Synthesis of batracylin and its N-sulfonamido analogues in [b-3C-im][NTf2] ionic liquid

Article abstract of DOI:10.1016/j.tet.2014.02.076

Starting with commercial and inexpensive reagents, a high-yielding chemical process carried out in [b-3C-im][NTf₂] ionic liquid was achieved to afford the synthesis of batracylin and its N-sulfonamido analogues. Among all compounds synthesized, compounds 1, 11, and 14 exhibit potent inhibitory activity against human topoisomerase 1 (hTop1).

Full text of DOI:10.1016/j.tet.2014.02.076

Tetrahedron 70 (2014) 2629e2633
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of batracylin and its N-sulfonamido analogues
in [b-3C-im][NTf2] ionic liquid
,
,
,
Ming-Chung Tseng a y, Peng-Yeh Lai b y, Lin Shi a z, Hsin-Yi Li a, Min-Jen Tseng b,
,
Yen-Ho Chu a
*
a Department of Chemistry and Biochemistry, National Chung Cheng University, 168 University Road, Minhsiung, Chiayi 62102, Taiwan, ROC
b Institute of Molecular Biology, National Chung Cheng University, 168 University Road, Minhsiung, Chiayi 62102, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting with commercial and inexpensive reagents, a high-yielding chemical process carried out in [b-
3C-im][NTf2] ionic liquid was achieved to afford the synthesis of batracylin and its N-sulfonamido an-
alogues. Among all compounds synthesized, compounds 1, 11, and 14 exhibit potent inhibitory activity
against human topoisomerase 1 (hTop1).
Received 14 January 2014
Received in revised form 23 February 2014
Accepted 26 February 2014
Available online 5 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Batracylin
Ionic liquid
Microwave-assisted cyclodehydration
One-pot synthesis
DNA topoisomerase
1. Introduction
O
H2N
N
N
N
B
A
NTf2
This paper reports a high-yielding synthesis of batracylin 1 and
its N-sulfonamido analogues in [b-3C-im][NTf2] ionic liquid 2. Ionic
liquids are low-melting molten salts composed entirely of ions, and
many of them are liquid at room temperature.1e5 This class of ionic
solvents are known to carry numerous desirable properties, such as
negligible vapor pressure, good thermal and chemical stability,
high conductivity, and attractive recyclability that are suited for
a myriad of applications, including excellent reaction media for
organic synthesis, remarkable affinity separation of biomolecules,
outstanding electrolytes for rechargeable lithium ion batteries, and
unique solvents for cellulose dissolution.1e5
Many natural and unnatural products have quinazoline ring
embedded in their structures and batracylin 1 carries such struc-
tural motif (Fig. 1).6e8 A good number of quinazoline and quinoline
products have been sold as drugs in market9 and many others are
currently under different phases of clinical trial.10 This quinazoline
core has attracted great attention to chemists due primarily to its
diverse biological activities.11
C
Bu
D
N
batracylin, 1
[b-3C-im][NTf2], 2
Fig. 1. Structures of batracylin 1 and [b-3C-im][NTf2] ionic liquid 2.
In our laboratory, we have been interested in developing new
ionic liquids and have an ongoing program to evaluate ionic liquids
as novel and stable media for organic syntheses1,5,12e14 and bio-
chemistry applications.15,16 Also, our group recently reported syn-
theses of quinazolin-4-one containing natural products, such as
luotonin A,17 asperlicin C,18 circumdatin F,18,19 sclerotigenin,18,19 and
rutaecarpine,20 and their derivatives.19,21 We therefore envisaged
that ionic liquids, such as the chemically stable [b-3C-im][NTf2] 2
previously developed in our laboratory,1,5 are non-volatile and
should be excellent reaction media for other quinazoline alkaloid
synthesis and, for exactly this reason, specifically targeted batra-
cylin 1 and its analogues. In this work, we report a synthetic
strategy for simultaneous construction of quinazoline and iso-
indolinone cores (BC rings) applied to the total synthesis of 1. This
synthesis of batracylin 1 completed in ionic liquid, to our knowl-
edge, has not been reported in the literature and its approach may
potentially be of use for the synthesis of other complex natural
products.
