Synthesis of bisquinoline-pyrrole oligoamide as G-quadruplex binding ligand

Article abstract of DOI:10.1016/j.tet.2012.05.001

A one-pot procedure using ammonium formate under palladium catalysis for the reductive dechlorination and reduction of nitro group of 4-chloro-8-nitro-quinoline derivatives has be successfully carried out. This has lead to the synthesis of bisquinoline-py

Full text of DOI:10.1016/j.tet.2012.05.001

Tetrahedron 68 (2012) 5453e5457
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Synthesis of bisquinolineepyrrole oligoamide as G-quadruplex binding ligand
,
a
a
a
a
a
Chi Wi Ong a , Meng-Chi Liu , Kun-Da Lee , Keng Wei Chang , Ya-Ting Yang , Hung-Wei Tung ,
*
Keith R. Fox b
a National Sun Yat-Sen University, No. 70, Lienhai Rd., Kaohsi0ung 804, Taiwan
b Centre for Biological Sciences, Life Sciences Building, University of Southampton, Southampton SO17 1BJ, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot procedure using ammonium formate under palladium catalysis for the reductive de-
chlorination and reduction of nitro group of 4-chloro-8-nitroequinoline derivatives has be successfully
carried out. This has lead to the synthesis of bisquinolineepyrrole oligoamide 1, which show significant
G-quadruplex selectivity in preference to duplex DNA. The cooperativity between the bisquinoline and
pyrrole oligoamide moieties for good binding affinity to G-quadruplex was proven by synthesizing 2 and
3 lacking a quinoline ring and pyrrole amide, respectively, and both show much reduce affinity to G-
quadruplex. Altogether, the results demostrate that the appropriate combination of two chromophores to
form the hybride can attenuate binding affinity and selectivity towards G-quadruplex, an important
criteria for the rational drug design.
Received 17 January 2012
Received in revised form 10 April 2012
Accepted 24 April 2012
Available online 9 May 2012
Keywords:
Bisquinoline
Polyamide
Quadruplex
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
architecture has been shown to have significant binding affinity
and selectivity for G-quadruplex without any evidence of DNA-
G-quadruplexes secondary structure are found in G-rich regions
of DNA through the association of four guanine to form the guanine
tetrad, followed by stacking of the guanine tetrad on top of each
other.1 The ability of G-rich sequences in telomeres and numerous
gene promoters to form quadruplex structures has been exploited
for the development of anticancer agents that promote or stabilize
G-quadruplex.2e6,14,23 The main strategy is the design of large flat
aromatic ligands with or without containing cationic side chains
duplex binding.15c It should be noted that the 4-position of the
quinoline ring contain a cationic side chains to confer electrostatic
interaction with the G-quadruplex, and possibly improved water
solubility. Interestingly, the bisquinoline adopting
crescent-like structure was found to be a poor G-quadruplex ligand.
Can the -rich bisquinoline be transform into a good G-quadruplex
a planar
p
ligand? Herein, we hope to use cooperative effect by incooperating
pyrrole oligoamide to the bisquinoline and study the ability to
stabilize G-quadruplex.
that binds to the G-tetrad through
p-p stacking and electrostatic
interaction,1b,3e,f,7 such as macrocyclic telomestatin,8 pentacyclic
acridinium ligands,9 cationic porphyrin,10 4,7-diamino-1,10-
phenanthroline derivatives11 and bisquinolinium compounds.12
However the grooves of quadruplex structures remains an oppor-
tunity for ligands binding. More recently, distamycin, a DNA minor
groove binding agent has been found to interact with the grooves of
quadruplexes.13 Till today, the design of quadruplex binding ligands
In this contribution we demonstrated that the incorperation of
pyrrole oligoamide to bisquinoline in 1 favours G-quadruplex sta-
bilization. As shown in Fig. 1, the bisquinoline can adopt a near
planar conformation (1b), whereby playing the role of pep stack-
ing with the G-tetrads, and the pyrrole oligoamide further atten-
uating the G-quadruplex stabilization. We next need to offer prove
of cooperativity between the bisquinoline and pyrrole amide
moieties for the good binding affinity and selectivity towards G-
has mainly focused individually on pep stacking at the G-tetrads or
hydrogen bond at the groove, while their cooperative interaction
quadruplex. The role of pep stacking ligand for bringing the groove
has rarely been discussed.14
binding ligand to close proximity was further tested by replacing
