Angular Furoquinolinones, Psoralen Analogs
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1299
was purified by column chromatography eluting with CHCl
acetone. The solvent was removed under reduced pressure,
3
1
and the residue was crystallized from MeOH to give 2 (1.8 g,
3
to give 9 (1.1 g, 80%): mp 238 °C; H NMR (CDCl ) δ 11.63 (s,
1
6
5
5
5
0%): mp 229 °C; H NMR (CDCl
3
) δ 7.36 (q, 1H, J ) 1.3 Hz,
1H, 1-H), 7.44 (s, 1H, 5-H), 6.58 (s, 1H, 8-H), 6.42 (q, 1H, J )
1.1 Hz, 3-H), 4.84 (q, 1H, J ) 6.8 Hz, 2′-H), 2.45 (d, 3H, J )
1.1 Hz, 4-Me), 2.34 (s, 3H, 6-Me), 2.25 (s, 3H, 4′-H), 1.57 (d,
3H, J ) 6.8 Hz, 1′-H).
-H), 6.75 (s, 1H, 8-H), 6.41 (q, 1H, J ) 1.0 Hz, 3-H), 6.15-
.99 (m, 1H, 2′-H), 5.52-5.26 (m, 2H, 3′-H), 4.01 (dt, 2H, J )
.1, 1.5 Hz, 1′-H), 2.43 (d, 3H, J ) 1.0 Hz, 4-Me), 2.27 (d, 3H,
J ) 1.3 Hz, 6-Me).
-(Allyloxy)-1,4,6-tr im eth ylqu in olin -2-on e (3). A mix-
ture of 2 (1.8 g, 8.3 mmol), dimethyl sulfate (1.2 g, 9.9 mmol),
and anhydrous K CO (30.0 g) in acetone (500 mL) was heated
4,6,8,9-Tetr a m eth yl-2H-fu r o[2,3-h ]qu in olin -2-on e (10).
Compound 3 (0.5 g, 1.9 mmol) was dissolved in H SO (20 mL),
2 4
and the solution was kept at room temperature for 0.5 h. The
mixture was poured into cold water (200 mL), and the obtained
precipitate was collected. The residue was purified by column
7
2
3
to reflux for 30 h. The reaction mixture was worked up as
previously described, and the residue was purified by column
chromatography, eluting with EtOAc to give 7-(allyloxy)-2-
methoxy-4,6-dimethylquinoline (4) (0.1 g, 6%) followed by the
chromatography, eluting with CHCl
3
to give 10 (0.4 g, 77%):
1
mp 231 °C (MeOH); H NMR (CD
3
OD) δ 7.19 (q, 1H, J ) 0.8
Hz, 5-H), 6.32 (q, 1H, J ) 1.0 Hz, 3-H), 2.44 (d, 3H, J ) 1.0
Hz, 4-Me), 2.41 (d, 3H, J ) 0.8 Hz, 6-Me), 2.37 (q, 3H, J ) 0.8
Hz, 8-Me or 9-Me), 2.34 (q, 3H, J ) 0.8 Hz, 8-Me or 9-Me).
2-Met h oxy-4,6,8,9-t et r a m et h yl-2H -fu r o[2,3-h ]q u in o-
lin e (11). A mixture of 10 (0.3 g, 1.4 mmol), dimethyl sulfate
1
desired product 3 (1.6 g, 78%). 4: mp 95-6 °C (MeOH); H
NMR (CDCl ) δ 7.59 (br s, 1H, 5-H), 7.16 (s, 1H, 8-H), 6.60 (q,
3
1
2
H, J ) 1.1 Hz, 3-H), 6.25-6.06 (m, 1H, 2′-H), 5.55-5.25 (m,
H, 3′-H), 4.69 (dt, 2H, J ) 5.0, 1.5 Hz, 1′-H), 4.03 (s, 3H,
-
OMe), 2.56 (d, 3H, J ) 1.1 Hz, 4-Me), 2.40 (d, 3H, J ) 0.8 Hz,
-Me).
: mp 132-3 °C (EtOAc/n-hexane); H NMR (CDCl
br s, 1H, 5-H), 6.71 (s, 1H, 6-H), 6.45 (q, 1H, J ) 1.1 Hz, 3-H),
.21-6.02 (m, 2H, 2′-H), 5.56-5.32 (m, 2H, 3′-H), 4.68 (dt, 2H,
J ) 5.1, 1.6 Hz, 1′-H), 3.68 (s, 3H, 1-Me), 2.42 (br s, 3H, 4-Me),
.31 (s, 3H, 6-Me).