* Corresponding author. Tel.: þ886 52428148; fax: þ886 52721040; e-mail ad-
dress: cheyhc@ccu.edu.tw (Y.-H. Chu).
y
These authors contributed equally to this work.
On leave from the Shenyang Agricultural University, Shenyang 110161, Liaoning,
z
PR China.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.076

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M.-C. Tseng et al. / Tetrahedron 70 (2014) 2629e2633
Batracylin 1 is a cytostatic and experimental anticancer agent,
same reactionwas performed in molecular solvent, such as the polar
DMF, incomplete reaction was resulted and the product 7 was ob-
tained only with marginal 9% yield after column chromatography.36
This result of the dehydrocyclization formation of 7 in ionic liquid 2
is consistent with our recent reports on the Lewis acidic nature of
ionic liquid, which likely activates phathalic anhydride 3 as well as
the corresponding imide intermediate.13 We also found that
a moderate 34% isolated yield of 7 was resulted if carried out in the
hydrophilic, water-soluble [b-3C-im][Br] ionic liquid. This may be
understood by the fact that the use of the water immiscible, hy-
drophobic [b-3C-im][NTf2] ionic liquid 2 potentially inhibit the re-
verse hydrolysis of product formed and the water, once produced,
became immiscible with the ionic liquid solvent and, in the end,
likely was carried away by microwave heating. If this reaction was
performed at ambient temperature, trace of 7 was not at all detected.
The proposed reaction sequence shown in Scheme 1 did occur in
a one-pot fashion under our optimized experimental conditions.
This one-pot synthesis of batracylin 1 started from inexpensive 2-
amino-5-nitrobenzonitrile 5. Upon reacting first with borane/THF
in [b-3C-im][NTf2] ionic liquid 2 at 80 ꢀC for 2.5 h, compound 5
was readily converted to 2-amino-5-nitrobenzylamine 4. After
removing THF and excessive reagent in vacuo, microwaves (60 W)
of 4 in ionic liquid 2 with phthalic anhydride 3 at 120 ꢀC for 10 min
furnished 8-nitroisoindolo[1,2-b]quinazolin-12(10H)-one as the 8-
nitro substituted 7 followed by catalytic hydrogenation at ambi-
ent temperature for 2 h to finally afford the desired fluorescent
product, batracylin 1, with an excellent 81% overall isolated yield
after column chromatography. In our hands, a slightly stringent
microwave heating condition (60 W, 120 ꢀC, 10 min) was needed
and used in the second step for the synthesis of 1. This is entirely
reasonable due primarily to the presence of a nitro substituent in 4
making this intermediate significantly less nucleophilic. This
sequence of reactions performed in ionic liquid 2 was remarkably
facile and the reactions required no special precautions.
not only displays potent antitumor activity in vivo against murine
solid tumors but is also effective against murine leukemia P-388
and colon adenocarcinoma 38 cell lines with acquired resistance to
adriamycin, cisplatin, and methotrexate.22e24 Batracylin 1 has been
tested and evaluated in phase I clinical trial, and the studies were
completed in 2011 and the data are currently being analyzed.22 It
was also demonstrated that 1 acted as a dual inhibitor of top-
oisomerases 1 and 2 to stabilize DNA/enzyme binary complexes,
induced unscheduled DNA synthesis of nonproliferating cells in rat
hepatocytes, and displayed growth inhibition in HT29 colon carci-
noma cells with a GI50 value of 10 m
M.25,26 Albeit it is far from being
potent enough for cancer chemotherapy, 1 is nevertheless a lead
compound and has been the subject of a number of synthetic
investigations.27e34 These reported syntheses of 1, however, often
required long hours in reactions, low to moderate yields in key
steps, and harsh experimental conditions.27e34 Thus, further de-
velopment of practical and efficient synthesis of
1 and its
derivatives, such as N-sulfonamido analogues would be of immense
value for the structure-and-activity relationship (SAR) study.
