarboxylic bisimide trihydrochloride
This work was supported by MIUR, Grant FIRB-Ideas
RBID082ATK, Grants AIRC 5826 and 8861 (Associazione Itali-
ana per la Ricerca sul Cancro) and by Pavia University. The use
of FLAP software is a courtesy of Molecular Discovery Ltd, UK.
We thank Dr Giovanna Sattin and Dr Daniele Dal Zoppo (Uni-
versity of Padova) for assistance with the MS experiments.
(2·3HCl): Red solid. M.p. dec. >350 °C. 1H NMR(CD3OD,
300 MHz): δ = 8.36 (d, 1H, J = 7.8 Hz); 8.08 (d, 1H, J = 7.8
Hz); 7.94 (s, 1H); 7.40 (s, 1H); 7.37 (d, 1H, J = 8.4 Hz); 6.96
(d, 1H, J = 8.4 Hz); 4.53–4.52 (m, 4H); 4.34 (s, 2H); 3.82 (t,
2H, J = 6.8 Hz); 3.60–3.54 (m, 4H); 3.05 (s, 14H); 2.90 (s, 6H).
13C NMR (CD3OD): δ = 167.4; 165.1; 165.0; 164.7; 157.0;
153.7; 134.3; 133.8; 132.3; 131.5; 131.0; 129.0; 127.4; 125.6;
124.5; 121.3; 120.7; 118.3; 117.2; 100.5; 65.2; 57.6; 57.3; 45.9;
44.4; 44.3; 43.6; 37.2; 36.8; 35.7. Elemental analysis (%) calcd
for C33H43Cl3N6O5: C, 55.82; H, 6.10; Cl, 14.98; N, 11.84; O,
11.27. Found C, 55.78; H, 6.19; Cl, 15.03; N, 11.82.
Notes and references
1 D. Hanahan and R. A. Weinberg, Cell, 2011, 5, 646.
2 M. Folini, L. Venturini, G. Cimino-Reale and N. Zaffaroni, Expert Opin.
Ther. Targets, 2011, 15, 579.
3 T. De Lange, Science, 2009, 5955, 948.
4 J.-D. Henson and R.-R. Reddell, FEBS Lett., 2010, 584, 3800.
5 A.-J. Cesare and R.-R. Reddell, Nat. Rev. Genet., 2010, 11, 19.
6 J.-W. Shay and W.-E. Wright, Nat. Rev. Drug Discovery, 2006, 5, 577.
7 A. Roth, C.-B. Heraly and G.-M. Baerlocher, Recent Results Cancer Res.,
2010, 184, 221.
8 T.-M. Bryan and P. Baumann, Methods Mol. Biol., 2010, 608, 1.
9 D. Monchaud and M.-P. Teulade-Fichou, Org. Biomol. Chem., 2008, 6,
627.
N,N′-Bis-((dimethylamino)ethylamino)-2-bromo-6-(2-(3-
(dimethylamino)methyl-4-hydroxyphenyl)ethylamino)-1,4-5,8-
naphthalenetetracarboxylic bisimide trihydrochloride
10 H. Bertrand, S. Bombard, D. Monchaud, E. Talbot, A. Guedin, J.-
L. Mergny, R. Grunert, P.-J. Bednarskid and M.-P. Teulade-Fichou, Org.
Biomol. Chem., 2009, 6, 2866.
1
(2Br·3HCl): Blue solid. M.p. dec. >350 °C. H NMR (CD3OD,
300 MHz): δ = 8.44 (s, 1H); 8.15 (s. 1H); 7.15 (d, 1H, J = 8.2
Hz); 6.91 (s, 1H); 6.80 (d, 1H, J = 8.2 Hz); 4.40–4.33 (m, 4H);
3.73 (m, 2H); 3.65 (s, 2H); 2.99 (m, 2H); 2.71 (bs, 4 H); 2.45 (s,
6H); 2.42 (s, 6H); 2.33 (s, 6H). 13C NMR (CD3OD): δ = 166.0;
163.2; 161.7; 156.7; 150.9; 149.5; 129.0; 128.6.; 128.4; 126.7;
124.0; 123.4; 122.8; 122.0; 118.4; 116.1; 108.3; 101.1; 62.7;
56.9; 56.8; 45.5; 45.0; 44.4; 44.0; 38.2; 37.7; 35.0; 30.8.
Elemental analysis (%) calcd for C33H42BrCl3N6O5: C, 50.24;
H, 5.37; Br, 10.13; Cl, 13.48; N, 10.65; O, 10.14. Found C,
50.30; H, 5.39; Br, 10.08; Cl, 13.53; N, 10.61.
11 M. Di Antonio, F. Doria, S.-N. Richter, C. Bertipaglia, M. Mella,
C. Sissi, M. Palumbo and M. Freccero, J. Am. Chem. Soc., 2009, 131,
13132.
12 F. Cuenca, O. Greciano, M. Gunaratnam, S. Haider, D. Munnur,
R. Nanjunda, W.-D. Wilson and S. Neidle, Bioorg. Med. Chem. Lett.,
2008, 18, 1668.
13 S.-M. Hampel, A. Sidibe, M. Gunaratnam, J.-F. Riou and S. Neidle,
Bioorg. Med. Chem. Lett., 2010, 20, 6459.
14 M. Nadai, F. Doria, M. Di Antonio, G. Sattin, L. Germani, C. Percivalle,
M. Palumbo, R. S. Richter and M. Freccero, Biochimie, 2011, 93, 1328.
15 S. Cross, M. Baroni, E. Casorati, P. Benedetti and S. Clementi, J. Chem.
Inf. Model., 2010, 50, 1442.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 2798–2806 | 2805