Quadruplex-Interactive Agents as Telomerase Inhibitors
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 26 4519
anion-exchange resin in the chloride form, shaking slowly for
2 h. The resin was filtered off and washed with water, and
the filtrate was lyophilized to give the chloride salt. The salt
was further purified by chromatography on lipophilic Sephadex
using methanol as the eluent.53
(d, J ) 5.7 Hz, 4H), 8.00 (d, J ) 1.8 Hz, 2H), 7.85-7.80 (m,
2H), -3.01 (s, 2H); MS (CI) m/z 739 (M + H), 721.
5-(3-Ca r b oxyp h e n yl)-10,15,20-t r i(4-p yr id yl)p or p h y-
r in (11) an d 5,15-Di(3-car boxyph en yl)-10,20-di(4-pyr idyl)-
p or p h yr in (12). Condensation of 4-pyridinecarboxaldehyde
(1.51 mL, 15.82 mmol), 3-carboxybenzaldehyde (2.38 g, 15.82
mmol), and pyrrole (2.4 mL, 34.59 mmol) in 150 mL of
propionic acid according to general method A followed by
chromatography (twice) on silica gel eluting with chloroform-
methanol-acetic acid (110:10:1) gave 11 (7%) and 12 (4%).
Data for 11: 1H NMR (DMSO-d6) δ 13.01 (br s, 1H), 9.00 (br
s, 6H), 8.86 (br s, 8H), 8.71 (br s, 1H), 8.46-8.41 (m, 2H), 8.23
(br s, 6H), 7.95 (br s, 1H), -2.98 (br s, 2H); MS (CI) m/z 662
(M + H). Data for 12: 1H NMR (DMSO-d6) δ 12.80 (br s, 2H),
9.03 (d, J ) 5.4 Hz, 4H), 8.89-8.82 (m, 8H), 8.70 (be s, 2H),
8.44-8.41 (m, 4H), 8.26 (br d, 4H), 8.00-7.94 (m, 2H), -3.00
(s, 2H); MS (CI) m/z 705 (M + H).
5-(4-Ca r b oxyp h e n yl)-10,15,20-t r i(4-p yr id yl)p or p h y-
r in (13). 13 was prepared by condensation of 4-pyridinecar-
boxaldehyde (1.46 mL, 15 mmol), 4-carboxybenzaldehyde (0.77
g, 5 mmol), and pyrrole (1.49 mL, 21 mmol) in 15 mL of
propionic acid according to general method A. Chromatography
twice on silica eluting with chloroform-methanol (10:1 and
then 95:6) gave 13 (0.13 g, 4%): 1H NMR (DMSO-d6) δ 13.21
(br s, 1H), 9.06 (d, J ) 5.4 Hz, 6H), 8.84-8.80 (m, 8H), 8.36
(d, J ) 8.2 Hz, 2H), 8.28 (d, J ) 4.8 Hz, 6H), 8.20 (d, J ) 8.1
Hz, 2H), -2.89 (br s, 2H); MS (CI) m/z 662 (M + H).
5,10,15,20-Tetr a (6-m eth yl-2-p yr id yl)p or p h yr in (4). 4
was prepared by condensation of 6-methylpyridine-2-carbox-
aldehyde (0.78 g, 6.28 mmol) with pyrrole (0.454 mL, 6.28
mmol) in propionic acid (30 mL) according to general method
A followed by chromatography (twice) on silica gel using
chloroform-methanol (50:1 and then 20:1) as the eluent. The
porphyrin 4 was isolated as a brown powder that recrystallized
from dichloromethane-hexane (1:12) (0.13 g, 12%): 1H NMR
(CDCl3) δ 8.82 (s, 8H), 7.99-7.90 (m, 8H), 7.53 (d, J ) 7.0 Hz,
4H), 2.87 (s, 12H), -2.87 (s, 2H); MS (CI) m/z 675 (M + H).