2. Results and discussion
In literature, the most common approach in synthesis of 1 was
by using intermediate construction with either phthalic anhydride
or phathalimide and substituted benzyl halides or benzyl
amine.27e34 Scheme 1 outlines our one-pot synthesis of batracylin
1, of which the key BC rings were assembled from phathalic an-
hydride 3 and the intermediate 2-amino-5-nitrobenzylamine 4
obtained from very inexpensive 2-amino-5-nitrobenzonitrile 5 ($1/
g, Aldrich) by reduction with borane. We envisioned that the con-
comitant formation of BC rings, when formed, would require
heated conditions to drive two consecutive dehydrative cycliza-
tions to completion and, moreover, ionic liquids are non-volatile,
polar, ionic, and can be efficiently heated by microwaves,35 we
therefore decided to employ microwaves to deliberately promote
such cyclodehydration reactions in the water immiscible, hydro-
phobic [b-3C-im][NTf2] ionic liquid 2.
The success of the synthesis of batracylin 1 using microwaves in
ionic liquid 2 further prompted us to prepare its derivatives with
greater diversity. In this work, we focused on the preparation of the
A-ring, N-sulfonamide analogues containing alkyl and aromatic
groups on the batracylin pharmacophore (8e16, Fig. 2).
O
O
H
N
O
N
S
N
O
N
N
7
8
Me
Me3C
O
O
H
H
N
O
N
Scheme 1. One-pot synthesis of batracylin 1 in [b-3C-im][NTf2] 2.
S
N
S
N
O
O
O
N
N
To validate this key second step (Scheme 1), we selected 8-
desaminobatracylin 7 as the model compound for 1 and examined
the double cyclodehydrative reaction of commercial o-amino-
benzylamine 6 with phathalic anhydride 3 in ionic solvent 2 under
microwave condition. The result is summarized in Scheme 2. To our
delight, this microwave-assisted double cyclization in ionic liquid 2
proved to be highly effective and the synthesis of 7 was obtained
with 99% excellent isolated yield at 145 ꢀC after only 2 min of mi-
crowaves (10 W). Under identical experimental condition, if the
9
10
12
14
16
MeO
F
O
O
O
O
H
H
N
O
N
S
N
S
S
N
O
O
O
O
N
N
N
11
13
O2N
O
O
H
H
N
O
N
S
N
N
O
O
N
O
O
H
H
N
Me2N
N
Me
O
S
N
S
N
O
O
O
N
N
15
Scheme 2. Synthesis of 8-desaminobatracylin 7 in [b-3C-im][NTf2] 2.
Fig. 2. Structures of batracylin analogues 7e16.

M.-C. Tseng et al. / Tetrahedron 70 (2014) 2629e2633
2631
N-Sulfonamido analogues of 1 were selected for the reasons that
3. Conclusions
the sulfonamide group plays an important role in the topoisomer-
ase inhibitory activity of amsacrine37,38 and compounds, such as
sulfonamide derivatives of epipodophyllotoxin (etoposide, VP-16)
and chloroquinoxaline have been reported to be more potent in-
hibitors than VP-16 to human topoisomerase 2.39,40 The synthesis
of the N-sulfonamido analogues from the requisite 1 is depicted in
Scheme 3. Results show that regardless of the nature of sulfonyl
substituents, target compounds 8e16 were all prepared in the
presence of pyridine in ionic liquid 2 at ambient temperature (3 h)
with high to excellent isolated yields (Scheme 3). In our hands,
batracylin analogues 8 and 15 gave the highest (99%) and lowest
(82%) isolated yields, respectively. The successful application of our
one-pot protocol to access the core isoindolo[1,2-b]quinazolin-
12(10H)-one structure and its sulfonamide derivatives demon-
strates the utility of our synthetic method. With an ultimate goal of
developing new and more potent anticancer agents, the SAR of
batracylin 1, 8-desaminobatracylin 7 and N-sulfonamido batracy-
lins 8e16 was then studied.