one quinoline ring of compound 1 with a phenyl ring in compound
2. By replacing one of the quinoline ring of compound 1 with
a phenyl ring to form compound 2 we have reduced the available
Quinoline oligoamides has been reported to fold into predict-
able and very stable secondary motifs,15a,b and recently shown to be
a good candidate as G-quadruplex ligands.15c The tetramer of 8-
amino-2-quinoline carboxylic acid with a 1.5 turn helically folded
pep stacking interaction. Compound 3 was constructed to contain
two quinolines rings tethered to dimethylaminopropane, but
without an attached pyrrole amide. Both compound 2 and 3 have
a lower binding affinity fo G-quadruplex. Furthermore, our com-
pound 1e3 do not possess a functional group at 4-position of
* Corresponding author. Tel.: þ886 952311150; fax: þ886 7 5253908; e-mail
address: cong@mail.nsysu.edu.tw (C.W. Ong).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.001

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C.W. Ong et al. / Tetrahedron 68 (2012) 5453e5457
CO2Me
CO2Me
NO2
a
MeO2C
CO2Me
N
NO2
NH2
H
6
5
4
O
4
Cl
4
b
c
Table 1
N
CO2Me
N
CO2Me
H
NO2
4
NO2
8
7
N
NH2
CO2Me
9
Scheme 1. Preparation of quinoline motif. (a) MeOH, rt, 18 h then reflux 6 h, 82%. (b)
PPA/6¼2.26, 180 ꢀC, 45 min, 84%. (c) POCl3, reflux 2 h then rt, 1 h, 95%.
Table 1
Dehalogenation of 8
Entry
Conditions
Product
Fig. 1. Compounds 1e3 to probe the cooperative between guanine tetrad pep stacking
1
2
3
Na(Hg), rt, 4 h in THF/MeOH¼1:1
*
7
9
ligand and DNA minor goove binding ligands. 1a and 1b, top and side view of 1 with
one pyrrole ring showing the near planarity of the bisquinoline rings with the pyrrole
ring sticking outwards.
Hexanoic acid, Cu power, 160e170 ꢀC, 10 min.
Ammonium formate, 5% Pd/C, in MeOH, reflux 10.5 h
C Complex mixtures.
quinoline that may aid G-quadruplex stabilization. We have found
an expedient method for silencing the 4-position of quinoline by
converting 4-chloro-8-nitro-quinoline derivative to the 8-amino-
quinoline derivatives under hydrogenation condition, a one-pot
procedure for the reductive dechlorination with consecutive re-
duction of nitro group to amine.
show no protection mapping with concentration greater than
10 M. This substatiate the comparative thermal stabilization re-
sults, which showed that compounds 1e3 have minimal affinity to
duplex DNA.
m
The poor binding to duplex DNA of 1e3 upto a concentration of
over 10 mM encourages us to investigate whether these compounds
2. Results and discussion
can behave as a good selective G-quadruplex binding agent. The
stabilization to various G-quadruplexes was also investigated by
fluorescence melting analysis20 using human telomeric G-quad-
ruplex (HT), c-kit and c-myc promoters. The thermal melting tem-
peratures of the various quadruplexes were determined using the
fluorescence melting technique developed previously by Darby
et al.21a for assessing the stability of related quadruplexes21bee in
the present or absent of ligands. The stabilization of the quadruplex
Our synthesis began with the reaction of 2-nitroaniline 4 with
dimethyl-acetylenedicarboxylate 5 give 6, followed by cyclization to
7 and aromatization to give 4-choro-8-nitro-quinoline-2-carboxylic
ester 8 using reported procedures,16 but with slight modifications
(Scheme 1). We found that the cyclization of compound 6e7 was
best performed using a 1:2 w/w ratio of compound to poly-
phosphoric acid at 180 ꢀC for a short reaction time (<1 h), whereby
prolong reaction time gave a much lower yield. Our first task was to
dehalogenate compound 8 using several reported reductive delo-
genation conditions as shown inTable 1. The use of sodium amalgam
or copper powder in organic acid17 failed to give the required
product. Interestingly, the use of ammonium formate with Pd/C
catalysis18 for the dechlorination of 8 was found to simultaneously
reduced the nitro group to the amine in one-pot to give directly the
key intermediate 9. Compound 9 was subsequently reacted with
benzoyl chloride and quinoline-2-carbonyl chloride in the presence
of DIPEA to give 10 and 11, respectively, in high yield. The ester of 10
and 11 was hydrolyzed to the acid and then converted to the acid
chloride 10a and 11a, respectively, for the subsequent preparation of
our model 1e3. The coupling of 10a and 11a with the previous
reported pyrrole oligoamide 1219 gave the desired product 1 and 2,
respectively, in moderate yield. Similarly reaction of 11a with N,N-
dimethylaminopropylamine gave 3 (Scheme 2).