5,15-Di(3-pyr idyl)-10,20-di(3-qu in olyl)por ph yr in (5) an d
5-(3-P yr id yl)-10,15,20-tr i(3-qu in olyl)p or p h yr in (6). Con-
densation of 3-pyridinecarboxaldehyde (1.07 g, 9.8 mmol),
3-quinolinecarboxaldehyde (1.57 g, 9.8 mmol), and pyrrole
(1.39 mL, 19.6 mmol) in propionic acid (80 mL) according to
general method A followed by chromatography (twice) using
chloroform-methanol (8:1) and then chloroform-acetone (6:
1) as the eluent gave 5 (176 mg, 5%) and 6 (75 mg, 2%). Data
for 5: 1H NMR (CDCl3) δ 9.83 (d, J ) 1.7 Hz, 2H), 9.48 (s,
2H), 9.05 (dd, J ) 1.5, 4.8 Hz, 2H), 9.00 (br s, 2H), 8.95-8.88
(m, 8H), 8.57 (d, J ) 7.6 Hz, 2H), 8.49 (d, J ) 8.4 Hz, 2H),
8.12 (d, J ) 7.5 Hz, 2H), 7.98 (dt, J ) 1.3, 7.0 Hz, 2H), 7.82-
7.75 (m, 4H), -2.74 (br s, 2H); MS (CI) m/z 719 (M + H). Data
for 6: 1H NMR (CDCl3) δ 9.82 (d, J ) 1.9 Hz, 3H), 9.45 (br s,
1H), 9.01 (br s, 4H), 8.93-8.86 (m, 8H), 8.56 (d, J ) 7.8 Hz,
1H), 8.49 (d, J ) 8.5 Hz, 3H), 8.13 (d, J ) 7.8 Hz, 3H), 8.02-
7.94 (m, 3H), 7.81-7.61 (m, 4H), -2.75 (br s, 2H); MS (CI)
m/z 769 (M + H).
5-(4-P yr idyl)-10,15,20-tr i(4-m eth ylph en yl)por ph yr in (7)
a n d 5,15-Di(4-m eth ylp h en yl)-10,20-d i(4-p yr id yl)p or p h y-
r in . Condensation of 4-pyridinecarboxaldehyde (0.92 g, 8.42
mmol), 4-tolualdehyde (1.02 mL, 8.42 mmol), and pyrrole (1.17
mL, 16.8 mmol) in 60 mL of propionic acid according to general
method A followed by chromatography on silica gel using
dichloromethane-methanol (100:3) as the eluent gave 7 (4%)
and 5,15-di(4-methylphenyl)-10,20-di(4-pyridyl)porphyrin, which
was recrystallized from methanol-chloroform (4:1) as a purple
solid (8%). Data for 7: 1H NMR (CDCl3) δ 9.01 (d, J ) 4.9 Hz,
2H), 8.92 (d, J ) 4.8 Hz, 2H), 8.89 (s, 4H), 8.78 (d, J ) 4.9 Hz,
2H), 8.16 (d, J ) 5.7 Hz, 2H), 8.09 (d, J ) 7.7 Hz, 6H), 7.53 (d,
J ) 7.7 Hz, 6H), 2.65 (s, 9H), -2.77 (s, 2H); MS (CI) m/z 657
(M + H). Data for 5,15-di(4-methylphenyl)-10,20-di(4-pyridyl)-
porphyrin: 1H NMR (CDCl3) δ 9.02 (d, J ) 5.6 Hz, 6H), 8.93-
8.89 (m, 6H), 8.79 (d, J ) 5.0 Hz, 2H), 8.18 (d, J ) 6.0 Hz,
6H), 8.09 (d, J ) 7.8 Hz, 2H), 7.60 (d, J ) 7.7 Hz, 2H), -2.90
(s, 2H); MS (CI) m/z 645 (M + 1).
5,15-Di(3-n itr oph en yl)-10,20-di(4-pyr idyl)por ph yr in (8)
a n d 5-(3-Nit r op h en yl)-10,15,20-t r i(4-p yr id yl)p or p h yr in
(9). Condensation of 4-pyridinecarboxaldehyde (1.26 mL, 12.9
mmol), 3-nitrobenzaldehyde (1.97 g, 12.9 mmol), and pyrrole
(1.79 mL, 25.80 mmol) in 120 mL of propionic acid according
to general method A followed by chromatography (twice) on
silica gel eluting with chloroform-methanol (100:3) gave 8
(6%) and 9 (9%). Data for 8: 1H NMR (DMSO-d6) δ 9.18 (d, J
) 5.5 Hz, 4H), 9.00-8.85 (m, 4H), 8.90 (br s, 2H), 8.50 (br d,
4H), 8.41 (d, J ) 7.5 Hz, 4H), 8.36 (s, 2H), 8.02 (m, 2H), 7.60
(s, 2H), -3.01 (s, 2H); MS (CI) m/z 707 (M + H). Data for 9:
1H NMR (CDCl3) δ 9.05-8.96 (m, 8H), 8.84 (s, 6H), 8.78 (br d,
1H), 8.68 (d, J ) 7.8 Hz, 1H), 8.48 (d, J ) 7.9 Hz, 1H), 8.90 (d,
J ) 5.3 Hz, 6H), 7.96 (t, J ) 7.5 Hz, 1H), -2.90 (s, 2H); MS
(CI) m/z 663 (M + H).
5,10,15,20-Tetr a(4-ch lor o-3-n itr oph en yl)por ph yr in (14).