We have developed a one-pot protocol for the synthesis of
batracylin 1 in the chemically stable, water immiscible [b-3C-im]
[NTf2] ionic liquid 2. Our method avoids the need for harsh con-
ditions and allows concomitant construction of BC ring structure.
This is the shortest synthesis of batracylin.
Compared with previously reported syntheses, our ionic liq-
uid approach presents the advantages of a short synthesis route,
high isolated yield, and no need for the isolation and purification
of any intermediates. The chemistry presented in this work ef-
ficiently achieves the synthesis of batracylin as well as the
preparation of its N-sulfonamido analogues and should contrib-
ute to the SAR study in this family of antitumor agents to further
identify batracylin analogues with more potent anticancer
activity.
4. Experimental section
4.1. General
O
O
H
H2N
R
N
RSO2Cl, pyridine
Microwave irradiation experiments were performed using
a CEM Discover microwave reactor from CEM Corporation (North
Carolina, USA). Flash chromatography was performed on silica gel
(230e400 mesh). TLC was carried out on aluminum-backed silica
plates precoated with silica (0.2 mm), which were developed using
standard visualizing agents, such as UV fluorescence and iodine.
Unless otherwise indicated, all reactions were carried out without
the aid of dry nitrogen or argon. NMR spectra were recorded on
a Bruker AVANCE DPX 400 at 400 MHz (1H) and 100.6 MHz (13C)
both in CDCl3 unless otherwise stated. Chemical shifts were quoted
in parts per million (ppm). Melting points were determined on
a Fargo MP-2D apparatus (Taiwan, ROC) and are uncorrected. Sol-
vents and reagents were obtained from commercial sources and
were used without further purification.
N
S
N
O
O
ionic liquid 2, rt, 3 h
N
N
1
8, 99%; 9, 84%; 10, 90%
11, 92%; 12, 85%; 13, 94%
14, 83%; 15, 82%; 16, 95%
Scheme 3. Synthesis of N-sulfonamido batracylins 8e16 in [b-3C-im][NTf2] 2.
All compounds synthesized in this work were assayed for
biological activities (Fig. 3). In literature, no N-sulfonamido
batracylins were reported and showed promising biological activ-
ities. Inhibitory activities of compounds 1 and 7e16 to human
topoisomerase 1 (hTop1) were measured by assaying the relaxation
of a supercoiled pHOT-1 plasmid DNA.41
Fig. 3. Analysis of hTop1 inhibition by batracylin 1 and its analogues 7e16.
The assay result showed in Fig. 3 demonstrated that among all
4.2. Procedure for the synthesis of batracylin 1
To microwave reaction vessel containing 2-amino-5-
compounds synthesized (100
mM), compounds 1, 11, and 14
exhibited more potent inhibitory activities than the control com-
pound camptothecin (CPT) against hTop1: 92%, 91%, 82%, and 75%
inhibition, respectively. Others showed moderate inhibitory activ-
ity against hTop1 (Fig. 3). It is also noted that compounds 1 and 11
showed lower intensity of the migrating bands (corresponding to
nicked DNA) than CPT, suggesting that 1 and 11 may be potent
inducer of hTopo1-mediated DNA cleavage than CPT.42 Because of
their planar aromatic structure, these hTop1 inhibitors likely bind
at the interface of the hTop1-DNA complex by intercalating at the
a
nitrobenzonitrile 5 (30 mg, 0.18 mmol) and [b-3-C-im][NTf2] ionic
liquid 2 (0.1 mL) was carefully added borane (0.2 mL, 2 M in THF).