increases its melting temperature (
M, distamycin and compound 12 showed no stabilization for all
the G-quadruplex in this study (see ESI). As such, a concentration of
M for ligand 1e3 was chosen to study their ability to stabilize G-
DTm). At the concentration of
2
m
2
m
quadruplex. The synthesized ligand 1e3 showed good to moderate
stabilization of the G-quadruplex and the results are shown in Fig. 2
and Table 2. The Tm enhancement (DTm) for each compound is
tabulated in Table 2.
Our results indicate clearly that ligand 1 was the best in stabi-
lizing all the G-quadruplex, with a
Tm value of 7 ꢀC for HT, 5.4 ꢀ
for c-kit, and 4.1 ꢀC for c-myc, respectively. Compound 2, with re-
duced stacking, while compound 3, which lacks the bispyrrole
D
C
pep
oligoamide, in our design strategy were uniformly weaker G-
quadruplex binders. To our delight, the bisquinoline pyrrole oli-
goamide hybrid 1 has a cooperative effect in enhancing binding
affinity and selectivity for G-quadruplex.
Recently, there have been growing interest to design small
molecules that show some discrimination between G-quad-
ruplexes.22e25 These results provide some hints for designing li-
We next investigated the ability of these compounds 1e3 to
bind to duplex DNA and G-quadruplex. The comparative thermal
stabilization (
D
Tm) of calf thymus (CT) duplex by compounds 1e3
gand to discriminate between G-quadruplexes ligands based on
rich bisquinoline and pyrrole oligoamide. For the HT sequence, the
Tm produced by 1 is greater than that for 2 and 3. This suggests
that both stacking and pyrrole oligoamide are required for
optimal binding to HT sequence. Compound 1 and 3 has a higher
Tm than 2 with the c-kit sequence, this indicate that stacking
is playing a more predominant role for binding to c-kit sequence.
p-
was performed using UV absorbanceetemperature plot under
identical conditions of buffer and pH. The results show that 3 dis-
D
played slight binding for CT DNA (
D
Tm¼0.7 ꢀC) as compared with 1
pep
and 2 (
D
Tm<0.3 ꢀC) (see ESI). Deoxyribosenuclease I footprinting
analysis is a useful technique for locating the specific binding site of
small molecule on DNA. Footprinting of compounds 1e3 with Hex B
D
pep

C.W. Ong et al. / Tetrahedron 68 (2012) 5453e5457
5455
O
Cl
O
N
H
N
O
NH
N
N
a
N
N
CO2Me
COX
b
NH2
XOC
c,d
9
c,d
10: X=OMe
10a: X= Cl
11: X=OMe
11a: X= Cl
NH2
N
g
12
f
O
H
HN
N
e
N
O
N
H
N
12
N
O
O
HN
O
O
N
N
N
N
H
H
N
N
N
HN
H
N
O
N
HN
O
HN
O
N
O
N
2
N
HN
H
N
3
N
O
N
O
1
Scheme 2. Synthesis of model compounds 1e3. (a) PhCOCl, NEt3, CH2Cl2, rt, 77%. (b) DIEA, CH2Cl2, 0 ꢀC wrt, 30%. (c) KOH, THF:MeOH¼2:1, rt, 80%. (d). SOCl2, C6H6, reflux-rt (e) N1,N1-
Dimethyl-propane-1,3-diamine, DIEA, 0 ꢀC wrt, 52%. (f) 4-Amino-N-(5-(3-(dimethylamino)propylcarbamoyl)-1-methyl-1H-pyrrol-3-yl)-1-methyl-1H-pyrrole-2-carboxamide 12, DIEA,
0 wrt, 35%. (g). 12, DIEA, CH2Cl2, 0 ꢀC wrt, 32%.
Finally, we carried out a competition binding assay for G-
quadruplex versus duplex DNA. As shown in Table 3 (entry 2), CT
DNA has a minimal effect on the melting temperature of HT
quadruplex. Next, competitive binding for compound 1 to HT
quadruplex in the presence of varying amounts of CT-duplex DNA
was carried out. As shown in Table 3 (entry 7) the
DTm of the HT
quadruplex was largely unchanged in the presence of a 20-fold
excess of calf thymus DNA. This result indirectly shows that com-
pound 1 bind preferentially to quadruplex DNA.
