N. Desbois et al. / European Journal of Medicinal Chemistry 69 (2013) 719e727
725
Fig. 5. Influence of the polymethylene linker chain on IC50 values of substituted 5H-dibenzo[c,h][1,6]naphthyridin-6-ones trihydrochlorides (7aee) in human cancer colorectal HCT
116, HT-29 and SW480 cell lines after a 72 h-treatment. Statistics: *: p < 0.05; **: p < 0.01 (A). Ranking of IC50 values from the most to the less powerful derivatives according to the
size of the polymethylene linker; < expressed significant differences between compounds (B).
The mixture was purified using column chromatography (SiO2,
removed by rotary evaporation. The crude product was purified
using column chromatography (SiO2, CH2Cl2/MeOH/NH4OH, 90/15/
3). The instable product was diluted with dry dichloromethane
(2 mL) and treated with an anhydrous 1 N hydrochloric acideether
solution (2 mL). The solution was concentrated under vacuo started
again with dry ether (3 mL). The suspension was stirred overnight
and filtered. 7a: Yield: 49%. mp 223e225 ꢀC. 1H NMR (DMSO,
AcOEt).
6a: Yield: 63%. mp 230e232 ꢀC. 1H NMR (CDCl3, 300 MHz)
d 9.37
(s, 1H), 9.26 (s, 1H), 8.54 (d, 1H, J ¼ 9 Hz), 8.46 (d, 1H, J ¼ 9 Hz), 7.40
(m, 2H), 6.16 (s, 2H), 4.74 (t, 2H, J ¼ 7 Hz), 3.04e3.40 (m, 6H), 1.34
(m, 18H), 13C NMR (CDCl3, 75 MHz)
d 163.5, 156.1 (2C), 151.5, 148.5,
148.4, 147.2, 143.6, 143.3, 137.8, 127.4, 125.5, 124.8, 122.9, 114.4,
110.6, 106.7, 102.7, 101.3, 80.7 (2C), 50.3, 47.4, 45.6, 39.3, 28.4 (6C).
300 MHz)
d 9.94 (s, 1H), 9.62 (se, 2H), 9.00 (m, 2H), 8.67 (d, 1H,
6b: Yield: 56%. mp 109e111 ꢀC. 1H NMR (CDCl3, 300 MHz)
d
9.45 (s,
J ¼ 8 Hz), 9.37 (se, 3H), 7.78 (s, 1H), 7.75 (s, 1H), 6.41 (s, 2H), 5.00 (t,
1H), 9.31 (s, 1H), 8.58 (d, 1H, J ¼ 9 Hz), 8.49 (d, 1H, J ¼ 9 Hz), 7.53 (m,
2H, J ¼ 7 Hz), 3.44 (m, 2H), 3.13 (m, 4H), 13C NMR (DMSO, 75 MHz)
2H), 6.20 (s, 2H), 4.48 (t, 2H, J ¼ 7 Hz), 3.27e3.40 (m, 6H), 2.32 (t,
d
162.4, 152.3, 148.6, 147.1, 145.1, 141.1, 140.4, 137.1, 127.6, 125.1, 125.0,
2H, J ¼ 7 Hz), 1.42 (m, 18H), 13C NMR (CDCl3, 75 MHz)
d
163.0, 155.9
123.2, 114.5, 111.6, 103.6, 102.0, 101.8, 49.9, 46.9, 44.2, 35.1. HR-MS
(ESI) m/z ¼ 422.1450 [M þ H]þ 422.1459 calcd for C21H20N5O5.
Anal. Calc. for C21H19N5O5$3HCl$2H2O requires: C, 44.50; H, 4.62; N,
12.36. Found: C, 46.30; H, 4.72; N, 12.17. 7b: Yield: 80%. mp 240e
(2C), 151.1, 148.8, 148.1, 147.0, 143.9, 143.1, 137.5, 127.2, 125.5, 124.8,
122.8, 114.3, 110.3, 107.3, 102.6, 100.6, 80.2 (2C), 49.1, 46.4, 44.6,
39.3, 29.7, 28.3 (6C). 6c: Yield: 36%. mp 163e165 ꢀC. 1H NMR (CDCl3,
300 MHz)
d
9.46 (s, 1H), 9.33 (s, 1H), 8.59 (d, 1H, J ¼ 9 Hz), 8.50 (d,
242 ꢀC. 1H NMR (D2O, 300 MHz)
d 9.30 (s, 1H), 8.87 (s, 1H), 8.54 (d,
1H, J ¼ 9 Hz), 7.51 (s, 1H),7.48 (s, 1H), 6.21 (s, 2H), 4.50 (t, 2H,
1H, J ¼ 8 Hz), 8.38 (d, 1H, J ¼ 8 Hz), 7.38 (s, 1H), 7.24 (s, 1H), 6.33 (s,
J ¼ 7 Hz), 3.23 (m, 6H), 1.66e2.08 (m, 4H), 1.41 (m, 18H), 13C NMR
2H), 4.43 (m, 2H), 3.24e3.46 (m, 6H), 2.44 (m, 2H), 13C NMR (DMSO,
(CDCl3, 75 MHz)
d
163.0, 156.1 (2C), 151.3, 148.3, 148.1, 146.9, 143.7,
75 MHz) d 162.2, 152.8, 149.0, 147.2, 145.9, 140.3, 139.3, 136.4, 127.6,
143.1, 137.3, 127.3, 125.3, 124.7, 122.8,114.3, 110.5,106.7, 102.6,100.4,
125.2, 124.8, 123.1, 114.5, 110.9, 104.0, 101.6, 99.6, 48.3, 44.4, 44.0,
35.2, 24.8. HR-MS (ESI) m/z ¼ 436.1608 [M þ H]þ 436.1616 calcd for
C22H22N5O5. Anal. Calc. for C22H21N5O5$3HCl$OEt2$2H2O requires:
C, 47.68; H, 5.85; N, 10.69. Found: C, 48.96; H, 6.09; N, 10.21. 7c:
80.2 (2C), 50.7, 46.9, 46.4, 39.1, 28.1 (6C), 26.0 (2C). 6d: Yield: 62%.