The resulting solution was allowed to react at 80 ꢀC in a sand bath
for 2.5 h. After cooling down, the unreacted borane was quenched
with MeOH (0.5 mL) and then solvent was removed. Subsequently,
the vessel was added phthalic anhydride 3 (30 mg, 0.20 mmol) and
placed inside the CEM Discover single-mode microwave synthe-
sizer, where it was exposed to microwaves at 120 ꢀC (60 W) for
10 min. Finally, the reaction vessel was added catalytic amount of
Pd/C and methanol (2 mL). The resulting mixture was bubbled with
hydrogen at ambient temperature for 2 h. After completion of the
reduction reaction, Pd/C was filtered off, and the solvent was re-
moved under reducing pressure to give the crude product and then
purified by flash column chromatography (ethyl acetate/
cleavage site and
pep
stacking between base pairs.26 This
preliminary activity assay data shown in Fig. 3 could serve as
a useful starting point for hit identification in hTop inhibitor dis-
covery. Using the synthetic method developed in this work,
a combinatorial approach on the design and synthesis of focused
batracylin-templated libraries is in progress and the result on the
identification of potent inhibitors will be reported in due course.
hexane¼1:1) to afford batracylin
1
(37 mg, 81% yield).43

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M.-C. Tseng et al. / Tetrahedron 70 (2014) 2629e2633
Fluorescent yellow solid; mp 227 ꢀC (decomp.); 1H NMR (DMSO-d6,
400 MHz)
aryl H), 7.59 (d, J¼8.4 Hz, 2H, aryl H), 7.73e7.80 (m, 4H, aryl H), 7.86
(d, J¼7.2 Hz, 1H, aryl H), 7.96 (d, J¼7.0 Hz, 1H, aryl H). 13C NMR
d
4.80 (s, 2H, CH2), 6.46 (s, 1H, aryl H), 6.51 (dd, J¼8.4,
2.1 Hz, 1H, aryl H), 7.12 (d, J¼8.4 Hz, 1H, aryl H), 7.69 (t, J¼7.2 Hz, 1H,
aryl H), 7.76 (t, J¼7.2 Hz, 1H, aryl H), 7.84 (d, J¼7.4 Hz, 1H, aryl H),
(DMSO-d6, 100 MHz) d 31.1, 35.2, 40.9, 118.0, 119.2, 122.2, 123.2,
123.5, 126.6, 127.0, 128.6, 130.4, 132.7, 133.6, 134.3, 136.5, 137.1,
7.94 (d, J¼7.3 Hz, 1H, aryl H). 13C NMR (DMSO-d6, 100 MHz)
d
40.6,
137.4, 148.2, 156.4, 166.5. ESI-HRMS m/z [MꢂHꢂ] calcd for
111.9, 113.4, 121.4, 123.0, 129.0, 129.8, 131.5, 133.0, 134.4, 144.0,
148.9, 166.2. ESI-HRMS m/z [MþHþ] calcd for C15H12N3O 250.0980,
found 250.0980.
C25H22N3O3S 444.1382, found 444.1389.
4.4.4. N-Sulfonamido batracylin analogue 11. Yellow solid; mp
228 ꢀC (decomp.); 1H NMR (DMSO-d6, 400 MHz)
3.78 (s, 3H,
d
4.3. Procedure for the synthesis of 8-desaminobatracylin 7
CH3O), 4.84 (s, 2H, CH2), 7.02e7.08 (m, 4H, aryl H), 7.27 (d, J¼8.4 Hz,
1H, aryl H), 7.72e7.79 (m, 4H, aryl H), 7.86 (d, J¼6.8 Hz, 1H, aryl H),
7.95 (d, J¼7.2 Hz, 1H, aryl H), 10.39 (s, 1H, NH). 13C NMR (DMSO-d6,
To a microwave reaction vessel containing o-aminobenzyl-
amine 6 (30 mg, 0.25 mmol) and [b-3-C-im][NTf2] ionic liquid 2
(0.05 mL) was added phthalic anhydride 3 (36 mg, 0.25 mmol) and
placed inside the CEM Discover single-mode microwave synthe-
sizer, where it was exposed to microwaves at 145 ꢀC (10 W) for
2 min. After completion of the reaction, the crude product was
purified by flash column chromatography (ethyl acetate/
hexane¼1:6) to afford 8-desaminobatracylin 7 (58 mg, 99% yield).
