Peptidyl-Ametantrone–DNA Complexes
HRMS (ES+): m/z: calcd for C24H30N2O4 [M+H]+: 411.5793, found:
411.5145.
16.2 min, purity 98%. 1H NMR (300 MHz, [D6]DMSO): d=11.25 (t,
J=5.2 Hz, 2H), 8.25 (s,2H), 7.80 (dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.55
(dd, J=2.5 Hz, J=5.9 Hz, 2H), 6.50 (s, 2H), 4.20 (m, 4H), 3.95 (s,
4H), 3.20 (m, 4H), 2.80 (m, 8H), 1.40 ppm (s, 18H); 13C NMR
(300 MHz, [D6]DMSO): d=28.5, 42.3, 48.7, 49.5, 64.1, 79.5, 108.9,
125.5, 131.2, 132.7, 134.2, 138.4, 156.3, 169.6, 180.9 ppm; HRMS
(ES+): m/z: calcd for C36H50N6O10 [M+H]+: 727.8292, found:
727.8990.
1,4-bis{[2-(2-Hydroxyethoxy)ethyl]amino}-9,10-anthracenedione
(2): was obtained by using the same procedure as described
before by starting from leucoquinizarin (0.5 g, 2.08 mmol) and 2-(2-
aminoethoxy)ethanol (2.19 g, 20.80 mmol). The crude product was
purified by column chromatography (EtOAc/MeOH, 9:1), to yield
compound 2 as a blue powder (800 mg, 93%). HPLC: tR =12.9 min,
purity 99%. 1H NMR (300 MHz, [D6]DMSO): d=10.88 (t, J=5.2 Hz,
2H), 8.24 (dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.79 (dd, J=2.5 Hz, J=
5.9 Hz, 2H), 7.50 (s, 2H), 4.62 (t, J=5.0 Hz, 2H), 3.71 (t, J=5.0 Hz,
4H), 3.61 (m, 4H), 3.53 ppm (m, 8H); 13C NMR (300 MHz,
[D6]DMSO): d=42.5, 60.6, 69.6, 72.7, 108.8, 125.0, 126.1, 132.7,
134.2, 146.3, 181.1 ppm; HRMS (ES+): m/z: calcd for C22H26N2O6
[M+H]+: 415.7658, found: 415.7209.
1,4-bis{[5-(Glycyl)hydroxypentyl]amino}-9,10-anthracenedione
bistrifluoroacetate (7): A solution of 4 (40 mg, 0.055 mmol) in
90% TFA (50 mL) was stirred for 1 h at room temperature and then
cold Et2O (5 mL) was added. The reaction mixture was kept at 08C
for 30 min and filtered; the precipitate was washed twice with Et2O
(5 mL). Compound 7 was obtained as a blue powder (39 mg, 94%).
1
HPLC: tR =15.7 min, purity 99%. H NMR (300 MHz, [D6]DMSO): d=
10.80 (t, J=5.2 Hz, 2H), 8.25 (dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.78
(dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.50 (s, 2H), 4.10 (s, 4H), 3.64 (m,
4H), 3.44 (m, 4H), 1.80 (m, 4H), 1.55 ppm (m, 8H); 13C NMR
(300 MHz, [D6]DMSO): d=23.3, 28.7, 29.9, 39.8, 45.1, 65.0, 108.5,
117.4 (TFA), 125.2, 126.5, 132.7, 134.2, 146.7, 161.4 (TFA), 167.4,
180.9 ppm; HRMS (ES+): m/z: calcd for C28H36N4O6 [M+2H]+:
263.3247, found: 263.3163.
1,4-bis[{2-[(2-Hydroxyethyl)amino]ethyl}amino]-9,10-anthracene-
dione (3): was obtained by following literature preparation, from
1,4-difluoroanthraquinone (200 mg, 0.819 mmol) in DMSO (4 mL)
and N-(2-Hydroxyethyl)ethylenediamine (256 mg, 2.457 mmol).
Compound 3 was prepared as a blue powder (120 mg, 36%).