Table 3
Competitive binding assay of quadruplex versus duplex
Entry
Ratio of HT:CT: 1a
D
Tm (ꢀC)
1
2
3
4
5
6
7
1:0:0
1:20:0
1:0:2
1:1:2
1:5:2
0
0.9
6.7
6.3
6.3
5.5
5.4
1:10:2
1:20:2
a
Concentration in mM.
Fig. 2. Melting curve of 1 mM intramolecular G-quadruplex in the present of 2 mM
ligands.
3. Conclusion
On the other hand, the slightly lower stabilization of the c-myc
sequence by 3 indicate the pyrrole oligoamide might playing a role
for c-myc sequence. Highly specific recognize to a particular G-
quadruplex sequence may thus be achieved at the molecular level.
In summary, we have synthesized three new bisquinoline de-
rivatives and study their interaction with duplex and quadruplex
DNA. The results ascertain the importance of tethering pyrrole
polyamide groove binding ligand to bisquinoline
pep stacking li-
Table 2
gand in enhancing quadruplex stabilization, and more importantly
with the discrimination against duplex DNA. This can be a useful
strategy of choice for the future design of new anticancer agents.
Thermal stability of quadruplex DNA and ligands
D
D
Tm at 2
m
M conc./ꢀC
Compounds
Sequences
1
2
3
12a
Distamycina
4. Experimental section
4.1. General
HT
c-kit
c-myc
7.0
5.4
4.1
1.3
1.3
3.5
1.8
4.5
2.6
0
0
0
0
0
0
The experiments were performed in 10 mM Li2PO4 pH 7.4 containing 100 mM KCl
(HT and c-kit) or 0.1 mM KCl (c-myc). Each reactions contained 1 M oligonucleotide
and 2
M ligand; heated at 0.5 ꢀC minꢁ1
At 5 M,
Tm¼<1.0.
All reactions were conducted under an atmosphere of nitrogen
in oven-dried glassware. CH2Cl2 was distilled over calcium hydride.
DMSO, MeOH and EtOH were purchased from Merck and used as
m
m
.
a
m
D

5456
C.W. Ong et al. / Tetrahedron 68 (2012) 5453e5457
received. Nuclear magnetic resonance spectra were recorded on
a Varian Gemini-200 MHz and Varian Unity-INOVA-500 MHz
spectrometer. (CDCl3, MeOD-d3 or DMSO-d6). Chemical shifts are
further dried by vacuum to give the 8-[(quinoline-2-carbonyl)-
amino]-quinoline-2-carbonyl chloride. The residue was dissolved
in 10 mL CH2Cl2 and slowly added to the solution of amino poly-
pyrrole amide 12 in 20 ml CH2Cl2, which is mixed with DIEA (0.5 ml,
2.9 mmol) under 0 ꢀC. After reacting overnight at room tempera-
ture, the solvent was evaporated and the residue was extracted
with CH2Cl2, washed with brine, dried over Na2SO4, and concen-
trated to give the crude product, and purified by column chroma-
tography using CH2Cl2:MeOH¼2:1 as elution. The desired product 1
as a yellow solid was obtained (0.07 g, 35%). Mp 213e214 ꢀC. 1H
reported in parts per million relative to residual CHCl3 (
d
¼7.26, 1H;
77.0, 13C). Mass spectra were obtained on JEOL JMS-HX110, ESI on
Bruker APE (II) FT-MS or Bruker Autoflex MALDI-TOFMS. N,N-Di-
methyl-propane-1,3-diamine is commercially available. Synthesis
of 12 was referred to in Ref. 19.
4.2. Fluorescence melting studies
NMR (500 MHz, CDCl3) d: 12.32 (s, 1H), 10.05 (s, 1H), 10.04 (s, 1H),
The ligands were dissolved in DMSO, which was kept below 1%
final concentration in the capillary. Fluorescence melting experi-
ments were conducted in a Roche LightCycler as previously de-
9.01 (d, 1H, J¼7.5 Hz), 8.49 (d, 1H, J¼8.5 Hz), 8.43 (d, 1H, J¼8.5 Hz),
8.41w8.39 (m, 2H), 8.18 (d, 1H, J¼8.0 Hz), 7.91 (d, 1H, J¼8.0 Hz),
7.71w7.64 (m, 4H), 7.58 (t, 1H, J¼7.5 Hz), 7.38 (d, 1H, J¼15 Hz), 7.18
(d, 1H, J¼1.5 Hz), 6.95 (d, 1H, J¼1.5 Hz), 6.39 (d, 1H, J¼1.5 Hz), 4.03
(s, 3H), 3.96 (s, 3H), 3.48 (q, 2H, J¼6.0 Hz), 2.47 (t, 2H, J¼6.0 Hz),
2.28 (s, 6H), 1.75 (t, 2H, J¼6.0 Hz). 13C NMR (125 MHz, CDCl3);
162.26, 161.67, 161.57, 158.79, 150.18, 147.95, 146.31, 138.35, 138.05,
137.45, 134.23, 130.22, 130.19, 129.63, 129.42, 129.18, 128.49, 128.00,
123.94, 123.61, 122.13, 121.04, 120.97, 119.96, 119.44, 119.09, 118.46,
117.83, 104.39, 102.84, 58.88, 45.38, 39.28, 36.84, 36.69, 25.80.