Yellow solid; mp 186e188 ꢀC; 1H NMR (DMSO-d6, 400 MHz),
100 MHz)
d 40.6, 56.0, 114.8, 118.2, 119.4, 122.2, 123.2, 123.4, 128.6,
129.3, 130.4, 131.3, 132.7, 133.6, 134.3, 136.5, 137.5, 148.2, 162.9,
166.5. ESI-HRMS m/z [MꢂHꢂ] calcd for C22H16N3O4S 418.0862,
found 418.0868.
4.4.5. N-Sulfonamido batracylin analogue 12. Yellow solid; mp
189 ꢀC (decomp.); 1H NMR (DMSO-d6, 400 MHz)
d 4.27
(bd, J¼3.2 Hz, 4H, 2ꢁCH2O), 4.85 (s, 2H, CH2), 6.99e7.01 (m, 2H, aryl
H), 7.27e7.31 (m, 2H, aryl H), 7.75e7.79 (m, 2H, aryl H), 7.87
(d, J¼7.2 Hz, 1H, aryl H), 7.97 (d, J¼7.2 Hz, 1H, aryl H), 10.41 (s, 1H,
d
4.93 (s, 2H, CH2), 7.26e7.40 (m, 3H, aryl H), 7.40 (d, J¼7.5 Hz, 1H,
aryl H), 7.75e7.83 (m, 2H, aryl H), 7.89 (d, J¼7.0 Hz, 1H, aryl H),
8.01 (d, J¼7.5 Hz, 1H, aryl H). 13C NMR (DMSO-d6, 100 MHz)
d
40.4,
NH). 13C NMR (DMSO-d6, 100 MHz)
d 40.5, 64.2, 64.5, 115.9, 117.8,
122.2, 123.0, 127.5, 127.5, 127.6, 128.7, 130.4, 132.7, 133.4, 134.3,
140.3, 149.0, 166.4. ESI-HRMS m/z [MþHþ] calcd for C15H11N2O
235.0871, found 235.0869.
118.0, 119.2, 120.6, 122.0, 123.0, 123.3, 128.5, 130.2, 131.9, 132.5,
133.4, 134.2, 136.3, 137.2, 143.5, 147.5, 148.1, 166.3. ESI-HRMS m/z
[MꢂHꢂ] calcd for C23H16N3O3S 446.0811, found 446.0810.
4.4. General procedure for the synthesis of N-sulfonamido
batracylins 8e16
4.4.6. N-Sulfonamido batracylin analogue 13. Yellow solid; mp
231e233 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
d 4.83 (s, 2H, CH2),
7.01 (d, J¼9.2 Hz, 1H, aryl H), 7.04 (s, 1H, aryl H), 7.25 (d, J¼8.0 Hz,
1H, aryl H), 7.40 (t, J¼8.8 Hz, 2H, aryl H), 7.69e7.73 (m, 2H, aryl
H), 7.81 (d, J¼6.8 Hz, 1H, aryl H), 7.88e7.91 (m, 3H, aryl H), 10.54
To a stirred solution of batracylin 1 (15 mg, 0.06 mmol) and
pyridine (25
mL, 0.32 mmol) in [b-3C-im][NTf2] 2 (100 mL), the
corresponding sulfonyl chloride (0.24 mmol) was added portion-
wise. The resultant mixture was stirred at ambient temperature
for 3 h. After completion of the reaction, dichloromethane (2 mL)
was added and extracted with 10% citric acid (1 mLꢁ3) and dried
over anhydrous sodium sulfate. After filtration, solvent was re-
moved under reduced pressure to give crude product. The residue
was then purified by column chromatography (ethyl acetate/
hexane¼2:3) to afford the desired product as yellow solid (82e99 %
isolated yield).