HPLC: tR =9.4 min, purity >99%.[34] 1H NMR (300 MHz, [D6]DMSO):
d=10.69 (t, J=6.3 Hz, 2H), 8.24 (dd, J=3.2 Hz, J=5.8 Hz, 2H), 7.83
(dd, J=3.2 Hz, J=5.8 Hz, 2H), 7.68 (s, 2H), 3.59 (m, 4H), 3.30 (m,
4H), 2.80 ppm (m, 8H); 13C NMR (300 MHz, [D6]DMSO): d=48.5,
49.6, 52.5, 62.2, 109.7, 118.7, 129.8, 132.4, 133.8, 138.3, 182.2 ppm;
HRMS (ES+): m/z: calcd for C22H28N4O4 [M+H]+: 413.9581, found:
413.9256.
1,4-bis[{2-[2-(Glycyl)hydroxyethoxy]ethyl}amino]-9,10-anthrace-
nedione bistrifluoroacetate (8): With the same procedure de-
scribed for compound 7, from 5 (50 mg, 0.069 mmol) in 90% TFA
(50 mL), compound 8 was prepared as a blue powder (50 mg,
97%). HPLC: tR =10.9 min, purity 98%. 1H NMR (300 MHz,
[D6]DMSO): d=10.82 (t, J=5.2 Hz, 2H), 8.24 (dd, J=2.5 Hz, J=
5.9 Hz, 2H), 7.79 (dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.50 (s, 2H), 4.25
(m, 4H), 3.67 (m, 4H), 3.62 (s,4H), 3.58 (m, 4H), 3.23 ppm (m, 4H);
13C NMR (300 MHz, [D6]DMSO): d=40.9, 44.8, 64.1, 69.0, 70.2, 109.5,
117.4, 118.2, 129.5, 132.4, 133.7, 138.7, 161.4, 169.6, 182.2 ppm;
HRMS (ES+): m/z: calcd for C26H32N4O8 [M+2H]+: 265.1183, found:
265.1156.
1,4-bis{[5-(Boc-Glycyl)hydroxypentyl]amino}-9,10-anthracene-
dione
0.122 mmol),
(4):
N,N-Dicyclohexylcarbodiimide
N,N-dimethylaminopyridine
(DCC;
(DMAP;
25.2 mg,
14.9 mg,
0.122 mmol) and Boc-Gly-OH (214 mg, 1.22 mmol) were added to a
solution of 1 (50 mg, 0.122 mmol) in THF (10 mL) under an argon
atmosphere. The reaction mixture was stirred at room temperature
overnight. Then the solvent was evaporated under vacuum and
the residue was purified by column chromatography (toluene/
EtOAc, 8:2), to yield compound 4 as a blue powder (52 mg, 59%).
HPLC: tR =28.6 min, purity >99%. 1H NMR (300 MHz, [D6]DMSO):
d=10.88 (t, J=5.4 Hz, 2H), 8.25 (dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.78
(dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.50 (s, 2H), 7.20 (t, J=6.3 Hz, 2H),
4.08 (t, J=6.3 Hz, 4H), 3.67 (m, 4H), 3.45 (m, 4H), 1.68 (m, 8H),
1.50 (m, 4H), 1.36 ppm (s, 18H); 13C NMR (300 MHz, [D6][D6]DMSO):
d=23.2, 28.2, 28.5, 29.2, 42.3, 64.5, 78.6, 108.6, 125.1, 126.1, 132.6,
134.2, 146.4, 156.2, 170.8, 180.9 ppm; HRMS (ES+): m/z: calcd for
C38H52N4O10 [M+H]+: 725.3534, found: 725.3557.