HRMS (ESI): calcd for C37H38N9O4, 672.3051, found, 672.3047.
scribed21 in a total reaction volume of 20
ml. Intramolecular
oligonucleotides (final concentration 1
mM) were prepared in
10 mM lithium phosphate pH 7.5, which was supplemented with
various concentrations of potassium chloride or sodium chloride.
The LightCycler has one excitation source (488 nm) and the changes
in fluorescence were measured at 520 nm. As previously described,
hysteresis effects with the intramolecular quadruplexes were
suppressed by performing the melting experiments at a slow rate of
heating and cooling (0.5 ꢀC minꢁ1) by increasing the temperature in
1
ꢀC steps, leaving the samples to equilibrate for 2 min at each
4.3.2. 8-Benzamido-N-(5-(5-(3-(dimethylamino)propylcarbamoyl)-
1-methyl-1H-pyrrol-3-ylcarbamoyl)-1-methyl-1H-pyrrol-3-yl)-
quinoline-2-carboxamide (2). To a solution of benzoyl chloride
(1 mL, 3.1 mmol) was slowly added into the solution of 8-amino-
quinoline-2-carboxylic acid 6 (0.52 g, 2.6 mmol) in 20 ml CH2Cl2,
which is mixed with triethylamine (0.43 ml, 3.1 mmol) under 0 ꢀC.
After reacting 6 h at room temperature, the solvent was evaporated
and the residue was extracted with CH2Cl2, washed with brine,
dried over Na2SO4, and concentrated to give the crude product, and
purified by column chromatography using CH2Cl2. The desired
product 2 as a brown solid was obtained (0.60 g, 75%). Mp
temperature before recording the fluorescence. In a typical intra-
molecular sequences experiment, the oligonucleotides were first
denatured by heating to 95 ꢀC fꢁo1r 5 min. They were then annealed
by cooling to 30 ꢀC at 0.5 ꢀC.min and melted by heating to 95 ꢀC at
the same rate. Under these conditions, no hysteresis was observed.
Melting temperatures (Tm values) were determined from the first
derivatives of the melting profiles using the Roche LightCycler
software. The sequence code used in this study were HT: F-
A(GGGTTA)3GGGT-Q, c-kit: F-AGGGAGGGCGCTGGGAG GAGGG-Q
and c-myc: F-TGGGGAGGGTGGGGAGG-Q. Where F is dR-FAM at
50-end and Q is dR-Met Red at 30-end.
232e235 ꢀC. 1H NMR (500 MHz, DMSO-d6);
d: 11.23 (s, 1H), 11.03 (s,
1H), 10.04 (s, 1H), 8.90 (d, 1H, J¼7.5 Hz), 8.64 (d, 1H, J¼8.5 Hz), 8.28
4.3. Synthesis and characterization data for ligands 1e3
(d, 1H, J¼8.5 Hz), 8.15w8.17 (m, 2H), 7.82 (d, 1H, J¼8.5 Hz), 7.76 (t,
1H, J¼8.0 Hz), 7.4w7.70 (m, 3H), 7.36 (d, 1H, J¼1.5 Hz), 7.24 (d, 1H,
d
4.3.1. N-(5-(5-(3-(Dimethylamino)propylcarbamoyl)-1-methyl-1H-
pyrrol-3-ylcarbamoyl)-1-methyl-1H-pyrrol-3-yl)-8-(quinoline-2-
carboxamido)quinoline-2-carboxamide (1). To a solution of quinal-
dic acid (0.1 g, 0.58 mmol) in benzene (10 mL) was added 1 ml of
thionyl chloride and refluxed for 2 h. After further reacting in room
temperature for 1 h, the solvent and excess thionyl chloride were
removed by rotary evaporator and dried by vacuum. The residue
was dissolved in 10 mL CH2Cl2 and slowly added to the solution of
8-amino-quinoline-2-carboxylic acid 6 (0.52 g, 2.6 mmol) in 20 ml
CH2Cl2, which is mixed with DIEA (0.5 ml, 2.9 mmol) under 0 ꢀC.
