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L. Dalla Via / European Journal of Medicinal Chemistry 44 (2009) 2854–2861
(C-3a), 124.6 (C-40), 125 (C-
a
), 127 (C-4), 131 (C-30, C-50 and C-2), 133
(434.446): C, 71.88; H, 4.18; N, 12.90; found: C, 71.70; H, 4.45;
N, 12.78.
(C-5), 144 (C-
b
), 146 (C-10), 146.5 (C-5a), 147 (C-7), 148 (C-9), 198
(C-O); HRMS m/z [MHþ] 328.1332; anal. calcd. for C21H17N3O
(327.379): C, 77.04; H, 5.23; N, 12.84; found: C, 77.31; H, 5.45;
N, 12.73.
4.1.6. General procedure for synthesis of 1-phenyl-propenone-3-
substituted derivatives (8a, b)
The same procedure described above for the synthesis of
compounds 7a–c was applied to 8a, b, starting from acetophenone
and the appropriate aldehyde in an equimolar ratio (4–8 mmol).
4.1.5. General procedure for synthesis of pyrroloquinoline
substituted chalcones (7a–c)
A methanol solution of reagents, 6 [25] and 4-nitro-benzalde-
hyde in an equimolar ratio (0.188 g and 0.084 g, 0.56 mmol), was
added to aqueous NaOH 1 M (0.3 mL) and kept under stirring for
12 h at room temperature. A red solid separated, which was
collected and recrystallised from methanol.
4.1.6.1. (E)-1-Phenyl-3-(1H-pyrrol-2-yl)prop-2-en-1-one (8a). Yellowish-
orange crystalline solid: yield 48%; rf 0.26 (chloroform); mp 134–137 ꢀC
(Ref. [37] 138–139 ꢀC); 1H NMR (DMSO-d6)
d
6.16 (dd, 1H, J3 ,2 ¼ 2.1 Hz,
0
0
0
0
0
0
0
0
0
J3 ,4 ¼ 3.4 Hz, 3 -H), 6.70 (dd,1H, J4 ,NH ¼ 1.14 Hz, J4 ,3 ¼ 3.4 Hz, 4 -H), 7.10
(bs, 1H, 4-H), 7.35 (d, 1H, Ja ¼ 15.00 Hz,
-H), 7.5 (dt, 1H, 20-H), 7.52 (d,
-H),
a
,b
4.1.5.1. (E)-1-(40-(3H-Pyrrolo[3,2-f]quinolin-9-ylamino)phenyl)-3-(1H-
pyrrol-200-yl)prop-2-en-1-one (7a). Yield 17%; mp > 300 ꢀC; rf 0.50
(chloroform/methanol 8:2); IR (KBr) 3382 (NH), 1661 (C]O), 1594
2H, J2,3 and J6,5 ¼ 7.6 Hz, 2-H and H-6), 7.60 (d, 1H, Jb ¼ 15.00 Hz,
b
,a
7.95 (dd, 2H, J2,3 and J6,5 ¼ 8.0 Hz, J4,3/5 ¼1.33 Hz, 3-H, 5-H); HRMS m/z
[MHþ] 198.0903; anal. calcd. for C13H11NO (197.233): C, 79.16; H, 5.62; N,
7.10; found: C, 78.98; H, 5.52; N, 7.15.