-Allyl-7-h yd r oxy-1,4,6-tr im eth ylqu in olin -2-on e (5). A
2 3
(0.2 g, 1.4 mmol), and anhydrous K CO (10.0 g) in acetone
(200 mL) was heated to reflux for 2 h. The reaction mixture
was worked up as previously described, and the residue was
6
1
3
3
) δ 7.44
(
6
crystallized from MeOH to give 11 (0.3 g, 75%): mp 162 °C;
1
3
H NMR (CDCl ) δ 7.40 (q, 1H, J ) 1.0 Hz, 5-H), 6.69 (q, 1H,
J ) 1.0 Hz, 3-H), 4.08 (s, 3H, -OMe), 2.64 (q, 3H, J ) 0.8 Hz,
8-Me or 9-Me), 2.63 (d, 3H, J ) 1.0 Hz, 4-Me), 2.60 (d, 3H, J
) 0.8 Hz, 6-Me), 2.47 (q, 3H, J ) 0.8 Hz, 8-Me or 9-Me).
Nu cleic Acid . DNA from calf thymus (cat. D1501) from
Sigma Chemical Co, St. Louis, MO, was employed.
2
8
solution of 3 (1.5 g, 6.2 mmol) in N,N-diethylaniline (20 mL)
was refluxed for 3 h. The reaction mixture was cooled, and
n-hexane was added. The precipitate obtained was collected,
Lin ea r F low Dich r oism Mea su r em en ts. A DNA solu-
tion (3.8 mM) containing 2 mM NaCl and 1 mM EDTA was
used, either in the absence or presence of compound 8 or 10
washed with cyclohexane, and crystallized from EtOAc/n-
1
hexane to give 5 (1.3 g, 85%): mp 215-6 °C; H NMR (CDCl
3
)
δ 7.36 (br s, 1H, 5-H), 6.41 (q, 1H, J ) 1.1 Hz, 3-H), 6.38-
(0.17 mM). LD ) AII - A
⊥
was measured on a J asco J 500
6
3
3
.22 (m, 1H, 2′-H), 5.54 (s, 1H, -OH), 5.45-5.21 (m, 2H, 3′-H),
.64 (s, 3H, 1-Me), 3.61 (dt, 2H, J ) 4.4, 2.2 Hz, 1′-H), 2.38 (d,
H, J ) 1.1 Hz, 4-Me), 2.30 (d, 3H, J ) 0.8 Hz, 6-Me).
circular dichroism spectrometer converted for LD. The mea-
1
3
suring device was designed by Wada and Kozawa.
A
-1
constant shear gradient of 1000 s was used for recording the
LD spectra, and the base line was taken at zero gradient.
Equ ilibr iu m Dia lysis Exp er im en ts. Cylindrical contain-
ers, 4 cm in diameter, 1.6 cm deep, divided into two parts by
a Visking cellophane membrane (Serva, Heidelberg, Germany),
were used. One part of the cell contained the aqueous solution
of labeled compound containing NaCl (0.02 M) and EDTA (1
mM), at a concentration lower than its water solubility; the
other part contained aqueous DNA solution in the presence
of labeled compound 8, at the same ionic strength, DNA having
decreasing concentrations in the range 3-0.3 mM. The cells
were mechanically shaken for 12 h in a thermostat at 25 (
0.05 °C in the dark. After shaking, small (0.2 mL) volumes of
the two phases were used for radiochemical measurements,
to determine the furoquinolinone concentrations in the two
phases and calculate r and c values.15
7
-Acetoxy-8-a llyl-1,4,6-tr im eth ylqu in olin -2-on e (6). A
mixture of 5 (1.2 g, 4.9 mmol) and anhydrous sodium acetate
1.0 g) in acetic anhydride (25 mL) was refluxed for 45 min.