14 was prepared from 4-chloro-3-nitrobenzaldehyde and pyr-
role (1:1) in propionic acid according to general method A.
Chromatography on silica eluting with chloroform yielded 14
as a purple solid (25%): 1H NMR (CF3CO2D) δ 9.23 (s, 4H),
8.49 (s, 8H), 8.71 (d, J ) 8.2 Hz, 4H), 8.21 (dd, J ) 1.2, 8.0
Hz, 4H); MS (CI) m/z 933 (M + H); HRMS (M + H) calcd
931.0393, found 931.0396, C44H23Cl4N8O8.
5,10,15,20-Tetr a (4-m eth oxy-3-h yd r oxyp h en yl)p or p h y-
r in (15). 15 was prepared by condensation of pyrrole with
3-hydroxy-4-methoxybenzaldehyde (1:1) in propionic acid ac-
cording to general method A. Chromatography on silica eluting
with chloroform-methanol (25:1) gave 15 as a purple solid
(36%): 1H NMR (CDCl3) δ 8.86 (s, 8H), 7.79 (d, J ) 1.7 Hz,
4H), 7.63 (dd, J ) 1.9, 8.2 Hz, 4H), 7.16 (d, J ) 8.0 Hz, 4H),
5.88 (br s, 4H), 4.13 (s, 12H), -2.38 (s, 2H); MS (CI) m/z 799
(M + H); HRMS (M + H) calcd 799.2768, found 799.2772,
C
48H39N4O8.
5-(3-Am in oph en yl)-10,15,20-tr i(4-pyr idyl)por ph yr in (16).
Stannous chloride dihydrate (0.98 g, 4.33 mmol) was added
to a solution of the (nitrophenyl)porphyrin 9 (0.18 g, 0.272
mmol) in 6 M HCl (15 mL). The mixture was stirred at room
temperature for 16 h, after which the solution was diluted with
water (10 mL), neutralized with aqueous ammonia to pH 8,
and extracted with chloroform (3 × 80 mL). The combined
organic phase was washed with water, dried over anhydrous
K2CO3, and evaporated to give 16 (0.124 g, 72%): 1H NMR
(CDCl3) δ 9.04, (d, J ) 5.9 Hz, 6H), 8.89 (d, J ) 4.9 Hz, 2H),
8.85 (s, 4H), 8.80 (br s, 2H), 8.16 (br s, 6H), 7.99 (br s, 3H),
7.34 (s, 1H), -3.03 (s, 2H); MS (CI) m/z 633 (M + H).
5-(3-Acetylam in o)-10,15,20-tr i(4-pyr idyl)por ph yr in (17).
A mixture of 16 (30 mg, 47 µmol), acetic anhydride (2 mL),
and triethylamine (1 mL, 7.2 mmol) in 10 mL of dry chloroform
was heated overnight. After evaporation of solvents and
chromatography on silica eluting with chloroform-methanol-
acetic acid (100:10:1), 17 was obtained as a solid (21 mg,
65%): 1H NMR (CDCl3) δ 9.02 (d, J ) 5.8 Hz, 6H), 8.91 (d, J
) 4.9 Hz, 2H), 8.82 (s, 4H), 8.79 (br d, 2H), 8.30 (br s, 1H)
8.17 (d, J ) 6.2 Hz, 6H), 7.98 (br s, 1H), 7.69-7.65 (m, 2H),
6.82 (s, 1H), 2.23 (s, 3H), -3.03 (s, 2H); MS (CI) m/z 675 (M +
H); HRMS (M + H) calcd 675.2621, found 675.2613, C43H31N8O.
5-(3-Ca r b oxa m id op h en yl)-10,15,20-t r i(4-p yr id yl)p or -
p h yr in (18). Carbonyldiimidazole (14 mg, 86 µmol) was added
to a solution of porphyrin 11 (65 mg, 98 µmol) in 8 mL of dry
THF, and the mixture was heated under reflux for 1 h under
a nitrogen atmosphere. The reaction mixture was cooled to
room temperature, concentrated aqueous ammonium hydrox-
5,15-Di(3-h yd r oxy-4-n itr op h en yl)-10,20-d i(4-p yr id yl)-
p or p h yr in (10). Condensation of 4-pyridinecarboxaldehyde,
3-hydroxy-4-nitrobenzaldehyde, and pyrrole (1:1:2) in propionic
acid according to general method A followed by chromatogra-
phy on silica gel using chloroform-acetone (6:1) as the eluent
gave 10 (6%): 1H NMR (CDCl3) δ 11.06 (s, 2H), 9.03 (d, J )
5.4 Hz, 4H), 8.89-8.82 (m, 8H), 8.47 (d, J ) 8.6 Hz, 2H), 8.15