and 974 (CH]CH) cmꢃ1; 1H NMR (DMSO-d6)
d
6.19 (dd, 1H, 400-H),
6.67 (dd, 1H, 500-H), 7.02 (d, 1H, J ¼ 2.29 Hz, 1-H), 7.08 (bs, 1H, 300-H),
0
0
0
0
0
0
7.20 (d, 2H, J3 ,2 and J5 ,6 ¼ 8.58 Hz, 3 -H and 5 -H), 7.45 (m, 2H, 2-H
4.1.6.2. (E)-1-Phenyl-3-(thiophen-2-yl)prop-2-en-1-one (8b). Dusty
yellowish-green solid: yield 43%; rf 0.2 (n-hexane/chloroform 7:3),
and
a
-H), 7.56 (d, 1H, J8,7 ¼ 6.82 Hz, 8-H), 7.70 (d, 1H, J4,5 ¼ 8.87 Hz,
4-H), 7.85 (d, 1H, J ¼ 15.26 Hz,
b
-H), 7.87 0 (d, 1H, J05,4 ¼ 8.87 Hz,
mp 67–69 ꢀC (Ref. [38] 58–59 ꢀC); 1H NMR (DMSO-d6)
d
7.20 (dd,1H,
-H),
0
0
0
0
0
0
0
0
0
5-H), 7.98 (d, 2H, J2 ,3 and J6 ,5 ¼ 8.58 Hz, 2 -H and 6 -H), 8.62 (d,
J4 ,5 ¼ 5.01 Hz, J4 ,3 ¼ 3.61 Hz, 4 -H), 7.52 (m, 3H, 2-H, 6-H and
a
1H, J7,8 ¼ 4.95 Hz, 7-H), 8.93 (s, 1H, NH), 11.71 (bs, 2H, pyrrole
7.65 (dt, 1H, 30-H), 7.70 (d, 1H, J4,3/5 ¼ 3.61 Hz, 4-H), 7.79 (d, 1H,
2 ꢄ NH); 13C NMR (DMSO-d6)
d
105.6 (C-8), 111 (C-400), 113 (C-9a),
J4 ,5 ¼ 5.01 Hz, 5 -H), 7.92 (d,1H, Ja ¼ 15.44 Hz,
b-H), 8.08 (dd, 2H, 3-
0
0
0
,b
115 (C-200), 116 (C-20 and C-60), 117 (C-9b), 119.5 (C-1), 123.7
(C-3a), 124 (C-40), 124.5 (C-500), 130 (C-30 and C-50), 130.5 (C-4), 131
H and H-5); HRMS m/z [MHþ] 215.0472; anal. calcd. for C13H10OS
(214.283): C, 72.87; H, 4.70; S,14.96; found: C, 73.01; H, 4.65; S,14.82.
(C-5), 131.5 (C-a b), 147 (C-5a), 147.5
), 132 (C-2), 133 (C-200), 145 (C-
(C-9), 148.5 (C-7), 149 (C-10), 186.5 (C-O); HRMS m/z [MHþ]
379.1552; anal. calcd. for C24H18N4O (378.426): C, 76.17; H, 4.79; N,
14.81; found: C, 76.20; H, 4.59; N, 14.72.
4.2. Inhibition growth assay
HL-60 and JR8 were grown in RPMI 1640 (Sigma) supplemented
with 15% and 10% heat-inactivated fetal calf serum (Biological
Industries), respectively. HeLa were grown in Nutrient Mixture F-12
[HAM] (Sigma) supplemented with 10% heat-inactivated fetal calf
4.1.5.2. (E)-1-(40-(3H-Pyrrolo[3,2-f]quinolin-9-ylamino)phenyl)-3-
(thiophen-200-yl)prop-2-en-1-one (7b). Yield 15%; mp 289–290 ꢀC;
rf 0.52 (ethyl acetate/methanol 8:2); IR (KBr) 3382 (NH), 1660
(C]O),1598 and 979 (CH]CH)cmꢃ1; 1H NMR (DMSO-d6)
d
7.03 (bs,
serum (Biological Industries). 100 U/mL Penicillin, 100 mg/mL
0
0
00
streptomycin and 0.25 mg/mL amphotericin B (Sigma) were added
to both media. The cells were cultured at 37 ꢀC in a moist atmo-
sphere of 5% carbon dioxide in air.
0
0
0
0
1H, 1-H), 7.17 (m, 3H, J3 ,2 and J5 ,6 ¼ 8.71 Hz, 3 -H, 5 -H and 4 -H),
7.43 (d, 1H, J8,7 ¼ 5.15 Hz, 8-H), 7.46 (dd, 1H, 2-H)0,0 7.55 (d, 1H,
00 00
Ja ¼ 15.45 Hz,
a
-H), 7.64 (d, 1H, J3 ,4 ¼ 3.22 Hz, 3 -H), 7.70 (d,
,b
HL-60 cells (4 ꢄ104) were seeded into each well of a 24-well cell
culture plate. After incubation for 24 h, various concentrations of
the test compounds were added in complete medium and incu-
bated for a further 72 h. HeLa and JR8 cells (4 ꢄ104) were seeded
into each well of a 24-well cell culture plate. After incubation for
24 h, the medium was replaced with an equal volume of fresh
medium, and various concentrations of the test compounds were
added. The cells were then incubated in standard conditions for
a further 72 h.