(
The reaction mixture was carefully diluted with water (40 mL),
refluxed for 10 min, and poured into water (400 mL). The
precipitate was collected, washed with water, and crystallized
1
from MeOH to give 6 (1.1 g, 82%): mp 137-8 °C; H NMR
(
6
1
3
CDCl ) δ 7.46 (br s, 1H, 5-H), 6.54 (d, 1H, J ) 1.1 Hz, 3-H),
.17-5.98 (m, 1H, 2′-H), 5.27-5.02 (m, 2H, 3′-H), 3.71 (s, 3H,
-Me), 3.54 (br d, 2H, J ) 5.0 Hz, 1′-H), 2.43 (d, 3H, J ) 1.1
Hz, 4-Me), 2.33 (s, 3H, Ac), 2.23 (d, 3H, J ) 0.7 Hz, 6-Me).
7
-Acetoxy-8-(2′,3′-d ibr om op r op yl)-1,4,6-tr im eth ylqu in -
olin -2-on e (7). An acetic acid solution (20 mL) containing a
stoichiometric amount of bromine was dropped at room tem-
perature over the period of 20 min into an acetic acid solution
(
25 mL) of 6 (1.1 g, 3.8 mmol). After the addition was
Com p u ta tion of In ter a ction P a r a m eter s. The method
of computation involved an iterative procedure designed to
satisfy the following equation of McGhee and von Hippel:
completed, the solution was further stirred for 10 min and the
solvent was removed under reduced pressure to give 7 (1.5 g,
9
6
3
2
1
0%): mp 153-5 °C; H NMR (CDCl
3
) δ 7.47 (br s, 1H, 5-H),
n-1
.53 (d, 1H, J ) 1.1 Hz, 3-H), 4.27-4.14 (m, 1H, 2′-H), 3.94-
.34 (m, 4H, 1′-H, 3′-H), 3.67 (s, 3H, 1-Me), 2.43 (s, 3H, Ac),
.42 (d, 3H, J ) 1.1 Hz, 4-Me), 2.23 (br s, 3H, 6-Me).
r
c
1 - nr
1 - (n - 1)r
)
K(1 - nr)
[
]
1
,4,6,8-Tet r a m et h yl-2H-fu r o[2,3-h ]qu in olin -2-on e (8).
given the experimentally determined values of r and c and the
initial values of K (intrinsic binding constant to an isolated
site) and n (number of nucleotides occluded by a furoquinoli-
none molecule). A program based on the least-squares method
of the Taylor series expansion of the above equation was
recycled until K and n changed by <1% and then, to give final
values, with a calculated binding isotherm at 5% saturation
increments.
To an ethanol solution (50 mL) of 7 (1.5 g, 3.4 mmol) was added
an ethanolic 4% KOH solution (50 mL), and the mixture was
refluxed for 1.5 h. After cooling, the mixture was acidified
with 2 N HCl and diluted with water. The obtained precipitate
was collected and purified by column cromatography, eluting
1
with CHCl
CDCl
3
to give 8 (0.8 g, 73%): mp 213-24 °C; H NMR
(
3
) δ 7.32 (q, 1H, J ) 0.8 Hz, 5-H), 6.90 (q, 1H, J ) 1.1
Hz, 9-H), 6.55 (q, 1H, J ) 1.0 Hz, 3-H), 3.99 (s, 3H, 1-Me),
2
2
Com p u ta tion a l Meth od s. The molecular mechanics cal-
culations were performed on IBM RISC 6000/530 and IBM
.53 (d, 3H, J ) 0.8 Hz, 6-Me), 2.50 (d, 3H, J ) 1.1 Hz, 8-Me),
.48 (d, 3H, J ) 1.0 Hz, 4-Me).
Compound 8 was tritium-labeled by Amersham Interna-
3
0
PowerPC 7011 workstations using the Macromodel/Batchmin
3
1
software package, employing the AMBER* force field. For
the quantum mechanics calculations, the MOPAC 6.0 pro-
gram was used.
3
2
tional plc, Amersham, U.K. Its specific activity was 8.5 Ci
mol
-1
.
4
,6-Dim eth yl-7-(3′-oxo-2′-bu tyl)qu in olin -2-on e (9).
A
2
The model polynucleotide d(CGCGATATCGCG) was built
mixture of 1 (1.0 g, 5.3 mmol), 3-chlorobutan-2-one (0.7 g, 6.3
mmol), and anhydrous K CO (10.0 g) in acetone (200 mL) was
heated to reflux for 24 h. The reaction mixture was worked
using the standard coordinate for the B-form33 using the
polymer builder utility within the Macromodel software.
Furocoumarins moieties were built from a 2D sketch and
afterwards minimized using the full matrix Newton Raphson
2
3
up as previously described for compound 2, and the residue