After reacting overnight at room temperature, the solvent was
evaporated and the residue was extracted with CH2Cl2, washed
with brine, dried over Na2SO4, and concentrated to give the crude
product, and purified by column chromatography using CH2Cl2. The
desired product 11 as a yellow solid was obtained (0.15 g, 90%) and
used directly.
J¼2.0 Hz), 7.23 (d, 1H, J¼1.5 Hz), 6.87 (d, 1H, J¼1.5 Hz), 3.93 (s, 3H),
3.83 (s, 3H), 3.21 (q, 2H), 2.31 (t, 2H, J¼7.0, Hz), 2.19 (s, 6H),
1.61w1.67 (m, 2H), 13C NMR (125 MHz, DMSO-d6)
d: 165.90, 161.66,
161.29, 158.51, 149.12, 138.47, 137.15, 135.10, 134.73, 132.17, 128.94,
128.68, 128.17, 123.69, 123.13, 122.42, 122.09, 121.59, 119.69, 118.90,
118.36, 117.98, 105.08, 104.14, 57.01, 45.02, 37.09, 36.31, 36.04, 27.01.
HRMS (ESI): calcd for C34H36N8O4, 621.2938, found, 621.2935.
4.3.3. N-(3-(Dimethylamino)propyl)-8-(quinoline-2-carboxamido)-
quinoline-2-carboxamide (3). Synthesis of compound 3 was started
from 8 and similarly prepared as 1 with the use of N,N-dimethyl-
1,3-propanediamine. Yield: 0.13 g, 52%. Light yellow solid. Mp
144e145 ꢀC. 1H NMR (500 MHz, CDCl3)
d: 12.41 (s, 1H), 9.05 (d, 1H,
J¼7.5 Hz), 8.72 (br, 1H), 8.49 (d, 1H, J¼8.5 Hz), 8.44 (d, 2H, J¼4.0 Hz),
8.43 (d, 1H, J¼4.0 Hz), 8.38 (d, 1H, J¼8.5 Hz), 8.22 (d, 1H, J¼8.0 Hz),
7.97 (d, 1H, J¼8.5 Hz), 7.87 (t, 1H, J¼7.5 Hz), 7.73w7.69 (m, 2H), 7.65
(d,1H, J¼8.0 Hz), 3.82 (q, 2H, J¼7.0 Hz), 2.44 (t, 2H, J¼7.0 Hz), 2.11 (s,
Compound 11 (0.2 g, 0.56 mmol) was dissolved in
THF:MeOH¼2:1 (15 mL) and added KOH (0.2 g, 3.57 mmol). After
reacting at room temperature for 3 h, THF was removed from re-
action mixture by rotary evaporator and adjusted ph to 3e4 by 2 M
aqueous HCl, and on further cooling in an ice bath gave light yellow
6H), 1.75 (m, 2H). 13C NMR (125 MHz, CDCl3)
d: 164.40, 162.45,
150.16, 148.30, 146.46, 138.01, 138.00, 137.53, 134.45, 130.36, 129.63,
129.58, 129.36, 128.97, 128.31, 128.07, 122.02, 119.68, 118.98, 117.50,
57.32, 45.28, 38.46, 29.68, 27.87. HRMS (ESI): calcd for C25H26N5O2,
428.2089, found, 428.2086.
precipitate
of
8-[(quinoline-2-carbonyl)-amino]-quinoline-2-
carboxylic acid. The precipitate was collected, washed with addi-
tional cold water, and dried to give 0.15 g light yellow powder
product in 80% yield. The 0.1 g (0.29 mmol) of light yellow powder
was dissolved in 10 mL benzene with 1 mL of thionyl chloride and
refluxed for 1 h. After cooling to room temperature, benzene and
excess thionyl chloride were removed by rotary evaporator and
Acknowledgements
We thank the NSC, grant NSC98-2917-I-110-102 and NSC100-
2113-M-110-007-MY3 for the financial support.

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Supplementary data
UV melting temperature and DNase I footprinting experiments
of 1e3 and distamycin are available. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
j.tet.2012.05.001.
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