(s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz)
d 40.4, 116.6, 116.9,
118.5, 119.7, 121.9, 122.9, 123.3, 128.5, 130.0, 130.1, 130.2, 132.5,
133.3, 134.1, 135.9, 136.0, 136.8, 148.2, 163.4, 165.8, 166.2. ESI-
HRMS m/z [MꢂHꢂ] calcd for C21H13FN3O3S 406.0662, found
406.0665.
4.4.7. N-Sulfonamido batracylin analogue 14. Yellow solid; mp
189 ꢀC (decomp.); 1H NMR (DMSO-d6, 400 MHz)
d 4.86 (s, 2H, CH2),
7.03e7.07 (m, 2H, aryl H), 7.29 (d, J¼8.4 Hz, 1H, aryl H), 7.75e7.78
(m, 2H, aryl H), 7.86 (d, J¼6.8 Hz, 1H, aryl H), 7.95 (d, J¼7.2 Hz, 1H,
aryl H), 7.05 (d, J¼8.8 Hz, 2H, aryl H), 8.37 (d, J¼8.8 Hz, 2H, aryl H),
4.4.1. N-Sulfonamido batracylin analogue 8. Yellow solid; mp
229 ꢀC (decomp.); 1H NMR (DMSO-d6, 400 MHz)
d
4.83 (s, 2H, CH2),
10.82 (s, 1H, NH). 13C NMR (DMSO-d6, 100 MHz)
d 40.6, 119.2, 120.4,
7.03 (d, J¼10.4 Hz, 1H, aryl H), 7.05 (s, 1H, aryl H), 7.26 (d, J¼8.4 Hz,
1H, aryl H), 7.54e7.72 (m, 3H, aryl H), 7.72e7.76 (m, 2H, aryl H),
7.82e7.86 (m, 3H, aryl H), 7.94 (d, J¼7.2 Hz, 1H, aryl H), 10.52 (s, 1H,
122.3, 123.2, 123.7, 125.1, 128.7, 130.4, 132.8, 133.6, 134.3, 136.3,
137.3, 145.1, 148.7, 150.3, 166.5. ESI-HRMS m/z [MꢂHꢂ] calcd for
C21H13N4O5S 433.0607, found 433.0601.
NH). 13C NMR (DMSO-d6, 100 MHz)
d 40.6, 118.4, 119.6, 122.2, 123.2,
123.4, 127.1, 128.6, 129.7, 130.4, 132.7, 133.4, 133.6, 134.3, 136.6,
4.4.8. N-Sulfonamido batracylin analogue 15. Yellow solid; mp
209e212 ꢀC; 1H NMR (DMSO-d6, 400 MHz)
137.2, 139.8, 148.3, 166.4. ESI-HRMS m/z [MꢂHꢂ] calcd for
d
2.80 (s, 6H, 2ꢁCH3),
C
21H14N3O3S 388.0756, found 388.0761.