mp 189e191 ꢀC. 1H NMR (CDCl3, 300 MHz)
d 9.42 (s, 1H), 9.29 (s,
1H), 8.56 (d, 1H, J ¼ 9 Hz), 8.47 (d, 1H, J ¼ 9 Hz), 7.50 (s, 1H), 7.45 (s,
1H), 6.20 (s, 2H), 4.45 (t, 2H, J ¼ 7 Hz), 3.24 (m, 6H), 1.66e2.08 (m,
Yield: 85%. mp 259e261 ꢀC. 1H NMR (D2O, 300 MHz)
d 9.44 (s, 1H),
6H), 1.40 (m, 18H), 13C NMR (CDCl3, 75 MHz)
d
163.0, 156.1 (2C),
8.92 (s, 1H), 8.60 (d, 1H, J ¼ 8 Hz), 8.43 (d, 1H, J ¼ 8 Hz), 7.53 (s, 1H),
7.37 (s, 1H), 6.38 (s, 2H), 4.42 (t, 2H, J ¼ 7 Hz), 3.42 (m, 4H), 3.20 (t,
2H, J ¼ 7 Hz), 2.08 (m, 2H), 1.78 (m, 2H), 13C NMR (D2O, 75 MHz)
151.1, 148.5, 148.1, 147.1, 143.8, 143.2, 137.4, 127.2, 125.5, 124.8, 122.8,
114.4, 110.4, 106.9, 102.6, 100.6, 80.0 (2C), 51.0, 47.4, 46.2, 39.2, 29.7,
28.5, 28.3 (6C), 24.0. 6e: Yield: 68%. mp 72e74 ꢀC. 1H NMR (CDCl3,
d
163.6, 153.9, 149.7, 147.4, 146.7, 139.7, 138.6, 135.8, 128.2, 124.5,
300 MHz)
d
9.43 (s, 1H), 9.30 (s, 1H), 8.57 (d, 1H, J ¼ 9 Hz), 8.48 (d,
123.9, 123.7, 114.8, 110.8, 104.5, 101.3, 99.8, 51.0, 47.4, 44.0, 35.3, 25.0,
1H, J ¼ 9 Hz), 7.52 (s, 1H), 7.45 (s, 1H), 6.21 (s, 2H), 4.45 (t, 2H,
22.9. HR-MS (ESI) m/z ¼ 450.1752 [M þ H]þ 450.1772 calcd for
J ¼ 7 Hz), 3.24 (m, 6H), 1.66e2.07 (m, 6H), 1.41 (m, 18H), 13C NMR
C23H24N5O5. Anal. Calc. for C23H23N5O5$3HCl$H2O requires: C, 47.89;
(CDCl3, 75 MHz)
d
163.0, 156.1 (2C), 151.2, 148.8, 148.1, 147.1, 144.0,
H, 4.89; N,12.14. Found: C, 47.74; H, 4.73; N,11.98. 7d: Yield: 50%. mp
143.3, 137.6, 127.2, 125.6, 124.9, 122.8, 114.4, 110.3, 107.3, 102.6,
100.7, 79.9 (2C), 51.1, 47.4, 46.9, 39.7, 28.8, 28.6, 28.5 (7C), 26.6, 26.4.
208e210 ꢀC. 1H NMR (D2O, 300 MHz)
d
9.46 (s,1H), 8.92 (s,1H), 8.58
(d,1H, J ¼ 8 Hz), 8.43 (d,1H, J ¼ 8 Hz), 7.55 (s,1H), 7.39 (s,1H), 6.37 (s,
2H), 4.38 (t, 2H, J ¼ 7 Hz), 3.38 (m, 4H), 3.11 (t, 2H, J ¼ 7 Hz), 2.00 (m,
4.1.5. Synthesis of 2,3-methylenedioxy-8-nitro-5-[N-[aminoalkyl]-
ethane-1,2-diamine]-5H-dibenzo[c,h][1,6]naphthyridin-6-ones
trihydrochlorides (7aee)
Boc deprotection of 6 was attained by dropwise addition of tri-
fluoroacetic acid (TFA) (1.2 mL, 16.2 mmol) at 0 ꢀC to a solution of 6
(0.15 mmol) in distilled CH2Cl2 (5 mL). The mixture was stirred at
room temperature under nitrogen for 1 h. The solvents were then
2H),1.73 (m, 2H),1.42 (m, 2H). 13C NMR (D2O, 75 MHz)
d 163.6,154.1,
149.8,147.5, 147.2, 139.4, 139.1, 135.6, 128.2, 124.5, 124.0, 123.9, 114.9,
110.7, 104.6, 101.5, 99.4, 51.6, 47.8, 44.0, 35.3, 27.3, 25.0, 22.8. HR-MS
(ESI) m/z ¼ 469.1919 [M þ H]þ 469.1929 calcd for C24H26N5O5. Anal.
Calc. for C24H25N5O5$3HCl$2H2O requires: C, 47.37; H, 5.30; N, 11.50.
Found: C, 47.80; H, 5.15; N, 11.21. 7e: Yield: 64%. mp 241e243 ꢀC. 1H
NMR (D2O, 300 MHz)
d
9.35 (s,1H), 8.83 (s,1H), 8.57 (d,1H, J ¼ 9 Hz),