1,4-bis{[2-{[2-(2-Glycyloxyethyl)]amino}ethyl]amino}-9,10-anthra-
cenedione bistrifluoroacetate (9): By using the same procedure
described for the preparation of compound 7, and by starting
from 6 (20 mg, 0.028 mmol), compound 9 was prepared as a blue
powder (18 mg, 85%). HPLC: tR =9.3 min, purity >99%. 1H NMR
(300 MHz, [D6]DMSO): d=11.25 (t, J=5.3 Hz, 2H), 8.25 (s, 2H), 7.82
(dd, J=2.6 Hz, J=5.8 Hz, 2H), 7.57 (dd, J=2.6 Hz, J=5.8 Hz, 2H),
6.48 (s, 2H), 4.16 (m, 4H), 3.97 (s, 4H), 3.22 (m,4H), 2.84 ppm (m,
8H); 13C NMR (300 MHz, [D6]DMSO): d=40.4, 48.5, 49.7, 64.1, 108.9,
117.4, 125.5, 131.2, 132.7, 134.2, 138.4, 169.6, 171.4, 180.9 ppm,
HRMS (ES+): m/z: calcd for C26H34N6O6 [M+2H]+: 264.3654, found:
264.3156.
1,4-bis[{2-[2-(Boc-Glycyl)hydroxyethoxy]ethyl}amino]-9,10-an-
thracenedione (5): By using the previous procedure from com-
pound
2
(50 mg, 0.122 mmol) and Boc-Gly-OH (214 mg,
1,4-bis{[5-(Boc-Lys(Boc)-Glycyl)hydroxypentyl]amino}-9,10-an-
1.22 mmol), compound 5 was prepared as a blue powder (73 mg,
82%). HPLC: tR =20.6 min, purity >99%. 1H NMR (300 MHz,
[D6]DMSO): d=10.87 (t, J=5.2 Hz, 2H), 8.23 (dd, J=2.5 Hz, J=
5.9 Hz, 2H), 7.81 (dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.50 (s, 2H), 7.22 (t,
J=6.1 Hz, 2H), 4.25 (m, 4H), 3.92 (t, J=6.1 Hz, 4H), 3.65 (m, 4H),
3.60 (m, 4H), 3.23 (m, 4H), 1.40 ppm (s, 18H); 13C NMR (300 MHz,
[D6]DMSO): d=28.5, 42.3, 44.0, 64.4, 69.1, 70.3, 79.5, 110.7, 118.7,
130.1, 132.2, 133.7, 138.2, 156.3, 169.6, 182.2 ppm; HRMS (ES+):
m/z: calcd for C36H48N4O12 [M+H]+: 729.8067, found: 729.3319.
thracenedione (10): A solution of Boc-Lys-(Boc)-OSu (80 mg,
0.180 mmol) in CH2Cl2 (14 mL), which had been adjusted to pH 9
with Et3N was added to a solution of 7 (31 mg, 0.042 mmol) in
DMF (2 mL). The reaction mixture was stirred for 2 h. Then H2O
was added, the product was extracted in CH2Cl2, and the organic
phase was evaporated under vacuum. The crude product was puri-
fied by column chromatography, (EtOAc/MeOH, 9:1), to obtain
compound 10 as a blue powder (25 mg, 50%). HPLC: tR =29.6 min,
purity 99%. 1H NMR (300 MHz, [D6]DMSO): d=10.82 (t, J=5.2 Hz,
2H), 8.25 (dd, J=2.5 Hz, J=5.9 Hz, 2H), 7.80 (dd, J=2.5 Hz, J=
5.9 Hz, 2H), 7.50 (s, 2H), 4.53 (m, 2H), 4.16 (s, 4H), 4.08 (m, 4H),
3.06 (m, 4H), 2.96 (m, 4H), 1.79 (m, 4H), 1.57 (m, 8H), 1.52 (m, 4H),
1.40 (s, 36H), 1.29 ppm (m, 8H); 13C NMR (300 MHz, [D6]DMSO): d=
23.3, 28.5, 28.7, 29.4, 29.9, 31.5, 40.8, 42.1, 45.1, 55.4, 65.0, 79.7,
1,4-bis{[2-{[2-(2-Boc-Glycyloxyethyl)]amino}ethyl]amino}-9,10-an-
thracenedione (6): By using the same procedure described previ-
ously for the preparation of compound 4, and starting from 3
(70 mg, 0.170 mmol) and Boc-Gly-OH (214 mg, 1.22 mmol), com-
pound 6 was obtained as a blue powder (22 mg, 18%). HPLC: tR =
ChemMedChem 2010, 5, 1080 – 1091
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