4.75 (s, 2H, CH2), 6.97e6.98 (m, 2H, aryl H), 7.18 (d, J¼9.2 Hz, 1H,
aryl H), 7.23 (d, J¼7.6 Hz, 1H, aryl H), 7.62e7.65 (m, 4H aryl H), 7.78
(d, J¼7.2 Hz, 1H, aryl H), 7.88 (d, J¼7.2 Hz, 1H, aryl H), 8.30
(d, J¼7.2 Hz, 1H, aryl H), 8.37 (d, J¼8.6 Hz, 1H, aryl H), 8.44
4.4.2. N-Sulfonamido batracylin analogue 9. Yellow solid; mp
237 ꢀC (decomp.); 1H NMR (DMSO-d6, 400 MHz)
2.32 (s, 3H,
d
CH3), 4.82 (s, 2H, CH2), 7.03 (d, J¼9.2 Hz, 1H, aryl H), 7.04 (s, 1H,
aryl H), 7.36 (d, J¼8.4 Hz, 1H, aryl H), 7.51 (d, J¼8.0 Hz, 1H, aryl H),
7.70e7.78 (m, 4H, aryl H), 7.84 (d, J¼7.2 Hz, 1H, aryl H), 7.93 (d,
J¼7.2 Hz, 1H, aryl H), 10.46 (s, 1H, NH). 13C NMR (DMSO-d6,
(d, J¼8.4 Hz, 1H, aryl H). 13C NMR (DMSO-d6, 100 MHz)
d 40.5, 45.3,
115.6, 117.1, 118.3, 118.8, 122.0, 123.0, 123.3, 123.8, 128.4, 128.6, 129.1,
129.2, 130.2, 130.3, 130.5, 133.4, 134.1, 134.8, 136.0, 137.1, 147.9, 151.8,
166.3. ESI-HRMS m/z [MꢂHꢂ] calcd for C27H21N4O3S 481.1334,
found 481.1340.
100 MHz)
d 21.1, 40.4, 118.1, 119.3, 122.0, 123.0, 123.2, 127.0, 128.4,
130.0, 130.2, 132.5, 133.4, 136.4, 136.8, 137.2, 143.6, 148.1, 166.3. ESI-
HRMS m/z [MꢂHꢂ] calcd for C21H14N3O3S 402.0912, found
402.0916.
4.4.9. N-Sulfonamido batracylin analogue 16. Yellow solid; mp
253 ꢀC (decomp.); 1H NMR (DMSO-d6, 400 MHz)
d 3.06 (s, 3H, CH3),
4.92 (s, 2H, CH2), 7.15 (d, J¼8.9 Hz, 2H, aryl H), 7.39 (d, J¼8.2 Hz, 1H,
aryl H), 7.76e7.82 (m, 2H, aryl H), 7.89 (d, J¼7.2 Hz, 1H, aryl H), 7.99
(d, J¼7.6 Hz, 1H, aryl H), 9.97 (s, 1H, NH). 13C NMR (DMSO-d6,
4.4.3. N-Sulfonamido batracylin analogue 10. Yellow solid; mp
238 ꢀC (decomp.); 1H NMR (DMSO-d6, 400 MHz) 1.25 (s, 9H, tBu),
d
4.85 (s, 2H, CH2), 7.06e7.07 (m, 2H, aryl H), 7.28 (d, J¼9.1 Hz, 1H,
100 MHz) d 40.7, 48.9, 118.2, 119.5, 122.2, 123.2, 123.5, 128.7, 130.4,

M.-C. Tseng et al. / Tetrahedron 70 (2014) 2629e2633
2633
132.7, 133.6, 134.4, 136.4, 137.9, 148.2, 166.5. ESI-HRMS m/z [MꢂHꢂ]
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100
DNA (15 ng) for another 30 min incubation in a 20
m
M compound at 37 ꢀC for 2 min followed by adding pHOT1
mL reaction so-
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0.1 mM spermidine, 5% glycerol) at 37 ꢀC. The reaction was termi-
nated by adding equal volume of phenol/chloroform¼1:1. The
aqueous phase was loaded onto a 1% agarose gel and electropho-
resis was performed in TBE buffer (90 mM Triseborate and 2 mM
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5e10 min then photographed under transmitted ultraviolet light.
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We gratefully acknowledge support of this work by grants from
the National Science Council of Taiwan, ROC (NSC100-2113-M-194-
003-MY3, NSC100-2811-M-194-026, and NSC101-2811-M-194-
028), and in part from the Industrial Technology Research Institute
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Institute (New Taipei City, Taiwan) (CCU101-01149-01), and
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ionic liquid was not recycled.