00
00 00
1H, J4,5 ¼ 8.90 Hz, 4-H), 7.75 (d, 1H, J5 ,4 ¼ 4.91 Hz, 5 -H), 7.85 (d,
1H, Ja ¼ 15.45 Hz,
b
-H), 7.89 (d0,01H, J5,4 ¼ 8.90 Hz, 5-H), 8.03 (d, 2H,
,b
00
00 00
00 00
J3 ,2 and 5 ,6 ¼ 8.71 Hz, 3 -H, 5 -H), 8.64 (d, 1H, J8,7 ¼ 5.15 Hz, 7-H),
9.05 (s, 1H, NH), 11.76 (bs, 1H, pyrrole NH); 13C NMR (DMSO-d6)
d
104.9 (C-8),116 (C-9a),117 (C-9b),119 (C-1),121 (C-300); 123 (C-3a),
125 (C-20 and C-60),125 (C-40),128.2 (C-4),128.7 (C-400),129.5 (C-500),
131 (C-5 and C-
a
),132.7 (C-2),133 (C-30 and C-50),135 (C-200),140 (C-
b
), 147 (C-5a), 148.5 (C-9), 148.5 (C-7), 149 (C-10), 186 (C–O); HRMS
m/z [MHþ] 396.1212; anal. calcd. for C24H17N3OS (395.476): C, 72.89;
A trypan blue assay was performed to determine cell viability.
Cytotoxicity data are expressed as IC50 values, i.e., the concentration
of the test agent inducing 50% reduction in cell number compared
with control cultures.
H, 4.33; N, 10.63, S, 8.11; found: C, 72.68; H, 4.51; N, 10.49; S, 8.08.
4.1.5.3. (E)-1-(40-(3H-Pyrrolo[3,2-f]quinolin-9-ylamino)phenyl)-3-
(400-nitrophenyl)prop-2-en-1-one (7c). Yield 13%; mp > 300 ꢀC; rf
0.52 (ethyl acetate/methanol 8:2); IR (KBr) 3381 (NH), 1663 (C]O),
1594 and 974 (CH]CH), 1540 and 1340 (NO2) cmꢃ1 1H NMR
;
4.3. Linear flow dichroism
0
0
0
0
(DMSO-d6)
d
7.01 (bs, 1H, 1-H), 7.17 (d, 2H, J3 ,2 and J5 ,6 ¼ 8.89 Hz,
30-H, 50-H), 7.45 (m, 2H, 8-H and 2-H), 7.72 (d, 1H, J4,5 ¼ 8.77 Hz,
Linear dichroism (LD) measurements were performed on a Jasco
J500A circular dichroism spectropolarimeter, converted for LD and
equipped with an IBM PC and a Jasco J interface.
4-H), 7.75 (d, 1H, Ja ¼ 15.45 Hz,
a
-H), 7.88 (d, 1H, J5,4 ¼ 8.77 Hz,
,b
5-H), 8.1 (m, 5H, 020 0-H, 60-H, 200-H, 600-H,
00 00
b-H), 8.27 (d, 2H, J3 ,2 and
00
00 00
J5 ,6 ¼ 8.89 Hz, 3 -H and 5 -H), 8.65 (d, 1H, J8,7 ¼4.91 Hz, 7-H), 9.10
Linear dichroism was defined as:
(s, 1H, NH), 11.8 (bs, 1H, pyrrole NH); 13C NMR (DMSO-d6)
d 105.5
(C-8), 116 (C-9a), 118 (C-9b), 119.5 (C-1), 123 (C-3a), 124.5 (C-20 and
C-60), 124.7(C-40), 127 (C-4), 129 (C-2), 130 (C-200 and C-600), 131.5
LDðl ¼ Akð Þ ꢃ Atð
Þ
Þ
l
l
(C-5 and C-
a
), 133 (C-30 and C-50), 140 (C-
b
), 142 (C-300 and C-500),
where A and At correspond to the absorbances of the sample
k
146.5 (C-5a), 146.5 (C-9), 147 (C-400), 148.5 (C-7), 149.5 (C-10), 187
when polarised light was oriented parallel or perpendicular to the
flow direction, respectively. The orientation was produced by
(C-O); HRMS m/z [MHþ] 435.1478; anal. calcd. for C26H18N4O3